tag:blogger.com,1999:blog-32075479562895709272024-03-28T23:27:26.792-04:00A Medley of PotpourriA Medley of Potpourri is just what it says; various thoughts, opinions, ruminations, and contemplations on a variety of subjects.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comBlogger22922125tag:blogger.com,1999:blog-3207547956289570927.post-1478057759712884322024-03-28T22:35:00.003-04:002024-03-28T22:35:27.446-04:00Gene<div aria-labelledby="firstHeading" class="vector-body ve-init-mw-desktopArticleTarget-targetContainer" data-mw-ve-target-container="" id="bodyContent"><div class="vector-body-before-content"><div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Gene">https://en.wikipedia.org/wiki/Gene</a></div></div></div>
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<div style="left: 0px; position: absolute; top: 0px; width: 350px;"> <span><a href="https://en.wikipedia.org/wiki/File:Chromosome_DNA_Gene.svg" title="File:Chromosome DNA Gene.svg"><img alt="A chromosome unravelling into a long string of DNA, a section of which is highlighted as the gene" class="mw-file-element" data-file-height="658" data-file-width="1200" height="192" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d0/Chromosome_DNA_Gene_unannotated.svg/350px-Chromosome_DNA_Gene_unannotated.svg.png" width="350" /></a></span>
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<div style="background-color: transparent; color: black;"><div id="annotation_150x52" style="left: 150px; line-height: 110%; position: absolute; top: 52px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">Chromosome </a> </span></div>
<div id="annotation_230x52" style="left: 230px; line-height: 110%; position: absolute; top: 52px;"><span style="background-color: transparent;"> (<a href="https://en.wikipedia.org/wiki/Base_pair#Length_measurements" title="Base pair">10<sup>7</sup> - 10<sup>10</sup> bp</a>)</span></div>
<div id="annotation_25x117" style="left: 25px; line-height: 110%; position: absolute; top: 117px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA </a> </span></div>
<div id="annotation_150x130" style="left: 150px; line-height: 110%; position: absolute; top: 130px;"><span style="background-color: transparent;"> <a class="mw-selflink selflink">Gene </a> </span></div>
<div id="annotation_190x130" style="left: 190px; line-height: 110%; position: absolute; top: 130px;"><span style="background-color: transparent;"> (<a href="https://en.wikipedia.org/wiki/Base_pair#Length_measurements" title="Base pair">10<sup>3</sup> - 10<sup>6</sup> bp </a>)</span></div>
<div id="annotation_183x178" style="left: 183px; line-height: 110%; position: absolute; top: 178px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">Function </a> </span></div></div>
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<div class="thumbcaption" style="clear: left;"><div style="float: left; margin-right: 0.5em;"><span><span title="The image above contains clickable links"></span></span></div>A chromosome and its <a href="https://en.wikipedia.org/wiki/Nuclear_organization" title="Nuclear organization">packaged</a> long strand of DNA unraveled. The DNA's <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Base_pairs" title="Base pairs">base pairs</a> encode genes, which provide functions. A human DNA can have up to 500 million base pairs with thousands of genes.</div>
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<p>In <a href="https://en.wikipedia.org/wiki/Biology" title="Biology">biology</a>, the word <b>gene</b> (<a href="https://en.wikipedia.org/wiki/Greek_language" title="Greek language">Greek</a>: <span lang="el">γένος</span>, <span title="Greek-language romanization"><i lang="el-Latn"><a class="extiw" href="https://en.wiktionary.org/wiki/%CE%B3%CE%AD%CE%BD%CE%BF%CF%82" title="wiktionary:γένος">génos</a></i></span>; <i>generation,</i> or <i>birth,</i> or <i>gender</i>) has two meanings. The Mendelian gene is a basic unit of <a href="https://en.wikipedia.org/wiki/Heredity" title="Heredity">heredity</a>. The molecular gene is a sequence of <a href="https://en.wikipedia.org/wiki/Nucleotide" title="Nucleotide">nucleotides</a> in <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a>, that is transcribed to produce a functional <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a>. There are two types of molecular genes: protein-coding genes and non-coding genes.
</p><p>During <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a>, DNA is first <a href="https://en.wikipedia.org/wiki/Transcription_(biology)" title="Transcription (biology)">copied into RNA</a>. RNA can be <a href="https://en.wikipedia.org/wiki/Non-coding_RNA" title="Non-coding RNA">directly functional</a> or be the intermediate <a href="https://en.wikipedia.org/wiki/Protein_biosynthesis" title="Protein biosynthesis">template</a> for the synthesis of a protein.
</p><p>The transmission of genes to an organism's <a href="https://en.wikipedia.org/wiki/Offspring" title="Offspring">offspring</a>, is the basis of the inheritance of <a href="https://en.wikipedia.org/wiki/Phenotypic_trait" title="Phenotypic trait">phenotypic traits</a> from one generation to the next. These genes make up different DNA sequences, together called a <a href="https://en.wikipedia.org/wiki/Genotype" title="Genotype">genotype</a>, that is specific to every given individual, within the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genepool" title="Genepool">genepool</a> of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Population_(biology)" title="Population (biology)">population</a> of a given <a href="https://en.wikipedia.org/wiki/Species" title="Species">species</a>. The genotype, along with environmental and developmental factors, ultimately determines the <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">phenotype</a> of the individual. Most biological traits occur under the combined influence of <a href="https://en.wikipedia.org/wiki/Polygene" title="Polygene">polygenes</a> (a set of different genes) and <a href="https://en.wikipedia.org/wiki/Gene%E2%80%93environment_interaction" title="Gene–environment interaction">gene–environment interactions</a>. Some genetic traits are instantly visible, such as <a href="https://en.wikipedia.org/wiki/Eye_color" title="Eye color">eye color</a> or the number of limbs, others are not, such as <a href="https://en.wikipedia.org/wiki/Blood_type" title="Blood type">blood type</a>, the risk for specific diseases, or the thousands of basic <a href="https://en.wikipedia.org/wiki/Biochemistry" title="Biochemistry">biochemical</a> processes that constitute <a href="https://en.wikipedia.org/wiki/Life" title="Life">life</a>.
</p><p>A gene can acquire <a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">mutations</a> in its <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gene_sequence" title="Gene sequence">sequence</a>, leading to different variants, known as <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">alleles</a>, in the <a href="https://en.wikipedia.org/wiki/Population" title="Population">population</a>. These alleles encode slightly different versions of a gene, which may cause different <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phenotypical" title="Phenotypical">phenotypical</a> traits. Genes <a href="https://en.wikipedia.org/wiki/Evolution" title="Evolution">evolve</a> due to <a href="https://en.wikipedia.org/wiki/Natural_selection" title="Natural selection">natural selection</a> / <a href="https://en.wikipedia.org/wiki/Survival_of_the_fittest" title="Survival of the fittest">survival of the fittest</a> and <a href="https://en.wikipedia.org/wiki/Genetic_drift" title="Genetic drift">genetic drift</a> of the alleles.
</p><p>The term <i>gene</i> was introduced by Danish botanist, plant physiologist and geneticist <a href="https://en.wikipedia.org/wiki/Wilhelm_Johannsen" title="Wilhelm Johannsen">Wilhelm Johannsen</a> in 1909. It is inspired by the <a href="https://en.wikipedia.org/wiki/Ancient_Greek" title="Ancient Greek">Ancient Greek</a>: γόνος, <i>gonos</i>, that means offspring and procreation.
</p>
<h2><span class="mw-headline" id="Definitions">Definitions</span></h2><p>There
are many different ways to use the term "gene" based on different
aspects of their inheritance, selection, biological function, or
molecular structure but most of these definitions fall into two
categories, the Mendelian gene or the molecular gene.
</p><p>The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. This is the gene described in <i>The Selfish Gene</i>. More thorough discussions of this version of a gene can be found in the articles on <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">Genetics</a> and <a href="https://en.wikipedia.org/wiki/Gene-centered_view_of_evolution" title="Gene-centered view of evolution">Gene-centered view of evolution</a>.
</p><p>The molecular gene definition is more commonly used across
biochemistry, molecular biology, and most of genetics — the gene that is
described in terms of DNA sequence. There are many different definitions of this gene — some of which are misleading or incorrect.
</p><p>Very early work in the field that became <a href="https://en.wikipedia.org/wiki/Molecular_genetics" title="Molecular genetics">molecular genetics</a> suggested the concept that <a class="mw-redirect" href="https://en.wikipedia.org/wiki/One_gene-one_enzyme_hypothesis" title="One gene-one enzyme hypothesis">one gene makes one protein</a> (originally 'one gene - one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s
and by the 1960s, textbooks were using molecular gene definitions that
included those that specified functional RNA molecules such as ribosomal
RNA and tRNA (noncoding genes) as well as protein-coding genes.
</p><p>This idea of two kinds of genes is still part of the definition of a gene in most textbooks. For example,
</p>
<dl><dd><dl><dd>"The primary function of the genome is to produce RNA
molecules. Selected portions of the DNA nucleotide sequence are copied
into a corresponding RNA nucleotide sequence, which either encodes a
protein (if it is an mRNA) or forms a 'structural' RNA, such as a
transfer RNA (tRNA) or ribosomal RNA (rRNA) molecule. Each region of the
DNA helix that produces a functional RNA molecule constitutes a gene."</dd></dl></dd></dl>
<dl><dd><dl><dd>"We define a gene as a DNA sequence that is transcribed.
This definition includes genes that do not encode proteins (not all
transcripts are messenger RNA). The definition normally excludes regions
of the genome that control transcription but are not themselves
transcribed. We will encounter some exceptions to our definition of a
gene - surprisingly, there is no definition that is entirely
satisfactory."</dd></dl></dd></dl>
<dl><dd><dl><dd>"A gene is a DNA sequence that codes for a diffusible
product. This product may be protein (as is the case in the majority of
genes) or may be RNA (as is the case of genes that code for tRNA and
rRNA). The crucial feature is that the product diffuses away from its
site of synthesis to act elsewhere."</dd></dl></dd></dl>
<p>The important parts of such definitions are: (1) that a gene
corresponds to a transcription unit; (2) that genes produce both mRNA
and noncoding RNAs; and (3) regulatory sequences control gene expression
but are not part of the gene itself. However, there's one other
important part of the definition and it is emphasized in Kostas
Kampourakis' book <i>Making Sense of Genes</i>.
</p>
<dl><dd><dl><dd>"Therefore in this book I will consider genes as DNA
sequences encoding information for functional products, be it proteins
or RNA molecules. With 'encoding information,' I mean that the DNA
sequence is used as a template for the production of an RNA molecule or a
protein that performs some function.'</dd></dl></dd></dl>
<p>The emphasis on function is essential because there are stretches of
DNA that produce non-functional transcripts and they do not qualify as
genes. These include obvious examples such as transcribed pseudogenes as
well as less obvious examples such as junk RNA produced as noise due to
transcription errors. In order to qualify as a true gene, by this
definition, one has to prove that the transcript has a biological
function.
</p><p>Early speculations on the size of a typical gene were based on
high resolution genetic mapping and on the size of proteins and RNA
molecules. A length of 1500 base pairs seemed reasonable at the time
(1965).
This was based on the idea that the gene was the DNA that was directly
responsible for production of the functional product. The discovery of
introns in the 1970s meant that many eukaryotic genes were much larger
than the size of the functional product would imply. Typical mammalian
protein-coding genes, for example, are about 62,000 base pairs in length
(transcribed region) and since there are about 20,000 of them they
occupy about 35–40% of the mammalian genome (including the human
genome).
</p><p>In spite of the fact that both protein-coding genes and noncoding
genes have been known for more than 50 years, there are still a number
of textbooks, websites, and scientific publications that define a gene
as a DNA sequence that specifies a protein. In other words, the
definition is restricted to protein-coding genes. Here is an example
from a recent article in American Scientist.
</p>
<dl><dd><dl><dd>... to truly assess the potential significance of de
novo genes, we relied on a strict definition of the word "gene" with
which nearly every expert can agree. First, in order for a nucleotide
sequence to be considered a true gene, an open reading frame (ORF) must
be present. The ORF can be thought of as the "gene itself"; it begins
with a starting mark common for every gene and ends with one of three
possible finish line signals. One of the key enzymes in this process,
the RNA polymerase, zips along the strand of DNA like a train on a
monorail, transcribing it into its messenger RNA form. This point brings
us to our second important criterion: A true gene is one that is both
transcribed and translated. That is, a true gene is first used as a
template to make transient messenger RNA, which is then translated into a
protein.</dd></dl></dd></dl>
<p>This restricted definition is so common that it has spawned many
recent articles that criticize this "standard definition" and call for a
new expanded definition that includes noncoding genes.
However, this so-called "new" definition has been around for more than
half a century and it is not clear why some modern writers are ignoring
noncoding genes.
</p><p>Although some definitions can be more broadly applicable than
others, the fundamental complexity of biology means that no definition
of a gene can capture all aspects perfectly. Not all genomes are DNA
(e.g. <a href="https://en.wikipedia.org/wiki/RNA_virus" title="RNA virus">RNA viruses</a>), bacterial <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">operons</a> are multiple protein-coding regions transcribed into single large mRNAs, <a href="https://en.wikipedia.org/wiki/Alternative_splicing" title="Alternative splicing">alternative splicing</a> enables a single genomic region to encode multiple district products and <a href="https://en.wikipedia.org/wiki/Trans-splicing" title="Trans-splicing">trans-splicing</a> concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors and other <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">regulatory regions</a>, these are instead thought of as 'associated' with the gene and affect its function.
</p><p>An even broader operational definition is sometimes used to
encompass the complexity of these diverse phenomena, where a gene is
defined as a union of genomic sequences encoding a coherent set of
potentially overlapping functional products.
This definition categorizes genes by their functional products
(proteins or RNA) rather than their specific DNA loci, with regulatory
elements classified as <i>gene-associated</i> regions.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/History_of_genetics" title="History of genetics">History of genetics</a></div>
<h3><span class="mw-headline" id="Discovery_of_discrete_inherited_units">Discovery of discrete inherited units</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gregor_Mendel.png"><img alt="Photograph of Gregor Mendel" class="mw-file-element" data-file-height="304" data-file-width="300" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d3/Gregor_Mendel.png/180px-Gregor_Mendel.png" width="396" /></a><figcaption>Gregor Mendel</figcaption></figure>
<p>The existence of discrete inheritable units was first suggested by <a href="https://en.wikipedia.org/wiki/Gregor_Mendel" title="Gregor Mendel">Gregor Mendel</a> (1822–1884). From 1857 to 1864, in <a href="https://en.wikipedia.org/wiki/Brno" title="Brno">Brno</a>, <a href="https://en.wikipedia.org/wiki/Austrian_Empire" title="Austrian Empire">Austrian Empire</a> (today's Czech Republic), he studied inheritance patterns in 8000 common edible <a href="https://en.wikipedia.org/wiki/Pea" title="Pea">pea plants</a>, tracking distinct traits from parent to offspring. He described these mathematically as 2<sup>n</sup> combinations where n is the number of differing characteristics in the original peas. Although he did not use the term <i>gene</i>,
he explained his results in terms of discrete inherited units that give
rise to observable physical characteristics. This description
prefigured <a href="https://en.wikipedia.org/wiki/Wilhelm_Johannsen" title="Wilhelm Johannsen">Wilhelm Johannsen</a>'s distinction between <a href="https://en.wikipedia.org/wiki/Genotype" title="Genotype">genotype</a> (the genetic material of an organism) and <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">phenotype</a> (the observable traits of that organism). Mendel was also the first to demonstrate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Independent_assortment" title="Independent assortment">independent assortment</a>, the distinction between <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dominant_gene" title="Dominant gene">dominant</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Recessive" title="Recessive">recessive</a> traits, the distinction between a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heterozygote" title="Heterozygote">heterozygote</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Homozygote" title="Homozygote">homozygote</a>, and the phenomenon of discontinuous inheritance.
</p><p>Prior to Mendel's work, the dominant theory of heredity was one of <a href="https://en.wikipedia.org/wiki/Blending_inheritance" title="Blending inheritance">blending inheritance</a>,
which suggested that each parent contributed fluids to the
fertilization process and that the traits of the parents blended and
mixed to produce the offspring. <a href="https://en.wikipedia.org/wiki/Charles_Darwin" title="Charles Darwin">Charles Darwin</a> developed a theory of inheritance he termed <a href="https://en.wikipedia.org/wiki/Pangenesis" title="Pangenesis">pangenesis</a>, from <a href="https://en.wikipedia.org/wiki/Ancient_Greek" title="Ancient Greek">Greek</a> pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used the term <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gemmule_(pangenesis)" title="Gemmule (pangenesis)">gemmule</a></i> to describe hypothetical particles that would mix during reproduction.
</p><p>Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by <a href="https://en.wikipedia.org/wiki/Hugo_de_Vries" title="Hugo de Vries">Hugo de Vries</a>, <a href="https://en.wikipedia.org/wiki/Carl_Correns" title="Carl Correns">Carl Correns</a>, and <a href="https://en.wikipedia.org/wiki/Erich_von_Tschermak" title="Erich von Tschermak">Erich von Tschermak</a>, who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book <i>Intracellular Pangenesis</i>,
in which he postulated that different characters have individual
hereditary carriers and that inheritance of specific traits in organisms
comes in particles. De Vries called these units "pangenes" (<i>Pangens</i> in German), after Darwin's 1868 pangenesis theory.
</p><p>Twenty years later, in 1909, <a href="https://en.wikipedia.org/wiki/Wilhelm_Johannsen" title="Wilhelm Johannsen">Wilhelm Johannsen</a> introduced the term 'gene' and in 1906, <a href="https://en.wikipedia.org/wiki/William_Bateson" title="William Bateson">William Bateson</a>, that of '<a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetics</a>'<sup> </sup>while <a href="https://en.wikipedia.org/wiki/Eduard_Strasburger" title="Eduard Strasburger">Eduard Strasburger</a>, amongst others, still used the term 'pangene' for the fundamental physical and functional unit of heredity.
</p>
<h3><span class="mw-headline" id="Discovery_of_DNA">Discovery of DNA</span></h3><p>Advances in understanding genes and inheritance continued throughout the 20th century. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Deoxyribonucleic_acid" title="Deoxyribonucleic acid">Deoxyribonucleic acid</a> (DNA) was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by <a href="https://en.wikipedia.org/wiki/Rosalind_Franklin" title="Rosalind Franklin">Rosalind Franklin</a> and <a href="https://en.wikipedia.org/wiki/Maurice_Wilkins" title="Maurice Wilkins">Maurice Wilkins</a> using <a href="https://en.wikipedia.org/wiki/X-ray_crystallography" title="X-ray crystallography">X-ray crystallography</a>, which led <a class="mw-redirect" href="https://en.wikipedia.org/wiki/James_D._Watson" title="James D. Watson">James D. Watson</a> and <a href="https://en.wikipedia.org/wiki/Francis_Crick" title="Francis Crick">Francis Crick</a> to publish a model of the double-stranded DNA molecule whose paired <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nucleotide_base" title="Nucleotide base">nucleotide bases</a> indicated a compelling hypothesis for the mechanism of genetic replication.
</p><p>In the early 1950s the prevailing view was that the genes in a
chromosome acted like discrete entities arranged like beads on a string.
The experiments of <a href="https://en.wikipedia.org/wiki/Seymour_Benzer" title="Seymour Benzer">Benzer</a> using <a href="https://en.wikipedia.org/wiki/Mutant" title="Mutant">mutants</a> defective in the <a href="https://en.wikipedia.org/wiki/T4_rII_system" title="T4 rII system">rII region of bacteriophage T4</a>
(1955–1959) showed that individual genes have a simple linear structure
and are likely to be equivalent to a linear section of DNA.
</p><p>Collectively, this body of research established the <a href="https://en.wikipedia.org/wiki/Central_dogma_of_molecular_biology" title="Central dogma of molecular biology">central dogma of molecular biology</a>, which states that <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">proteins</a> are translated from <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a>, which is transcribed from <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a>. This dogma has since been shown to have exceptions, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Reverse_transcription" title="Reverse transcription">reverse transcription</a> in <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retroviruses</a>. The modern study of <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetics</a> at the level of DNA is known as <a href="https://en.wikipedia.org/wiki/Molecular_genetics" title="Molecular genetics">molecular genetics</a>.
</p><p>In 1972, <a href="https://en.wikipedia.org/wiki/Walter_Fiers" title="Walter Fiers">Walter Fiers</a> and his team were the first to determine the sequence of a gene: that of <a href="https://en.wikipedia.org/wiki/Bacteriophage_MS2" title="Bacteriophage MS2">Bacteriophage MS2</a> coat protein. The subsequent development of <a href="https://en.wikipedia.org/wiki/Sanger_sequencing" title="Sanger sequencing">chain-termination</a> <a href="https://en.wikipedia.org/wiki/DNA_sequencing" title="DNA sequencing">DNA sequencing</a> in 1977 by <a href="https://en.wikipedia.org/wiki/Frederick_Sanger" title="Frederick Sanger">Frederick Sanger</a> improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the <a href="https://en.wikipedia.org/wiki/Human_Genome_Project" title="Human Genome Project">Human Genome Project</a>.
</p>
<h3><span class="mw-headline" id="Modern_synthesis_and_its_successors">Modern synthesis and its successors</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Modern_synthesis_(20th_century)" title="Modern synthesis (20th century)">Modern synthesis (20th century)</a></div>
<p>The theories developed in the early 20th century to integrate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mendelian_genetics" title="Mendelian genetics">Mendelian genetics</a> with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Darwinian_evolution" title="Darwinian evolution">Darwinian evolution</a> are called the <a href="https://en.wikipedia.org/wiki/Modern_synthesis_(20th_century)" title="Modern synthesis (20th century)">modern synthesis</a>, a term introduced by <a href="https://en.wikipedia.org/wiki/Julian_Huxley" title="Julian Huxley">Julian Huxley</a>.
</p><p>This view of evolution was emphasized by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/George_C._Williams_(biologist)" title="George C. Williams (biologist)">George C. Williams</a>' <a href="https://en.wikipedia.org/wiki/Gene-centered_view_of_evolution" title="Gene-centered view of evolution">gene-centric view of evolution</a>. He proposed that the Mendelian gene is a <a href="https://en.wikipedia.org/wiki/Unit_of_selection" title="Unit of selection">unit</a> of <a href="https://en.wikipedia.org/wiki/Natural_selection" title="Natural selection">natural selection</a> with the definition: "that which segregates and recombines with appreciable frequency."<sup class="reference nowrap"><span title="Page / location: 24"> </span></sup>
Related ideas emphasizing the centrality of Mendelian genes and the
importance of natural selection in evolution were popularized by <a href="https://en.wikipedia.org/wiki/Richard_Dawkins" title="Richard Dawkins">Richard Dawkins</a>.
</p><p>The development of the <a href="https://en.wikipedia.org/wiki/Neutral_theory_of_molecular_evolution" title="Neutral theory of molecular evolution">neutral theory of evolution</a>
in the late 1960s led to the recognition that random genetic drift is a
major player in evolution and that neutral theory should be the null
hypothesis of molecular evolution. This led to the construction of <a href="https://en.wikipedia.org/wiki/Phylogenetic_tree" title="Phylogenetic tree">phylogenetic trees</a> and the development of the <a href="https://en.wikipedia.org/wiki/Molecular_clock" title="Molecular clock">molecular clock</a>,
which is the basis of all dating techniques using DNA sequences. These
techniques are not confined to molecular gene sequences but can be used
on all DNA segments in the genome.
</p>
<h2><span class="mw-headline" id="Molecular_basis">Molecular basis</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:DNA_chemical_structure_2.svg"><img alt="DNA chemical structure diagram showing how the double helix consists of two chains of sugar-phosphate backbone with bases pointing inwards and specifically base pairing A to T and C to G with hydrogen bonds." class="mw-file-element" data-file-height="532" data-file-width="1200" height="177" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b2/DNA_chemical_structure_2.svg/330px-DNA_chemical_structure_2.svg.png" width="400" /></a><figcaption>The chemical structure of a four base pair fragment of a <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Double_helix" title="Double helix">double helix</a>. The <a href="https://en.wikipedia.org/wiki/Deoxyribose" title="Deoxyribose">sugar</a>-<a href="https://en.wikipedia.org/wiki/Phosphate" title="Phosphate">phosphate</a> backbone chains run in opposite directions with the <a href="https://en.wikipedia.org/wiki/Nucleobase" title="Nucleobase">bases</a> pointing inwards, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Base-pair" title="Base-pair">base-pairing</a> <a href="https://en.wikipedia.org/wiki/Adenine" title="Adenine">A</a> to <a href="https://en.wikipedia.org/wiki/Thymine" title="Thymine">T</a> and <a href="https://en.wikipedia.org/wiki/Cytosine" title="Cytosine">C</a> to <a href="https://en.wikipedia.org/wiki/Guanine" title="Guanine">G</a> with <a href="https://en.wikipedia.org/wiki/Hydrogen_bond" title="Hydrogen bond">hydrogen bonds</a>.</figcaption></figure>
<h3><span class="mw-headline" id="DNA">DNA</span></h3><p>The vast majority of organisms encode their genes in long strands of <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> (deoxyribonucleic acid). DNA consists of a <a href="https://en.wikipedia.org/wiki/Polymer" title="Polymer">chain</a> made from four types of <a href="https://en.wikipedia.org/wiki/Nucleotide" title="Nucleotide">nucleotide</a> subunits, each composed of: a five-carbon sugar (<a href="https://en.wikipedia.org/wiki/Deoxyribose" title="Deoxyribose">2-deoxyribose</a>), a <a href="https://en.wikipedia.org/wiki/Phosphate" title="Phosphate">phosphate</a> group, and one of the four <a href="https://en.wikipedia.org/wiki/Nucleobase" title="Nucleobase">bases</a> <a href="https://en.wikipedia.org/wiki/Adenine" title="Adenine">adenine</a>, <a href="https://en.wikipedia.org/wiki/Cytosine" title="Cytosine">cytosine</a>, <a href="https://en.wikipedia.org/wiki/Guanine" title="Guanine">guanine</a>, and <a href="https://en.wikipedia.org/wiki/Thymine" title="Thymine">thymine</a>.
</p><p>Two chains of DNA twist around each other to form a DNA <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Double_helix" title="Double helix">double helix</a> with the phosphate-sugar backbone spiraling around the outside, and the bases pointing inwards with adenine <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Base_pairing" title="Base pairing">base pairing</a> to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two <a href="https://en.wikipedia.org/wiki/Hydrogen_bond" title="Hydrogen bond">hydrogen bonds</a>, whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be <a href="https://en.wikipedia.org/wiki/Complementarity_(molecular_biology)" title="Complementarity (molecular biology)">complementary</a>,
with their sequence of bases matching such that the adenines of one
strand are paired with the thymines of the other strand, and so on.
</p><p>Due to the chemical composition of the <a href="https://en.wikipedia.org/wiki/Pentose" title="Pentose">pentose</a> residues of the bases, DNA strands have directionality. One end of a DNA <a href="https://en.wikipedia.org/wiki/Polymer" title="Polymer">polymer</a> contains an exposed <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hydroxyl" title="Hydroxyl">hydroxyl</a> group on the <a href="https://en.wikipedia.org/wiki/Deoxyribose" title="Deoxyribose">deoxyribose</a>; this is known as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27_end" title="3' end">3' end</a> of the molecule. The other end contains an exposed <a href="https://en.wikipedia.org/wiki/Phosphate" title="Phosphate">phosphate</a> group; this is the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27_end" title="5' end">5' end</a>. The two strands of a double-helix run in opposite directions. Nucleic acid synthesis, including <a href="https://en.wikipedia.org/wiki/DNA_replication" title="DNA replication">DNA replication</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> occurs in the 5'→3' direction, because new nucleotides are added via a <a href="https://en.wikipedia.org/wiki/Dehydration_reaction" title="Dehydration reaction">dehydration reaction</a> that uses the exposed 3' hydroxyl as a <a href="https://en.wikipedia.org/wiki/Nucleophile" title="Nucleophile">nucleophile</a>.
</p><p>The <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">expression</a> of genes encoded in DNA begins by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcribing</a> the gene into <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a>, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar <a href="https://en.wikipedia.org/wiki/Ribose" title="Ribose">ribose</a> rather than <a href="https://en.wikipedia.org/wiki/Deoxyribose" title="Deoxyribose">deoxyribose</a>. RNA also contains the base <a href="https://en.wikipedia.org/wiki/Uracil" title="Uracil">uracil</a> in place of <a href="https://en.wikipedia.org/wiki/Thymine" title="Thymine">thymine</a>.
RNA molecules are less stable than DNA and are typically
single-stranded. Genes that encode proteins are composed of a series of
three-<a href="https://en.wikipedia.org/wiki/Nucleotide" title="Nucleotide">nucleotide</a> sequences called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codons</a>, which serve as the "words" in the genetic "language". The <a href="https://en.wikipedia.org/wiki/Genetic_code" title="Genetic code">genetic code</a> specifies the correspondence during <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">protein translation</a> between codons and <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acids</a>. The genetic code is nearly the same for all known organisms.
</p>
<h3><span class="mw-headline" id="Chromosomes">Chromosomes</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:NHGRI_human_male_karyotype.png"><img class="mw-file-element" data-file-height="2417" data-file-width="3084" height="313" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/53/NHGRI_human_male_karyotype.png/220px-NHGRI_human_male_karyotype.png" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Micrograph" title="Micrograph">Micrographic</a> <a href="https://en.wikipedia.org/wiki/Karyotype" title="Karyotype">karyogram</a> of human male, showing 23 pairs of chromosomes. The largest <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a> are around 10 times the size of the smallest.</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_karyotype_with_bands_and_sub-bands.png"><img class="mw-file-element" data-file-height="16008" data-file-width="9684" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b1/Human_karyotype_with_bands_and_sub-bands.png/220px-Human_karyotype_with_bands_and_sub-bands.png" width="242" /></a><figcaption>Schematic <a href="https://en.wikipedia.org/wiki/Karyotype" title="Karyotype">karyogram</a> of a human, with annotated <a href="https://en.wikipedia.org/wiki/Locus_(genetics)" title="Locus (genetics)">bands and sub-bands</a>. It shows dark and white regions on <a href="https://en.wikipedia.org/wiki/G_banding" title="G banding">G banding</a>. It shows 22 <a href="https://en.wikipedia.org/wiki/Homologous_chromosome" title="Homologous chromosome">homologous chromosomes</a>, both the male (XY) and female (XX) versions of the <a href="https://en.wikipedia.org/wiki/Sex_chromosome" title="Sex chromosome">sex chromosome</a> (bottom right), as well as the <a href="https://en.wikipedia.org/wiki/Human_mitochondrial_genetics" title="Human mitochondrial genetics">mitochondrial genome</a> (at bottom left). <div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Karyotype" title="Karyotype">Karyotype</a></div></figcaption></figure>
<p>The total complement of genes in an organism or cell is known as its <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a>, which may be stored on one or more <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a>. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded.<sup class="reference nowrap"><span title="Page / location: 4.2"> </span></sup> The region of the chromosome at which a particular gene is located is called its <a href="https://en.wikipedia.org/wiki/Locus_(genetics)" title="Locus (genetics)">locus</a>. Each locus contains one <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">allele</a>
of a gene; however, members of a population may have different alleles
at the locus, each with a slightly different gene sequence.
</p><p>The majority of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Eukaryotic" title="Eukaryotic">eukaryotic</a> genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">nucleus</a> in complex with storage proteins called <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histones</a> to form a unit called a <a href="https://en.wikipedia.org/wiki/Nucleosome" title="Nucleosome">nucleosome</a>. DNA packaged and condensed in this way is called <a href="https://en.wikipedia.org/wiki/Chromatin" title="Chromatin">chromatin</a>.<sup class="reference nowrap"><span title="Page / location: 4.2"> </span></sup>
The manner in which DNA is stored on the histones, as well as chemical
modifications of the histone itself, regulate whether a particular
region of DNA is accessible for <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a>.
In addition to genes, eukaryotic chromosomes contain sequences involved
in ensuring that the DNA is copied without degradation of end regions
and sorted into daughter cells during cell division: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Replication_origin" title="Replication origin">replication origins</a>, <a href="https://en.wikipedia.org/wiki/Telomere" title="Telomere">telomeres</a> and the <a href="https://en.wikipedia.org/wiki/Centromere" title="Centromere">centromere</a>. Replication origins are the sequence regions where <a href="https://en.wikipedia.org/wiki/DNA_replication" title="DNA replication">DNA replication</a>
is initiated to make two copies of the chromosome. Telomeres are long
stretches of repetitive sequences that cap the ends of the linear
chromosomes and prevent degradation of coding and regulatory regions
during <a href="https://en.wikipedia.org/wiki/DNA_replication" title="DNA replication">DNA replication</a>. The length of the telomeres decreases each time the genome is replicated and has been implicated in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aging" title="Aging">aging</a> process. The centromere is required for binding <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spindle_fibre" title="Spindle fibre">spindle fibres</a> to separate sister chromatids into daughter cells during <a href="https://en.wikipedia.org/wiki/Cell_division" title="Cell division">cell division</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Prokaryote" title="Prokaryote">Prokaryotes</a> (<a href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a> and <a href="https://en.wikipedia.org/wiki/Archaea" title="Archaea">archaea</a>) typically store their genomes on a single large, <a href="https://en.wikipedia.org/wiki/DNA_supercoil" title="DNA supercoil">circular chromosome</a>. Similarly, some eukaryotic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Organelles" title="Organelles">organelles</a> contain a remnant circular chromosome with a small number of genes.<sup class="reference nowrap"><span title="Page / location: 14.4"> </span></sup> Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called <a href="https://en.wikipedia.org/wiki/Plasmid" title="Plasmid">plasmids</a>, which usually encode only a few genes and are transferable between individuals. For example, the genes for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibiotic_resistance" title="Antibiotic resistance">antibiotic resistance</a> are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via <a href="https://en.wikipedia.org/wiki/Horizontal_gene_transfer" title="Horizontal gene transfer">horizontal gene transfer</a>.
</p><p>Whereas the chromosomes of prokaryotes are relatively gene-dense,
those of eukaryotes often contain regions of DNA that serve no obvious
function. Simple single-celled eukaryotes have relatively small amounts
of such DNA, whereas the genomes of complex <a href="https://en.wikipedia.org/wiki/Multicellular_organism" title="Multicellular organism">multicellular organisms</a>, including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as "<a href="https://en.wikipedia.org/wiki/Junk_DNA" title="Junk DNA">junk DNA</a>". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the <a href="https://en.wikipedia.org/wiki/Human_genome" title="Human genome">human genome</a>, about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer.
</p>
<h2><span class="mw-headline" id="Structure_and_function">Structure and function</span></h2><h3><span class="mw-headline" id="Structure">Structure</span></h3><table style="clear: right; float: right;">
<tbody><tr>
<td>
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<td><div class="thumb tright">
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<div style="background-color: white; border: solid #ccc 1px; height: 325px; overflow: hidden; position: relative; width: 600px;">
<div style="left: 0px; position: absolute; top: 0px; width: 600px;"> <span><a href="https://en.wikipedia.org/wiki/File:Gene_structure_eukaryote_2_annotated.svg" title="File:Gene structure eukaryote 2 annotated.svg"><img alt="Eukaryote gene structure diagram" class="mw-file-element" data-file-height="640" data-file-width="1190" height="323" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/ac/Gene_structure_eukaryote_2_unannotated.svg/600px-Gene_structure_eukaryote_2_unannotated.svg.png" width="600" /></a></span>
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<div style="font-size: 11px; line-height: 110%; text-align: left;">
<div style="background-color: transparent; color: black;"><div id="annotation_115x2" style="left: 115px; line-height: 110%; position: absolute; top: 2px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence </a> </span></div>
<div id="annotation_473x2" style="left: 473px; line-height: 110%; position: absolute; top: 2px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence </a> </span></div>
<div id="annotation_71x30" style="left: 71px; line-height: 110%; position: absolute; top: 30px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">Enhancer</a> </span></div>
<div id="annotation_71x41" style="left: 71px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> /<a href="https://en.wikipedia.org/wiki/Silencer_(genetics)" title="Silencer (genetics)">silencer</a> </span></div>
<div id="annotation_164x41" style="left: 164px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">Promoter</a> </span></div>
<div id="annotation_234x41" style="left: 234px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27UTR" title="5'UTR">5'UTR </a> </span></div>
<div id="annotation_320x41" style="left: 320px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Open_reading_frame" title="Open reading frame">Open reading frame </a> </span></div>
<div id="annotation_475x41" style="left: 475px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27UTR" title="3'UTR">3'UTR </a> </span></div>
<div id="annotation_535x30" style="left: 535px; line-height: 110%; position: absolute; top: 30px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">Enhancer</a> </span></div>
<div id="annotation_535x41" style="left: 535px; line-height: 110%; position: absolute; top: 41px;"><span style="background-color: transparent;"> /<a href="https://en.wikipedia.org/wiki/Silencer_(genetics)" title="Silencer (genetics)">silencer</a> </span></div>
<div id="annotation_145x67" style="left: 145px; line-height: 110%; position: absolute; top: 67px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)#Elements" title="Promoter (genetics)">Proximal </a> </span></div>
<div id="annotation_198x67" style="left: 198px; line-height: 110%; position: absolute; top: 67px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)#Elements" title="Promoter (genetics)">Core </a> </span></div>
<div id="annotation_268x67" style="left: 268px; line-height: 110%; position: absolute; top: 67px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Start_codon" title="Start codon">Start </a> </span></div>
<div id="annotation_450x67" style="left: 450px; line-height: 110%; position: absolute; top: 67px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Stop_codon" title="Stop codon">Stop </a> </span></div>
<div id="annotation_483x67" style="left: 483px; line-height: 110%; position: absolute; top: 67px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Terminator_(genetics)" title="Terminator (genetics)">Terminator</a> </span></div>
<div id="annotation_51x120" style="left: 51px; line-height: 110%; position: absolute; top: 120px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">Transcription</a> </span></div>
<div id="annotation_18x89" style="left: 18px; line-height: 110%; position: absolute; top: 89px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA </a> </span></div>
<div id="annotation_260x125" style="left: 260px; line-height: 110%; position: absolute; top: 125px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Exon" title="Exon">Exon </a> </span></div>
<div id="annotation_341x125" style="left: 341px; line-height: 110%; position: absolute; top: 125px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Exon" title="Exon">Exon </a> </span></div>
<div id="annotation_440x125" style="left: 440px; line-height: 110%; position: absolute; top: 125px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Exon" title="Exon">Exon </a> </span></div>
<div id="annotation_314x138" style="left: 314px; line-height: 110%; position: absolute; top: 138px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Intron" title="Intron">Intron </a> </span></div>
<div id="annotation_367x138" style="left: 367px; line-height: 110%; position: absolute; top: 138px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Intron" title="Intron">Intron </a> </span></div>
<div id="annotation_51x171" style="left: 51px; line-height: 110%; position: absolute; top: 171px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Post-transcriptional_modification" title="Post-transcriptional modification">Post-transcriptional<br />modification</a> </span></div>
<div id="annotation_14x157" style="left: 14px; line-height: 110%; position: absolute; top: 157px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Primary_transcript" title="Primary transcript">Pre-<br />mRNA </a> </span></div>
<div id="annotation_315x186" style="left: 315px; line-height: 110%; position: absolute; top: 186px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_coding_region" title="Protein coding region">Protein coding region </a> </span></div>
<div id="annotation_250x198" style="left: 250px; line-height: 110%; position: absolute; top: 198px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27cap" title="5'cap">5'cap </a> </span></div>
<div id="annotation_477x198" style="left: 477px; line-height: 110%; position: absolute; top: 198px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Poly-A_tail" title="Poly-A tail">Poly-A tail </a> </span></div>
<div id="annotation_51x248" style="left: 51px; line-height: 110%; position: absolute; top: 248px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">Translation</a> </span></div>
<div id="annotation_14x221" style="left: 14px; line-height: 110%; position: absolute; top: 221px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">Mature<br />mRNA </a> </span></div>
<div id="annotation_14x285" style="left: 14px; line-height: 110%; position: absolute; top: 285px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">Protein </a> </span></div></div>
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<div class="thumbcaption" style="clear: left;"><div style="float: left; margin-right: 0.5em;"><span><span title="The image above contains clickable links"></span></span></div>The structure of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Eukaryotic" title="Eukaryotic">eukaryotic</a> protein-coding gene. <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence</a> controls when and where expression occurs for the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_coding_region" title="Protein coding region">protein coding region</a> (red). <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">Promoter</a> and <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancer</a> regions (yellow) regulate the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> of the gene into a pre-mRNA which is <a href="https://en.wikipedia.org/wiki/Post-transcriptional_modification" title="Post-transcriptional modification">modified</a> to remove <a href="https://en.wikipedia.org/wiki/Intron" title="Intron">introns</a> (light grey) and add a 5' cap and poly-A tail (dark grey). The mRNA <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27_UTR" title="5' UTR">5'</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27_UTR" title="3' UTR">3'</a> untranslated regions (blue) regulate <a href="https://en.wikipedia.org/wiki/Translation_(biology)" title="Translation (biology)">translation</a> into the final protein product.</div>
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<div style="left: 0px; position: absolute; top: 0px; width: 600px;"> <span><a href="https://en.wikipedia.org/wiki/File:Gene_structure_prokaryote_2_annotated.svg" title="File:Gene structure prokaryote 2 annotated.svg"><img alt="Prokaryote gene structure diagram" class="mw-file-element" data-file-height="586" data-file-width="1190" height="295" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d9/Gene_structure_prokaryote_2_unannotated.svg/600px-Gene_structure_prokaryote_2_unannotated.svg.png" width="600" /></a></span>
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<div style="background-color: transparent; color: black;"><div id="annotation_310x2" style="left: 310px; line-height: 110%; position: absolute; top: 2px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">Polycistronic operon</a> </span></div>
<div id="annotation_115x37" style="left: 115px; line-height: 110%; position: absolute; top: 37px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence </a> </span></div>
<div id="annotation_475x37" style="left: 475px; line-height: 110%; position: absolute; top: 37px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence </a> </span></div>
<div id="annotation_71x66" style="left: 71px; line-height: 110%; position: absolute; top: 66px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">Enhancer</a> </span></div>
<div id="annotation_535x66" style="left: 535px; line-height: 110%; position: absolute; top: 66px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">Enhancer</a> </span></div>
<div id="annotation_535x77" style="left: 535px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> /<a href="https://en.wikipedia.org/wiki/Silencer_(genetics)" title="Silencer (genetics)">silencer</a> </span></div>
<div id="annotation_71x77" style="left: 71px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> /<a href="https://en.wikipedia.org/wiki/Silencer_(genetics)" title="Silencer (genetics)">silencer</a> </span></div>
<div id="annotation_139x77" style="left: 139px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Operator_(genetics)" title="Operator (genetics)">Operator</a> </span></div>
<div id="annotation_187x77" style="left: 187px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">Promoter</a> </span></div>
<div id="annotation_236x77" style="left: 236px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27UTR" title="5'UTR">5'UTR </a> </span></div>
<div id="annotation_301x77" style="left: 301px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Open_reading_frame" title="Open reading frame">ORF </a> </span></div>
<div id="annotation_431x77" style="left: 431px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Open_reading_frame" title="Open reading frame">ORF </a> </span></div>
<div id="annotation_375x77" style="left: 375px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Untranslated_region" title="Untranslated region">UTR </a> </span></div>
<div id="annotation_475x77" style="left: 475px; line-height: 110%; position: absolute; top: 77px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27UTR" title="3'UTR">3'UTR </a> </span></div>
<div id="annotation_268x103" style="left: 268px; line-height: 110%; position: absolute; top: 103px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Start_codon" title="Start codon">Start </a> </span></div>
<div id="annotation_410x103" style="left: 410px; line-height: 110%; position: absolute; top: 103px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Start_codon" title="Start codon">Start </a> </span></div>
<div id="annotation_344x103" style="left: 344px; line-height: 110%; position: absolute; top: 103px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Stop_codon" title="Stop codon">Stop </a> </span></div>
<div id="annotation_450x103" style="left: 450px; line-height: 110%; position: absolute; top: 103px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Stop_codon" title="Stop codon">Stop </a> </span></div>
<div id="annotation_483x103" style="left: 483px; line-height: 110%; position: absolute; top: 103px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Terminator_(genetics)" title="Terminator (genetics)">Terminator</a> </span></div>
<div id="annotation_51x155" style="left: 51px; line-height: 110%; position: absolute; top: 155px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">Transcription</a> </span></div>
<div id="annotation_18x124" style="left: 18px; line-height: 110%; position: absolute; top: 124px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA </a> </span></div>
<div id="annotation_239x170" style="left: 239px; line-height: 110%; position: absolute; top: 170px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ribosome_binding_site" title="Ribosome binding site">RBS </a> </span></div>
<div id="annotation_382x170" style="left: 382px; line-height: 110%; position: absolute; top: 170px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ribosome_binding_site" title="Ribosome binding site">RBS </a> </span></div>
<div id="annotation_264x156" style="left: 264px; line-height: 110%; position: absolute; top: 156px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_coding_region" title="Protein coding region">Protein coding region </a> </span></div>
<div id="annotation_408x156" style="left: 408px; line-height: 110%; position: absolute; top: 156px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_coding_region" title="Protein coding region">Protein coding region </a> </span></div>
<div id="annotation_14x195" style="left: 14px; line-height: 110%; position: absolute; top: 195px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">mRNA </a> </span></div>
<div id="annotation_51x219" style="left: 51px; line-height: 110%; position: absolute; top: 219px;"><span style="background-color: transparent;"> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">Translation</a> </span></div>
<div id="annotation_14x256" style="left: 14px; line-height: 110%; position: absolute; top: 256px;"><span style="background-color: transparent;"> <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">Protein </a> </span></div></div>
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<div class="thumbcaption" style="clear: left;"><div style="float: left; margin-right: 0.5em;"><span><span title="The image above contains clickable links"></span></span></div>The structure of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Prokaryotic" title="Prokaryotic">prokaryotic</a> <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">operon</a> of protein-coding genes. <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence</a> controls when expression occurs for the multiple <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_coding_region" title="Protein coding region">protein coding regions</a> (red). <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">Promoter</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Operator_(biology)" title="Operator (biology)">operator</a> and <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancer</a> regions (yellow) regulate the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> of the gene into an mRNA. The mRNA <a href="https://en.wikipedia.org/wiki/Untranslated_region" title="Untranslated region">untranslated regions</a> (blue) regulate <a href="https://en.wikipedia.org/wiki/Translation_(biology)" title="Translation (biology)">translation</a> into the final protein products.</div>
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<p>The <a href="https://en.wikipedia.org/wiki/Gene_structure" title="Gene structure">structure of a protein-coding gene</a> consists of many elements of which the actual <a href="https://en.wikipedia.org/wiki/Coding_region" title="Coding region">protein coding sequence</a>
is often only a small part. These include introns and untranslated
regions of the mature mRNA. Noncoding genes can also contain introns
that are removed during processing to produce the mature functional RNA.
</p><p>All genes are associated with <a href="https://en.wikipedia.org/wiki/Regulatory_sequence" title="Regulatory sequence">regulatory sequences</a> that are required for their expression. First, genes require a <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">promoter</a> sequence. The promoter is recognized and bound by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_factors" title="Transcription factors">transcription factors</a> that recruit and help <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a> bind to the region to initiate transcription.<sup class="reference nowrap"><span title="Page / location: 7.1"> </span></sup> The recognition typically occurs as a <a href="https://en.wikipedia.org/wiki/Consensus_sequence" title="Consensus sequence">consensus sequence</a> like the <a href="https://en.wikipedia.org/wiki/TATA_box" title="TATA box">TATA box</a>. A gene can have more than one promoter, resulting in messenger RNAs (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">mRNA</a>) that differ in how far they extend in the 5' end.
Highly transcribed genes have "strong" promoter sequences that form
strong associations with transcription factors, thereby initiating
transcription at a high rate. Others genes have "weak" promoters that
form weak associations with transcription factors and initiate
transcription less frequently.<sup class="reference nowrap"><span title="Page / location: 7.2"> </span></sup> <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">Eukaryotic</a> <a href="https://en.wikipedia.org/wiki/Promoter_(genetics)" title="Promoter (genetics)">promoter</a> regions are much more complex and difficult to identify than <a href="https://en.wikipedia.org/wiki/Prokaryote" title="Prokaryote">prokaryotic</a> promoters.
</p><p>Additionally, genes can have regulatory regions many kilobases
upstream or downstream of the gene that alter expression. These act by <a href="https://en.wikipedia.org/wiki/DNA_binding_site" title="DNA binding site">binding</a>
to transcription factors which then cause the DNA to loop so that the
regulatory sequence (and bound transcription factor) become close to the
RNA polymerase binding site. For example, <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancers</a> increase transcription by binding an <a href="https://en.wikipedia.org/wiki/Activator_(genetics)" title="Activator (genetics)">activator</a> protein which then helps to recruit the RNA polymerase to the promoter; conversely <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Silencer_(DNA)" title="Silencer (DNA)">silencers</a> bind <a href="https://en.wikipedia.org/wiki/Repressor" title="Repressor">repressor</a> proteins and make the DNA less available for RNA polymerase.
</p><p>The mature messenger RNA produced from protein-coding genes contains <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Untranslated_regions" title="Untranslated regions">untranslated regions</a> at both ends which contain binding sites for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ribosome_binding_site" title="Ribosome binding site">ribosomes</a>, <a href="https://en.wikipedia.org/wiki/RNA-binding_protein" title="RNA-binding protein">RNA-binding proteins</a>, <a href="https://en.wikipedia.org/wiki/MicroRNA" title="MicroRNA">miRNA</a>, as well as <a href="https://en.wikipedia.org/wiki/Terminator_(genetics)" title="Terminator (genetics)">terminator</a>, and <a href="https://en.wikipedia.org/wiki/Start_codon" title="Start codon">start</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stop_codons" title="Stop codons">stop codons</a>. In addition, most eukaryotic <a href="https://en.wikipedia.org/wiki/Open_reading_frame" title="Open reading frame">open reading frames</a> contain untranslated <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Introns" title="Introns">introns</a>, which are removed and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Exons" title="Exons">exons</a>, which are connected together in a process known as <a href="https://en.wikipedia.org/wiki/RNA_splicing" title="RNA splicing">RNA splicing</a>. Finally, the ends of gene transcripts are defined by <a href="https://en.wikipedia.org/wiki/Polyadenylation" title="Polyadenylation">cleavage and polyadenylation (CPA) sites</a>, where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The <a href="https://en.wikipedia.org/wiki/Polyadenylation" title="Polyadenylation">poly(A)</a>
tail protects mature mRNA from degradation and has other functions,
affecting translation, localization, and transport of the transcript
from the nucleus. Splicing, followed by CPA, generate the final <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mature_mRNA" title="Mature mRNA">mature mRNA</a>, which encodes the protein or RNA product.
Although the general mechanisms defining locations of human genes are
known, identification of the exact factors regulating these cellular
processes is an area of active research. For example, known sequence
features in the <a href="https://en.wikipedia.org/wiki/Three_prime_untranslated_region" title="Three prime untranslated region">3'-UTR</a> can only explain half of all human gene ends.
</p><p>Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails.
</p><p>Many prokaryotic genes are organized into <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">operons</a>, with multiple protein-coding sequences that are transcribed as a unit.<sup> </sup>The genes in an <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">operon</a> are transcribed as a continuous <a href="https://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA">messenger RNA</a>, referred to as a <a href="https://en.wikipedia.org/wiki/Messenger_RNA#Monocistronic_versus_polycistronic_mRNA" title="Messenger RNA">polycistronic mRNA</a>. The term <a href="https://en.wikipedia.org/wiki/Cistron" title="Cistron">cistron</a> in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a <a href="https://en.wikipedia.org/wiki/Repressor" title="Repressor">repressor</a> that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the <a href="https://en.wikipedia.org/wiki/Operon#Operator" title="Operon">operator region</a>, and represses <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> of the <a href="https://en.wikipedia.org/wiki/Operon" title="Operon">operon</a>; when the repressor is inactive transcription of the operon can occur (see e.g. <a href="https://en.wikipedia.org/wiki/Lac_operon" title="Lac operon">Lac operon</a>). The products of operon genes typically have related functions and are involved in the same <a href="https://en.wikipedia.org/wiki/Gene_regulatory_network" title="Gene regulatory network">regulatory network</a>.<sup class="reference nowrap"><span title="Page / location: 7.3"> </span></sup>
</p>
<h3><span class="mw-headline" id="Complexity">Complexity</span></h3><p>Though
many genes have simple structures, as with much of biology, others can
be quite complex or represent unusual edge-cases. Eukaryotic genes often
have introns are often much larger than their exons, and those introns can even have other genes <a href="https://en.wikipedia.org/wiki/Nested_gene" title="Nested gene">nested inside them</a>.
Associated enhancers may be many kilobase away, or even on entirely
different chromosomes operating via physical contact between two
chromosomes. A single gene can encode multiple different functional products by <a href="https://en.wikipedia.org/wiki/Alternative_splicing" title="Alternative splicing">alternative splicing</a>,
and conversely gene may be split across chromosomes but those
transcripts are concatenated back together into a functional sequence by
<a href="https://en.wikipedia.org/wiki/Trans-splicing" title="Trans-splicing">trans-splicing</a>. It is also possible for <a href="https://en.wikipedia.org/wiki/Overlapping_gene" title="Overlapping gene">overlapping genes</a>
to share some of their DNA sequence, either on opposite strands or the
same strand (in a different reading frame, or even the same reading
frame).
</p>
<h2><span class="mw-headline" id="Gene_expression">Gene expression</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">Gene expression</a></div>
<p>In all organisms, two steps are required to read the information
encoded in a gene's DNA and produce the protein it specifies. First, the
gene's DNA is <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcribed</a></i> to messenger RNA (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">mRNA</a>).<sup> </sup>Second, that mRNA is <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">translated</a></i> to protein.<sup class="reference nowrap"><span title="Page / location: 6.2"> </span></sup> RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a>, and the resulting molecule is called a <a href="https://en.wikipedia.org/wiki/Gene_product" title="Gene product">gene product</a>.
</p>
<h3><span class="mw-headline" id="Genetic_code">Genetic code</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:RNA-codons-aminoacids.svg"><img alt="An RNA molecule consisting of nucleotides. Groups of three nucleotides are indicated as codons, with each corresponding to a specific amino acid." class="mw-file-element" data-file-height="137" data-file-width="512" height="107" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/6d/RNA-codons-aminoacids.svg/330px-RNA-codons-aminoacids.svg.png" width="400" /></a><figcaption>Schematic of a single-stranded RNA molecule illustrating a series of three-base <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codons</a>. Each three-<a href="https://en.wikipedia.org/wiki/Nucleotide" title="Nucleotide">nucleotide</a> codon corresponds to an <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acid</a> when translated to protein.</figcaption></figure>
<p>The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the <a href="https://en.wikipedia.org/wiki/Genetic_code" title="Genetic code">genetic code</a>. Sets of three nucleotides, known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codons</a>, each correspond to a specific amino acid.<sup class="reference nowrap"><span title="Page / location: 6"> </span></sup>
The principle that three sequential bases of DNA code for each amino
acid was demonstrated in 1961 using frameshift mutations in the rIIB
gene of bacteriophage T4 (see <a href="https://en.wikipedia.org/wiki/Crick,_Brenner_et_al._experiment" title="Crick, Brenner et al. experiment">Crick, Brenner et al. experiment</a>).
</p><p>Additionally, a "<a href="https://en.wikipedia.org/wiki/Start_codon" title="Start codon">start codon</a>", and three "<a href="https://en.wikipedia.org/wiki/Stop_codon" title="Stop codon">stop codons</a>" indicate the beginning and end of the <a href="https://en.wikipedia.org/wiki/Coding_region" title="Coding region">protein coding region</a>. There are 64 possible codons (four possible nucleotides at each of three positions, hence 4<sup>3</sup> possible
codons) and only 20 standard amino acids; hence the code is redundant
and multiple codons can specify the same amino acid. The correspondence
between codons and amino acids is nearly universal among all known
living organisms.
</p>
<h3><span class="mw-headline" id="Transcription">Transcription</span></h3><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">Transcription</a> produces a single-stranded <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a> molecule known as <a href="https://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA">messenger RNA</a>, whose nucleotide sequence is complementary to the DNA from which it was transcribed.<sup class="reference nowrap"><span title="Page / location: 6.1"> </span></sup>
The mRNA acts as an intermediate between the DNA gene and its final
protein product. The gene's DNA is used as a template to generate a <a href="https://en.wikipedia.org/wiki/Base_pair" title="Base pair">complementary</a> mRNA. The mRNA matches the sequence of the gene's DNA <a href="https://en.wikipedia.org/wiki/Coding_strand" title="Coding strand">coding strand</a> because it is synthesised as the complement of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Template_strand" title="Template strand">template strand</a>. Transcription is performed by an <a href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzyme</a> called an <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a>, which reads the template strand in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27_end" title="3' end">3'</a> to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27_end" title="5' end">5'</a> direction and synthesizes the RNA from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5%27_end" title="5' end">5'</a> to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/3%27_end" title="3' end">3'</a>. To initiate transcription, the polymerase first recognizes and binds a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Promoter_(biology)" title="Promoter (biology)">promoter</a> region of the gene. Thus, a major mechanism of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gene_regulation" title="Gene regulation">gene regulation</a> is the blocking or sequestering the promoter region, either by tight binding by <a href="https://en.wikipedia.org/wiki/Repressor" title="Repressor">repressor</a> molecules that physically block the polymerase or by organizing the DNA so that the promoter region is not accessible.
</p><p>In <a href="https://en.wikipedia.org/wiki/Prokaryote" title="Prokaryote">prokaryotes</a>, transcription occurs in the <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a>; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">eukaryotes</a>,
transcription occurs in the nucleus, where the cell's DNA is stored.
The RNA molecule produced by the polymerase is known as the <a href="https://en.wikipedia.org/wiki/Primary_transcript" title="Primary transcript">primary transcript</a> and undergoes <a href="https://en.wikipedia.org/wiki/Post-transcriptional_modification" title="Post-transcriptional modification">post-transcriptional modifications</a> before being exported to the cytoplasm for translation. One of the modifications performed is the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Splicing_(genetics)" title="Splicing (genetics)">splicing</a> of <a href="https://en.wikipedia.org/wiki/Intron" title="Intron">introns</a> which are sequences in the transcribed region that do not encode a protein. <a href="https://en.wikipedia.org/wiki/Alternative_splicing" title="Alternative splicing">Alternative splicing</a>
mechanisms can result in mature transcripts from the same gene having
different sequences and thus coding for different proteins. This is a
major form of regulation in eukaryotic cells and also occurs in some
prokaryotes.
</p>
<h3><span class="mw-headline" id="Translation">Translation</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:DNA_to_protein_or_ncRNA.svg"><img alt="A protein-coding gene in DNA being transcribed and translated to a functional protein or a non-protein-coding gene being transcribed to a functional RNA" class="mw-file-element" data-file-height="824" data-file-width="1200" height="275" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fa/DNA_to_protein_or_ncRNA.svg/330px-DNA_to_protein_or_ncRNA.svg.png" width="400" /></a><figcaption>Protein coding genes are transcribed to an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">mRNA</a> intermediate, then translated to a functional <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a>. RNA-coding genes are transcribed to a functional <a href="https://en.wikipedia.org/wiki/Non-coding_RNA" title="Non-coding RNA">non-coding RNA</a> (<span class="plainlinks"><a href="https://en.wikipedia.org/wiki/Protein_Data_Bank" title="Protein Data Bank">PDB</a>: <a class="external text" href="https://www.rcsb.org/structure/3BSE" rel="nofollow">3BSE</a>, <a class="external text" href="https://www.rcsb.org/structure/1OBB" rel="nofollow">1OBB</a>, <a class="external text" href="https://www.rcsb.org/structure/3TRA" rel="nofollow">3TRA</a></span>).</figcaption></figure>
<p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">Translation</a> is the process by which a <a href="https://en.wikipedia.org/wiki/Mature_messenger_RNA" title="Mature messenger RNA">mature mRNA</a> molecule is used as a template for synthesizing a new <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a>.<sup class="reference nowrap"><span title="Page / location: 6.2"> </span></sup> Translation is carried out by <a href="https://en.wikipedia.org/wiki/Ribosome" title="Ribosome">ribosomes</a>, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acids</a> to a growing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Polypeptide_chain" title="Polypeptide chain">polypeptide chain</a> by the formation of <a href="https://en.wikipedia.org/wiki/Peptide_bond" title="Peptide bond">peptide bonds</a>. The genetic code is read three nucleotides at a time, in units called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codons</a>, via interactions with specialized RNA molecules called <a href="https://en.wikipedia.org/wiki/Transfer_RNA" title="Transfer RNA">transfer RNA</a> (tRNA). Each tRNA has three unpaired bases known as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anticodon" title="Anticodon">anticodon</a> that are complementary to the codon it reads on the mRNA. The tRNA is also <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Covalent" title="Covalent">covalently</a> attached to the <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acid</a>
specified by the complementary codon. When the tRNA binds to its
complementary codon in an mRNA strand, the ribosome attaches its amino
acid cargo to the new polypeptide chain, which is synthesized from <a href="https://en.wikipedia.org/wiki/N-terminus" title="N-terminus">amino terminus</a> to <a href="https://en.wikipedia.org/wiki/C-terminus" title="C-terminus">carboxyl terminus</a>. During and after synthesis, most new proteins must <a href="https://en.wikipedia.org/wiki/Protein_folding" title="Protein folding">fold</a> to their active <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tertiary_structure" title="Tertiary structure">three-dimensional structure</a> before they can carry out their cellular functions.
</p>
<h3><span class="mw-headline" id="Regulation">Regulation</span></h3><p><a href="https://en.wikipedia.org/wiki/Regulation_of_gene_expression" title="Regulation of gene expression">Genes are regulated</a> so that they are <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">expressed</a> only when the product is needed, since expression draws on limited resources. A cell regulates its gene expression depending on its <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Environment_(biophysical)" title="Environment (biophysical)">external environment</a> (e.g. <a href="https://en.wikipedia.org/wiki/Nutrient" title="Nutrient">available nutrients</a>, <a href="https://en.wikipedia.org/wiki/Heat_shock_protein" title="Heat shock protein">temperature</a> and other <a href="https://en.wikipedia.org/wiki/Cellular_stress_response" title="Cellular stress response">stresses</a>), its internal environment (e.g. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cell_division_cycle" title="Cell division cycle">cell division cycle</a>, <a href="https://en.wikipedia.org/wiki/Metabolism" title="Metabolism">metabolism</a>, <a href="https://en.wikipedia.org/wiki/Infection" title="Infection">infection status</a>), and its <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">specific role</a> if in a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multicellular" title="Multicellular">multicellular</a> organism. Gene expression can be regulated at any step: from <a href="https://en.wikipedia.org/wiki/Transcriptional_regulation" title="Transcriptional regulation">transcriptional initiation</a>, to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/RNA_processing" title="RNA processing">RNA processing</a>, to <a href="https://en.wikipedia.org/wiki/Post-translational_modification" title="Post-translational modification">post-translational modification</a> of the protein. The regulation of <a href="https://en.wikipedia.org/wiki/Lactose" title="Lactose">lactose</a> metabolism genes in <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/E._coli" title="E. coli">E. coli</a></i> (<a href="https://en.wikipedia.org/wiki/Lac_operon" title="Lac operon"><i>lac</i> operon</a>) was the first such mechanism to be described in 1961.
</p>
<h3><span class="mw-headline" id="RNA_genes">RNA genes</span></h3><p>A typical protein-coding gene is first copied into <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a> as an intermediate in the manufacture of the final protein product.<sup class="reference nowrap"><span title="Page / location: 6.1"> </span></sup> In other cases, the RNA molecules are the actual functional products, as in the synthesis of <a href="https://en.wikipedia.org/wiki/Ribosomal_RNA" title="Ribosomal RNA">ribosomal RNA</a> and <a href="https://en.wikipedia.org/wiki/Transfer_RNA" title="Transfer RNA">transfer RNA</a>. Some RNAs known as <a href="https://en.wikipedia.org/wiki/Ribozyme" title="Ribozyme">ribozymes</a> are capable of <a href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzymatic function</a>, while others such as <a href="https://en.wikipedia.org/wiki/MicroRNA" title="MicroRNA">microRNAs</a> and <a href="https://en.wikipedia.org/wiki/Riboswitch" title="Riboswitch">riboswitches</a> have regulatory roles. The <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> sequences from which such RNAs are transcribed are known as <a href="https://en.wikipedia.org/wiki/Non-coding_RNA" title="Non-coding RNA">non-coding RNA genes</a>.
</p><p>Some <a href="https://en.wikipedia.org/wiki/Virus" title="Virus">viruses</a> store their entire genomes in the form of <a href="https://en.wikipedia.org/wiki/RNA" title="RNA">RNA</a>, and contain no DNA at all. Because they use RNA to store genes, their <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cellular</a> <a href="https://en.wikipedia.org/wiki/Host_(biology)" title="Host (biology)">hosts</a> may synthesize their proteins as soon as they are <a href="https://en.wikipedia.org/wiki/Infection" title="Infection">infected</a> and without the delay in waiting for transcription. On the other hand, RNA <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retroviruses</a>, such as <a href="https://en.wikipedia.org/wiki/HIV" title="HIV">HIV</a>, require the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Reverse_transcription" title="Reverse transcription">reverse transcription</a> of their <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> from RNA into DNA before their proteins can be synthesized.
</p>
<h2><span class="mw-headline" id="Inheritance">Inheritance</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Autosomal_recessive_-_mini.svg"><img alt="Illustration of autosomal recessive inheritance. Each parent has one blue allele and one white allele. Each of their 4 children inherit one allele from each parent such that one child ends up with two blue alleles, one child has two white alleles and two children have one of each allele. Only the child with both blue alleles shows the trait because the trait is recessive." class="mw-file-element" data-file-height="1561" data-file-width="1201" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/46/Autosomal_recessive_-_mini.svg/220px-Autosomal_recessive_-_mini.svg.png" width="308" /></a><figcaption>Inheritance of a gene that has two different <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">alleles</a> (blue and white). The gene is located on an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autosomal_chromosome" title="Autosomal chromosome">autosomal chromosome</a>. The white allele is <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Recessive" title="Recessive">recessive</a> to the blue allele. The probability of each outcome in the children's generation is one quarter, or 25 percent.</figcaption></figure><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Mendelian_inheritance" title="Mendelian inheritance">Mendelian inheritance</a> and <a href="https://en.wikipedia.org/wiki/Heredity" title="Heredity">Heredity</a></div><p>Organisms inherit their genes from their parents. <a href="https://en.wikipedia.org/wiki/Asexual_reproduction" title="Asexual reproduction">Asexual</a> organisms simply inherit a complete copy of their parent's genome. <a href="https://en.wikipedia.org/wiki/Sexual_reproduction" title="Sexual reproduction">Sexual</a> organisms have two copies of each chromosome because they inherit one complete set from each parent.
</p><h3><span class="mw-headline" id="Mendelian_inheritance">Mendelian inheritance</span></h3><p>According to <a href="https://en.wikipedia.org/wiki/Mendelian_inheritance" title="Mendelian inheritance">Mendelian inheritance</a>, variations in an organism's <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">phenotype</a> (observable physical and behavioral characteristics) are due in part to variations in its <a href="https://en.wikipedia.org/wiki/Genotype" title="Genotype">genotype</a> (particular set of genes). Each gene specifies a particular trait with a different sequence of a gene (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alleles" title="Alleles">alleles</a>)
giving rise to different phenotypes. Most eukaryotic organisms (such as
the pea plants Mendel worked on) have two alleles for each trait, one
inherited from each parent.
</p><p>Alleles at a locus may be <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dominant_gene" title="Dominant gene">dominant</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Recessive_gene" title="Recessive gene">recessive</a>;
dominant alleles give rise to their corresponding phenotypes when
paired with any other allele for the same trait, whereas recessive
alleles give rise to their corresponding phenotype only when paired with
another copy of the same allele. If you know the genotypes of the
organisms, you can determine which alleles are dominant and which are
recessive. For example, if the allele specifying tall stems in pea
plants is dominant over the allele specifying short stems, then pea
plants that inherit one tall allele from one parent and one short allele
from the other parent will also have tall stems. Mendel's work
demonstrated that alleles assort independently in the production of <a href="https://en.wikipedia.org/wiki/Gamete" title="Gamete">gametes</a>, or <a href="https://en.wikipedia.org/wiki/Germ_cell" title="Germ cell">germ cells</a>,
ensuring variation in the next generation. Although Mendelian
inheritance remains a good model for many traits determined by single
genes (including a number of well-known <a href="https://en.wikipedia.org/wiki/Genetic_disorder#Single-gene_disorder" title="Genetic disorder">genetic disorders</a>) it does not include the physical processes of DNA replication and cell division.
</p>
<h3><span class="mw-headline" id="DNA_replication_and_cell_division">DNA replication and cell division</span></h3><p>The growth, development, and reproduction of organisms relies on <a href="https://en.wikipedia.org/wiki/Cell_division" title="Cell division">cell division</a>; the process by which a single <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cell</a> divides into two usually identical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Daughter_cell" title="Daughter cell">daughter cells</a>. This requires first making a duplicate copy of every gene in the <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> in a process called <a href="https://en.wikipedia.org/wiki/DNA_replication" title="DNA replication">DNA replication</a>.<sup class="reference nowrap"><span title="Page / location: 5.2"> </span></sup> The copies are made by specialized <a href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzymes</a> known as <a href="https://en.wikipedia.org/wiki/DNA_polymerase" title="DNA polymerase">DNA polymerases</a>,
which "reads" one strand of the double-helical DNA, known as the
template strand, and synthesize a new complementary strand. Because the
DNA double helix is held together by <a href="https://en.wikipedia.org/wiki/Base_pair" title="Base pair">base pairing</a>,
the sequence of one strand completely specifies the sequence of its
complement; hence only one strand needs to be read by the enzyme to
produce a faithful copy. The process of DNA replication is <a href="https://en.wikipedia.org/wiki/Semiconservative_replication" title="Semiconservative replication">semiconservative</a>; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.
</p><p>The rate of DNA replication in living cells was first measured as the rate of phage T4 DNA elongation in phage-infected <i>E. coli</i> and found to be impressively rapid. During the period of exponential DNA increase at 37 °C, the rate of elongation was 749 nucleotides per second.
</p><p>After DNA replication is complete, the cell must physically
separate the two copies of the genome and divide into two distinct
membrane-bound cells. In <a href="https://en.wikipedia.org/wiki/Prokaryote" title="Prokaryote">prokaryotes</a> (<a href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a> and <a href="https://en.wikipedia.org/wiki/Archaea" title="Archaea">archaea</a>) this usually occurs via a relatively simple process called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Binary_fission" title="Binary fission">binary fission</a>, in which each circular genome attaches to the <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">cell membrane</a> and is separated into the daughter cells as the membrane <a href="https://en.wikipedia.org/wiki/Invagination" title="Invagination">invaginates</a> to split the <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a> into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">eukaryotes</a>. Eukaryotic cell division is a more complex process known as the <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a>; DNA replication occurs during a phase of this cycle known as <a href="https://en.wikipedia.org/wiki/S_phase" title="S phase">S phase</a>, whereas the process of segregating <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a> and splitting the <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a> occurs during <a class="mw-redirect" href="https://en.wikipedia.org/wiki/M_phase" title="M phase">M phase</a>.
</p>
<h3><span class="mw-headline" id="Molecular_inheritance">Molecular inheritance</span></h3><p>The
duplication and transmission of genetic material from one generation of
cells to the next is the basis for molecular inheritance and the link
between the classical and molecular pictures of genes. Organisms inherit
the characteristics of their parents because the cells of the offspring
contain copies of the genes in their parents' cells. In <a href="https://en.wikipedia.org/wiki/Asexual_reproduction" title="Asexual reproduction">asexually reproducing</a> organisms, the offspring will be a genetic copy or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Clone_(genetics)" title="Clone (genetics)">clone</a> of the parent organism. In <a href="https://en.wikipedia.org/wiki/Sexual_reproduction" title="Sexual reproduction">sexually reproducing</a> organisms, a specialized form of cell division called <a href="https://en.wikipedia.org/wiki/Meiosis" title="Meiosis">meiosis</a> produces cells called <a href="https://en.wikipedia.org/wiki/Gamete" title="Gamete">gametes</a> or <a href="https://en.wikipedia.org/wiki/Germ_cell" title="Germ cell">germ cells</a> that are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Haploid" title="Haploid">haploid</a>, or contain only one copy of each gene.<sup class="reference nowrap"><span title="Page / location: 20.2"> </span></sup> The gametes produced by females are called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Egg_(biology)" title="Egg (biology)">eggs</a> or ova, and those produced by males are called <a href="https://en.wikipedia.org/wiki/Sperm" title="Sperm">sperm</a>. Two gametes fuse to form a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diploid" title="Diploid">diploid</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fertilized_egg" title="Fertilized egg">fertilized egg</a>, a single cell that has two sets of genes, with one copy of each gene from the mother and one from the father.
</p><p>During the process of meiotic cell division, an event called <a href="https://en.wikipedia.org/wiki/Genetic_recombination" title="Genetic recombination">genetic recombination</a> or <i>crossing-over</i> can sometimes occur, in which a length of DNA on one <a href="https://en.wikipedia.org/wiki/Chromatid" title="Chromatid">chromatid</a>
is swapped with a length of DNA on the corresponding homologous
non-sister chromatid. This can result in reassortment of otherwise
linked alleles.<sup class="reference nowrap"><span title="Page / location: 5.5"> </span></sup>
The Mendelian principle of independent assortment asserts that each of a
parent's two genes for each trait will sort independently into gametes;
which allele an organism inherits for one trait is unrelated to which
allele it inherits for another trait. This is in fact only true for
genes that do not reside on the same chromosome or are located very far
from one another on the same chromosome. The closer two genes lie on the
same chromosome, the more closely they will be associated in gametes
and the more often they will appear together (known as <a href="https://en.wikipedia.org/wiki/Genetic_linkage" title="Genetic linkage">genetic linkage</a>).
Genes that are very close are essentially never separated because it is
extremely unlikely that a crossover point will occur between them.
</p>
<h2><span class="mw-headline" id="Molecular_evolution">Molecular evolution</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Molecular_evolution" title="Molecular evolution">Molecular evolution</a></div>
<h3><span class="mw-headline" id="Mutation">Mutation</span></h3><p>DNA replication is for the most part extremely accurate, however errors (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mutations" title="Mutations">mutations</a>) do occur.<sup> </sup>The error rate in <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">eukaryotic</a> <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a> can be as low as 10<sup>−8</sup> per <a href="https://en.wikipedia.org/wiki/Nucleotide" title="Nucleotide">nucleotide</a> per replication, whereas for some RNA viruses it can be as high as 10<sup>−3</sup>. This means that each generation, each human genome accumulates around 30 new mutations. Small mutations can be caused by <a href="https://en.wikipedia.org/wiki/DNA_replication" title="DNA replication">DNA replication</a> and the aftermath of <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA damage</a> and include <a href="https://en.wikipedia.org/wiki/Point_mutation" title="Point mutation">point mutations</a> in which a single base is altered and <a href="https://en.wikipedia.org/wiki/Frameshift_mutation" title="Frameshift mutation">frameshift mutations</a> in which a single base is inserted or deleted. Either of these mutations can change the gene by <a href="https://en.wikipedia.org/wiki/Missense_mutation" title="Missense mutation">missense</a> (change a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codon</a> to encode a different amino acid) or <a href="https://en.wikipedia.org/wiki/Nonsense_mutation" title="Nonsense mutation">nonsense</a> (a premature <a href="https://en.wikipedia.org/wiki/Stop_codon" title="Stop codon">stop codon</a>). Larger mutations can be caused by errors in recombination to cause <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chromosomal_abnormality" title="Chromosomal abnormality">chromosomal abnormalities</a> including the <a href="https://en.wikipedia.org/wiki/Gene_duplication" title="Gene duplication">duplication</a>,
deletion, rearrangement or inversion of large sections of a chromosome.
Additionally, DNA repair mechanisms can introduce mutational errors
when repairing physical damage to the molecule. The repair, even with
mutation, is more important to survival than restoring an exact copy,
for example when repairing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Double-strand_breaks" title="Double-strand breaks">double-strand breaks</a>.
</p><p>When multiple different <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">alleles</a> for a gene are present in a species's population it is called <a href="https://en.wikipedia.org/wiki/Polymorphism_(biology)" title="Polymorphism (biology)">polymorphic</a>. Most different alleles are functionally equivalent, however some alleles can give rise to different <a href="https://en.wikipedia.org/wiki/Phenotypic_trait" title="Phenotypic trait">phenotypic traits</a>. A gene's most common allele is called the <a href="https://en.wikipedia.org/wiki/Wild_type" title="Wild type">wild type</a>, and rare alleles are called <a href="https://en.wikipedia.org/wiki/Mutant" title="Mutant">mutants</a>. The <a href="https://en.wikipedia.org/wiki/Genetic_variation" title="Genetic variation">genetic variation</a> in relative frequencies of different alleles in a population is due to both <a href="https://en.wikipedia.org/wiki/Natural_selection" title="Natural selection">natural selection</a> and <a href="https://en.wikipedia.org/wiki/Genetic_drift" title="Genetic drift">genetic drift</a>. The wild-type allele is not necessarily the <a href="https://en.wikipedia.org/wiki/Ancestor" title="Ancestor">ancestor</a> of less common alleles, nor is it necessarily <a href="https://en.wikipedia.org/wiki/Fitness_(biology)" title="Fitness (biology)">fitter</a>.
</p><p>Most mutations within genes are <a href="https://en.wikipedia.org/wiki/Neutral_mutation" title="Neutral mutation">neutral</a>, having no effect on the organism's phenotype (<a href="https://en.wikipedia.org/wiki/Silent_mutation" title="Silent mutation">silent mutations</a>). Some mutations do not change the amino acid sequence because multiple codons encode the same amino acid (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Synonymous_mutations" title="Synonymous mutations">synonymous mutations</a>).
Other mutations can be neutral if they lead to amino acid sequence
changes, but the protein still functions similarly with the new amino
acid (e.g. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Conservative_mutation" title="Conservative mutation">conservative mutations</a>). Many mutations, however, are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Deleterious_mutation" title="Deleterious mutation">deleterious</a> or even <a href="https://en.wikipedia.org/wiki/Lethal_allele" title="Lethal allele">lethal</a>,
and are removed from populations by natural selection. Genetic
disorders are the result of deleterious mutations and can be due to
spontaneous mutation in the affected individual, or can be inherited.
Finally, a small fraction of mutations are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beneficial_mutation" title="Beneficial mutation">beneficial</a>, improving the organism's <a href="https://en.wikipedia.org/wiki/Fitness_(biology)" title="Fitness (biology)">fitness</a> and are extremely important for evolution, since their <a href="https://en.wikipedia.org/wiki/Directional_selection" title="Directional selection">directional selection</a> leads to adaptive <a href="https://en.wikipedia.org/wiki/Evolution" title="Evolution">evolution</a>.
</p>
<h3><span class="mw-headline" id="Sequence_homology">Sequence homology</span></h3><p>The relationship between genes can be measured by comparing the <a href="https://en.wikipedia.org/wiki/Sequence_alignment" title="Sequence alignment">sequences</a>
of their DNA. If the level of similarity exceeds a minimum value, one
can conclude that the genes descend from a common ancestor; they are <a href="https://en.wikipedia.org/wiki/Sequence_homology" title="Sequence homology">homologous</a>.
Genes that are related by direct descent from a common ancestor are
orthologous genes - they are usually found at the same locus in
different species. Genes that are related as a result of a gene
duplication event are parologous genes.
</p><p>It is often assumed that the functions of orthologous genes are
more similar than those of paralogous genes, although the difference is
minimal.
</p>
<h3><span class="mw-headline" id="Origins_of_new_genes">Origins of new genes</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Evolution_fate_duplicate_genes_-_vector.svg"><img class="mw-file-element" data-file-height="360" data-file-width="576" height="251" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b9/Evolution_fate_duplicate_genes_-_vector.svg/300px-Evolution_fate_duplicate_genes_-_vector.svg.png" width="400" /></a><figcaption>Evolutionary fate of duplicate genes</figcaption></figure>
<p>The most common source of new genes in eukaryotic lineages is <a href="https://en.wikipedia.org/wiki/Gene_duplication" title="Gene duplication">gene duplication</a>, which creates <a href="https://en.wikipedia.org/wiki/Copy_number_variation" title="Copy number variation">copy number variation</a> of an existing gene in the genome. The resulting genes (paralogs) may then diverge in sequence and in function. Sets of genes formed in this way compose a <a href="https://en.wikipedia.org/wiki/Gene_family" title="Gene family">gene family</a>. Gene duplications and losses within a family are common and represent a major source of evolutionary <a href="https://en.wikipedia.org/wiki/Biodiversity" title="Biodiversity">biodiversity</a>.
Sometimes, gene duplication may result in a nonfunctional copy of a
gene, or a functional copy may be subject to mutations that result in
loss of function; such nonfunctional genes are called <a href="https://en.wikipedia.org/wiki/Pseudogene" title="Pseudogene">pseudogenes</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Orphan_gene" title="Orphan gene">"Orphan" genes</a>,
whose sequence shows no similarity to existing genes, are less common
than gene duplicates. The human genome contains an estimate 18 to 60 genes with no identifiable homologs outside humans. Orphan genes arise primarily from either <a href="https://en.wikipedia.org/wiki/De_novo_gene_birth" title="De novo gene birth"><i>de novo</i> emergence</a> from previously <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Non-coding_sequence" title="Non-coding sequence">non-coding sequence</a>, or gene duplication followed by such rapid sequence change that the original relationship becomes undetectable. <i>De novo</i> genes are typically shorter and simpler in structure than most eukaryotic genes, with few if any introns. Over long evolutionary time periods, <i>de novo</i> gene birth may be responsible for a significant fraction of taxonomically restricted gene families.
</p><p><a href="https://en.wikipedia.org/wiki/Horizontal_gene_transfer" title="Horizontal gene transfer">Horizontal gene transfer</a> refers to the transfer of genetic material through a mechanism other than <a href="https://en.wikipedia.org/wiki/Reproduction" title="Reproduction">reproduction</a>. This mechanism is a common source of new genes in <a href="https://en.wikipedia.org/wiki/Prokaryote" title="Prokaryote">prokaryotes</a>, sometimes thought to contribute more to genetic variation than gene duplication. It is a common means of spreading <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibiotic_resistance" title="Antibiotic resistance">antibiotic resistance</a>, <a href="https://en.wikipedia.org/wiki/Virulence" title="Virulence">virulence</a>, and adaptive <a href="https://en.wikipedia.org/wiki/Metabolism" title="Metabolism">metabolic</a> functions. Although horizontal gene transfer is rare in eukaryotes, likely examples have been identified of <a href="https://en.wikipedia.org/wiki/Protist" title="Protist">protist</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alga" title="Alga">alga</a> genomes containing genes of bacterial origin.
</p>
<h2><span class="mw-headline" id="Genome">Genome</span></h2><p>The <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> is the total genetic material of an organism and includes both the genes and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Non-coding_sequence" title="Non-coding sequence">non-coding sequences</a>. Eukaryotic genes can be annotated using FINDER.
</p>
<h3><span class="mw-headline" id="Number_of_genes">Number of genes</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gene_numbers.svg"><img class="mw-file-element" data-file-height="376" data-file-width="1200" height="175" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/89/Gene_numbers.svg/560px-Gene_numbers.svg.png" width="560" /></a><figcaption>Depiction of numbers of genes for representative <a href="https://en.wikipedia.org/wiki/Plant" title="Plant">plants</a> (green), <a href="https://en.wikipedia.org/wiki/Vertebrate" title="Vertebrate">vertebrates</a> (blue), <a href="https://en.wikipedia.org/wiki/Invertebrate" title="Invertebrate">invertebrates</a> (orange), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fungi" title="Fungi">fungi</a> (yellow), <a href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a> (purple), and <a href="https://en.wikipedia.org/wiki/Virus" title="Virus">viruses</a> (grey). An inset on the right shows the smaller genomes expanded 100-fold area-wise.</figcaption></figure>
<p>The <a href="https://en.wikipedia.org/wiki/Genome_size" title="Genome size">genome size</a>, and the number of genes it encodes varies widely between organisms. The smallest genomes occur in <a href="https://en.wikipedia.org/wiki/Virus" title="Virus">viruses</a>, and <a href="https://en.wikipedia.org/wiki/Viroid" title="Viroid">viroids</a> (which act as a single non-coding RNA gene). Conversely, plants can have extremely large genomes, with <a href="https://en.wikipedia.org/wiki/Oryza_sativa" title="Oryza sativa">rice</a> containing >46,000 protein-coding genes. The total number of protein-coding genes (the Earth's <a href="https://en.wikipedia.org/wiki/Proteome" title="Proteome">proteome</a>) is estimated to be 5 million sequences.
</p><p>Although the number of base-pairs of DNA in the human genome has
been known since the 1950s, the estimated number of genes has changed
over time as definitions of genes, and methods of detecting them have
been refined. Initial theoretical predictions of the number of human
genes in the 1960s and 1970s were based on mutation load estimates and
the numbers of mRNAs and these estimates tended to be about 30,000
protein-coding genes. During the 1990s there were guesstimates of up to 100,000 genes and early data on detection of mRNAs (<a href="https://en.wikipedia.org/wiki/Expressed_sequence_tag" title="Expressed sequence tag">expressed sequence tags</a>) suggested more than the traditional value of 30,000 genes that had been reported in the textbooks during the 1980s.
</p><p>The initial draft sequences of the human genome confirmed the
earlier predictions of about 30,000 protein-coding genes however that
estimate has fallen to about 19,000 with the ongoing <a href="https://en.wikipedia.org/wiki/GENCODE" title="GENCODE">GENCODE</a> annotation project . The number of noncoding genes is not known with certainty but the latest estimates from Ensembl suggest 26,000 noncoding genes.
</p>
<h3><span class="mw-headline" id="Essential_genes">Essential genes</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Essential_gene" title="Essential gene">Essential gene</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Syn3_genome.svg"><img class="mw-file-element" data-file-height="203" data-file-width="340" height="239" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/5b/Syn3_genome.svg/300px-Syn3_genome.svg.png" width="400" /></a><figcaption>Gene functions in the minimal <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> of the <a href="https://en.wikipedia.org/wiki/Synthetic_biology" title="Synthetic biology">synthetic organism</a>, <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Syn_3" title="Syn 3">Syn 3</a></i></figcaption></figure>
<p>Essential genes are the set of genes thought to be critical for an organism's survival. This definition assumes the abundant availability of all relevant <a href="https://en.wikipedia.org/wiki/Nutrient" title="Nutrient">nutrients</a>
and the absence of environmental stress. Only a small portion of an
organism's genes are essential. In bacteria, an estimated 250–400 genes
are essential for <i><a href="https://en.wikipedia.org/wiki/Escherichia_coli" title="Escherichia coli">Escherichia coli</a></i> and <i><a href="https://en.wikipedia.org/wiki/Bacillus_subtilis" title="Bacillus subtilis">Bacillus subtilis</a></i>, which is less than 10% of their genes. Half of these genes are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ortholog" title="Ortholog">orthologs</a> in both organisms and are largely involved in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_synthesis" title="Protein synthesis">protein synthesis</a>. In the budding yeast <i><a href="https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae" title="Saccharomyces cerevisiae">Saccharomyces cerevisiae</a></i> the number of essential genes is slightly higher, at 1000 genes (~20% of their genes).
Although the number is more difficult to measure in higher eukaryotes,
mice and humans are estimated to have around 2000 essential genes (~10%
of their genes). The synthetic organism, <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Syn_3" title="Syn 3">Syn 3</a></i>,
has a minimal genome of 473 essential genes and quasi-essential genes
(necessary for fast growth), although 149 have unknown function.
</p><p>Essential genes include <a href="https://en.wikipedia.org/wiki/Housekeeping_gene" title="Housekeeping gene">housekeeping genes</a> (critical for basic cell functions) as well as genes that are expressed at different times in the organisms <a href="https://en.wikipedia.org/wiki/Developmental_biology" title="Developmental biology">development</a> or <a href="https://en.wikipedia.org/wiki/Biological_life_cycle" title="Biological life cycle">life cycle</a>. Housekeeping genes are used as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Experimental_control" title="Experimental control">experimental controls</a> when <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gene_expression_analysis" title="Gene expression analysis">analysing gene expression</a>, since they are <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">constitutively expressed</a> at a relatively constant level.
</p>
<h3><span class="mw-headline" id="Genetic_and_genomic_nomenclature">Genetic and genomic nomenclature</span></h3><p><a href="https://en.wikipedia.org/wiki/Gene_nomenclature" title="Gene nomenclature">Gene nomenclature</a> has been established by the <a href="https://en.wikipedia.org/wiki/HUGO_Gene_Nomenclature_Committee" title="HUGO Gene Nomenclature Committee">HUGO Gene Nomenclature Committee</a> (HGNC), a committee of the <a href="https://en.wikipedia.org/wiki/Human_Genome_Organisation" title="Human Genome Organisation">Human Genome Organisation</a>, for each known human gene in the form of an approved gene name and <a href="https://en.wikipedia.org/wiki/Symbol" title="Symbol">symbol</a> (short-form <a href="https://en.wikipedia.org/wiki/Abbreviation" title="Abbreviation">abbreviation</a>),
which can be accessed through a database maintained by HGNC. Symbols
are chosen to be unique, and each gene has only one symbol (although
approved symbols sometimes change). Symbols are preferably kept
consistent with other members of a <a href="https://en.wikipedia.org/wiki/Gene_family" title="Gene family">gene family</a> and with homologs in other species, particularly the <a href="https://en.wikipedia.org/wiki/Mouse" title="Mouse">mouse</a> due to its role as a common <a href="https://en.wikipedia.org/wiki/Model_organism" title="Model organism">model organism</a>.
</p>
<h2><span class="mw-headline" id="Genetic_engineering">Genetic engineering</span></h2><figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Breeding_transgenesis_cisgenesis.svg"><img class="mw-file-element" data-file-height="921" data-file-width="1077" height="343" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/80/Breeding_transgenesis_cisgenesis.svg/300px-Breeding_transgenesis_cisgenesis.svg.png" width="400" /></a><figcaption>Comparison of conventional plant breeding with transgenic and cisgenic genetic modification</figcaption></figure>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Genetic_engineering" title="Genetic engineering">Genetic engineering</a></div>
<p>Genetic engineering is the modification of an organism's <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> through <a href="https://en.wikipedia.org/wiki/Biotechnology" title="Biotechnology">biotechnology</a>. Since the 1970s, a <a href="https://en.wikipedia.org/wiki/Genetic_engineering_techniques" title="Genetic engineering techniques">variety of techniques</a> have been developed to specifically add, remove and edit genes in an organism. Recently developed <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genome_engineering" title="Genome engineering">genome engineering</a> techniques use engineered <a href="https://en.wikipedia.org/wiki/Nuclease" title="Nuclease">nuclease</a> <a href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzymes</a> to create targeted <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA repair</a> in a <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosome</a> to either disrupt or edit a gene when the break is repaired.<sup> </sup>The related term <a href="https://en.wikipedia.org/wiki/Synthetic_biology" title="Synthetic biology">synthetic biology</a> is sometimes used to refer to extensive genetic engineering of an organism.
</p><p>Genetic engineering is now a routine research tool with <a href="https://en.wikipedia.org/wiki/Model_organism" title="Model organism">model organisms</a>. For example, genes are easily added to <a href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a> and lineages of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Knockout_mice" title="Knockout mice">knockout mice</a> with a specific gene's function disrupted are used to investigate that gene's function.<sup> </sup>Many organisms have been genetically modified for applications in <a href="https://en.wikipedia.org/wiki/Agriculture" title="Agriculture">agriculture</a>, industrial biotechnology, and <a href="https://en.wikipedia.org/wiki/Medicine" title="Medicine">medicine</a>.
</p><p>For multicellular organisms, typically the <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryo</a> is engineered which grows into the adult <a href="https://en.wikipedia.org/wiki/Genetically_modified_organism" title="Genetically modified organism">genetically modified organism</a>. However, the genomes of cells in an adult organism can be edited using <a href="https://en.wikipedia.org/wiki/Gene_therapy" title="Gene therapy">gene therapy</a> techniques to treat genetic diseases.
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-30247697540479571132024-03-28T21:10:00.000-04:002024-03-28T21:10:36.637-04:00Transcription factor<div class="vector-column-end">
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<div id="contentSub"><div id="mw-content-subtitle"><span class="mw-redirectedfrom"><a href="https://en.wikipedia.org/wiki/Transcription_factor">https://en.wikipedia.org/wiki/Transcription_factor</a></span></div><div id="mw-content-subtitle"><span class="mw-redirectedfrom"> <br /></span></div></div>
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<table class="infobox" style="border-collapse: collapse; width: 452px;"><tbody><tr><th class="infobox-above" colspan="2" style="background: #FFCC66; box-shadow: inset 3px 3px 0 #fafafa, inset -3px -3px 0 #fafafa; font-size: 100%; padding: 5px;">Transcription factor glossary</th></tr><tr><td class="infobox-full-data" colspan="2" style="padding-left: 0; text-align: left;">
<ul><li><b><a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a></b> – the process by which information from a <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">gene</a> is used in the synthesis of a functional gene product such as a <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a></li><li><b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a></b> – the process of making <a href="https://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA">messenger RNA</a> (mRNA) from a <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> template by <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a></li><li><b><a class="mw-selflink selflink">transcription factor</a></b> – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription</li><li><b><a href="https://en.wikipedia.org/wiki/Transcriptional_regulation" title="Transcriptional regulation">transcriptional regulation</a></b> – <i>controlling</i> the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA</li><li><b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Upregulation" title="Upregulation">upregulation</a></b>, <b>activation</b>, or <b>promotion</b> – <i>increase</i> the rate of gene transcription</li><li><b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Downregulation" title="Downregulation">downregulation</a></b>, <b>repression</b>, or <b>suppression</b> – <i>decrease</i> the rate of gene transcription</li><li><b><a href="https://en.wikipedia.org/wiki/Coactivator_(genetics)" title="Coactivator (genetics)">coactivator</a></b> – a protein (or a small molecule) that works with transcription factors to <i>increase</i> the rate of gene transcription</li><li><b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Corepressor_(genetics)" title="Corepressor (genetics)">corepressor</a></b> – a protein (or a small molecule) that works with transcription factors to <i>decrease</i> the rate of gene transcription</li><li><b><a href="https://en.wikipedia.org/wiki/Response_element" title="Response element">response element</a></b> – a specific sequence of DNA that a transcription factor binds to<br /><br /><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Transcription_Factors.svg"><img class="mw-file-element" data-file-height="853" data-file-width="1572" height="217" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/80/Transcription_Factors.svg/390px-Transcription_Factors.svg.png" width="400" /></a></li></ul></td></tr><tr><td class="infobox-below" colspan="2" style="padding-right: 5px; padding-top: 0; text-align: right;"><br /></td></tr></tbody></table><figure class="mw-default-size"><figcaption>Illustration of an activator</figcaption></figure>
<p>In <a href="https://en.wikipedia.org/wiki/Molecular_biology" title="Molecular biology">molecular biology</a>, a <b>transcription factor</b> (<b>TF</b>) (or <b>sequence-specific DNA-binding factor</b>) is a <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> that controls the rate of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> of <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetic</a> information from <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> to <a href="https://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA">messenger RNA</a>, by binding to a specific <a class="mw-redirect" href="https://en.wikipedia.org/wiki/DNA_sequence" title="DNA sequence">DNA sequence</a>. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">expressed</a> in the desired <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a>
at the right time and in the right amount throughout the life of the
cell and the organism. Groups of TFs function in a coordinated fashion
to direct <a href="https://en.wikipedia.org/wiki/Cell_division" title="Cell division">cell division</a>, <a href="https://en.wikipedia.org/wiki/Cell_growth" title="Cell growth">cell growth</a>, and <a href="https://en.wikipedia.org/wiki/Cell_death" title="Cell death">cell death</a> throughout life; <a href="https://en.wikipedia.org/wiki/Cell_migration" title="Cell migration">cell migration</a> and organization (<a href="https://en.wikipedia.org/wiki/Body_plan" title="Body plan">body plan</a>) during embryonic development; and intermittently in response to signals from outside the cell, such as a <a href="https://en.wikipedia.org/wiki/Hormone" title="Hormone">hormone</a>. There are 1500-1600 TFs in the <a href="https://en.wikipedia.org/wiki/Human_genome" title="Human genome">human genome</a>. Transcription factors are members of the <a href="https://en.wikipedia.org/wiki/Proteome" title="Proteome">proteome</a> as well as <a href="https://en.wikipedia.org/wiki/Regulome" title="Regulome">regulome</a>.
</p><p>TFs work alone or with other proteins in a complex, by promoting (as an <a href="https://en.wikipedia.org/wiki/Activator_(genetics)" title="Activator (genetics)">activator</a>), or blocking (as a <a href="https://en.wikipedia.org/wiki/Repressor" title="Repressor">repressor</a>) the recruitment of <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a> (the enzyme that performs the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcription</a> of genetic information from DNA to RNA) to specific genes.
</p><p>A defining feature of TFs is that they contain at least one <a href="https://en.wikipedia.org/wiki/DNA-binding_domain" title="DNA-binding domain">DNA-binding domain</a> (DBD), which attaches to a specific sequence of DNA adjacent to the genes that they regulate. TFs are grouped into classes based on their DBDs. Other proteins such as <a href="https://en.wikipedia.org/wiki/Coactivator_(genetics)" title="Coactivator (genetics)">coactivators</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chromatin_Structure_Remodeling_(RSC)_Complex" title="Chromatin Structure Remodeling (RSC) Complex">chromatin remodelers</a>, <a href="https://en.wikipedia.org/wiki/Histone_acetyltransferase" title="Histone acetyltransferase">histone acetyltransferases</a>, <a href="https://en.wikipedia.org/wiki/Histone_deacetylase" title="Histone deacetylase">histone deacetylases</a>, <a href="https://en.wikipedia.org/wiki/Kinase" title="Kinase">kinases</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Methylase" title="Methylase">methylases</a> are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs.
</p><p>TFs are of interest in medicine because TF mutations can cause
specific diseases, and medications can be potentially targeted toward
them.
</p>
<h2><span class="mw-headline" id="Number">Number</span></h2></div></div></div><div class="hatnote navigation-not-searchable" role="note">Main listing: <a href="https://en.wikipedia.org/wiki/List_of_human_transcription_factors" title="List of human transcription factors">List of human transcription factors</a></div>
<p>Transcription factors are essential for the regulation of gene
expression and are, as a consequence, found in all living organisms. The
number of transcription factors found within an organism increases with
genome size, and larger genomes tend to have more transcription factors
per gene.
</p><p>There are approximately 2800 proteins in the <a href="https://en.wikipedia.org/wiki/Human_genome" title="Human genome">human genome</a> that contain DNA-binding domains, and 1600 of these are presumed to function as transcription factors, though other studies indicate it to be a smaller number.
Therefore, approximately 10% of genes in the genome code for
transcription factors, which makes this family the single largest family
of human proteins. Furthermore, genes are often flanked by several
binding sites for distinct transcription factors, and efficient
expression of each of these genes requires the cooperative action of
several different transcription factors (see, for example, <a href="https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors#Function" title="Hepatocyte nuclear factors">hepatocyte nuclear factors</a>).
Hence, the combinatorial use of a subset of the approximately 2000
human transcription factors easily accounts for the unique regulation of
each gene in the human genome during <a href="https://en.wikipedia.org/wiki/Developmental_biology" title="Developmental biology">development</a>.
</p>
<h2><span class="mw-headline" id="Mechanism">Mechanism</span></h2><p>Transcription factors bind to either <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancer</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Promoter_(biology)" title="Promoter (biology)">promoter</a>
regions of DNA adjacent to the genes that they regulate. Depending on
the transcription factor, the transcription of the adjacent gene is
either <a href="https://en.wikipedia.org/wiki/Downregulation_and_upregulation" title="Downregulation and upregulation">up- or down-regulated</a>. Transcription factors use a variety of mechanisms for the regulation of gene expression. These mechanisms include:
</p>
<ul><li>stabilize or block the binding of RNA polymerase to DNA</li><li>catalyze the <a href="https://en.wikipedia.org/wiki/Acetylation" title="Acetylation">acetylation</a> or deacetylation of <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histone</a>
proteins. The transcription factor can either do this directly or
recruit other proteins with this catalytic activity. Many transcription
factors use one or the other of two opposing mechanisms to regulate
transcription:
<ul><li><a href="https://en.wikipedia.org/wiki/Histone_acetyltransferase" title="Histone acetyltransferase">histone acetyltransferase</a> (HAT) activity – acetylates <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histone</a> proteins, which weakens the association of DNA with <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histones</a>, which make the DNA more accessible to transcription, thereby up-regulating transcription</li><li><a href="https://en.wikipedia.org/wiki/Histone_deacetylase" title="Histone deacetylase">histone deacetylase</a> (HDAC) activity – deacetylates <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histone</a>
proteins, which strengthens the association of DNA with histones, which
make the DNA less accessible to transcription, thereby down-regulating
transcription</li></ul></li><li>recruit <a href="https://en.wikipedia.org/wiki/Coactivator_(genetics)" title="Coactivator (genetics)">coactivator</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Corepressor_(genetics)" title="Corepressor (genetics)">corepressor</a> proteins to the transcription factor DNA complex</li></ul>
<h2><span class="mw-headline" id="Function">Function</span></h2><p>Transcription
factors are one of the groups of proteins that read and interpret the
genetic "blueprint" in the DNA. They bind to the DNA and help initiate a
program of increased or decreased gene transcription. As such, they
are vital for many important cellular processes. Below are some of the
important functions and biological roles transcription factors are
involved in:
</p>
<h3><span class="mw-headline" id="Basal_transcriptional_regulation">Basal transcriptional regulation</span></h3><p>In <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">eukaryotes</a>, an important class of transcription factors called <a href="https://en.wikipedia.org/wiki/General_transcription_factor" title="General transcription factor">general transcription factors</a> (GTFs) are necessary for transcription to occur. Many of these GTFs do not actually bind DNA, but rather are part of the large <a href="https://en.wikipedia.org/wiki/Transcription_preinitiation_complex" title="Transcription preinitiation complex">transcription preinitiation complex</a> that interacts with <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a> directly. The most common GTFs are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIA" title="TFIIA">TFIIA</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIB" title="TFIIB">TFIIB</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIID" title="TFIID">TFIID</a> (see also <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TATA_binding_protein" title="TATA binding protein">TATA binding protein</a>), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIE" title="TFIIE">TFIIE</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIF" title="TFIIF">TFIIF</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIH" title="TFIIH">TFIIH</a>. The preinitiation complex binds to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Promotor_(biology)" title="Promotor (biology)">promoter</a> regions of DNA upstream to the gene that they regulate.
</p>
<h3><span class="mw-headline" id="Differential_enhancement_of_transcription">Differential enhancement of transcription</span></h3><p>Other transcription factors differentially regulate the expression of various genes by binding to <a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancer</a>
regions of DNA adjacent to regulated genes. These transcription
factors are critical to making sure that genes are expressed in the
right cell at the right time and in the right amount, depending on the
changing requirements of the organism.
</p>
<h4><span class="mw-headline" id="Development">Development</span></h4><p>Many transcription factors in <a href="https://en.wikipedia.org/wiki/Multicellular_organism" title="Multicellular organism">multicellular organisms</a> are involved in development.
Responding to stimuli, these transcription factors turn on/off the
transcription of the appropriate genes, which, in turn, allows for
changes in cell <a href="https://en.wikipedia.org/wiki/Morphology_(biology)" title="Morphology (biology)">morphology</a> or activities needed for <a href="https://en.wikipedia.org/wiki/Cell_fate_determination" title="Cell fate determination">cell fate determination</a> and <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">cellular differentiation</a>. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hox_(gene)" title="Hox (gene)">Hox</a> transcription factor family, for example, is important for proper <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Regional_specification" title="Regional specification">body pattern formation</a> in organisms as diverse as fruit flies to humans. Another example is the transcription factor encoded by the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SRY" title="SRY">sex-determining region Y</a> (SRY) gene, which plays a major role in determining sex in humans.
</p>
<h4><span class="mw-headline" id="Response_to_intercellular_signals">Response to intercellular signals</span></h4><p>Cells can communicate with each other by releasing molecules that produce <a href="https://en.wikipedia.org/wiki/Signal_transduction" title="Signal transduction">signaling cascades</a>
within another receptive cell. If the signal requires upregulation or
downregulation of genes in the recipient cell, often transcription
factors will be downstream in the signaling cascade. <a href="https://en.wikipedia.org/wiki/Estrogen" title="Estrogen">Estrogen</a> signaling is an example of a fairly short signaling cascade that involves the <a href="https://en.wikipedia.org/wiki/Estrogen_receptor" title="Estrogen receptor">estrogen receptor</a> transcription factor: Estrogen is secreted by tissues such as the <a href="https://en.wikipedia.org/wiki/Ovary" title="Ovary">ovaries</a> and <a href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">placenta</a>, crosses the <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">cell membrane</a> of the recipient cell, and is bound by the estrogen receptor in the cell's <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a>. The estrogen receptor then goes to the cell's <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">nucleus</a> and binds to its <a href="https://en.wikipedia.org/wiki/DNA_binding_site" title="DNA binding site">DNA-binding sites</a>, changing the transcriptional regulation of the associated genes.
</p>
<h4><span class="mw-headline" id="Response_to_environment">Response to environment</span></h4><p>Not
only do transcription factors act downstream of signaling cascades
related to biological stimuli but they can also be downstream of
signaling cascades involved in environmental stimuli. Examples include <a href="https://en.wikipedia.org/wiki/Heat_shock_factor" title="Heat shock factor">heat shock factor</a> (HSF), which upregulates genes necessary for survival at higher temperatures, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hypoxia_inducible_factor" title="Hypoxia inducible factor">hypoxia inducible factor</a> (HIF), which upregulates genes necessary for cell survival in low-oxygen environments, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sterol_regulatory_element_binding_protein" title="Sterol regulatory element binding protein">sterol regulatory element binding protein</a> (SREBP), which helps maintain proper <a href="https://en.wikipedia.org/wiki/Lipid" title="Lipid">lipid</a> levels in the cell.
</p>
<h4><span class="mw-headline" id="Cell_cycle_control">Cell cycle control</span></h4><p>Many transcription factors, especially some that are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proto-oncogene" title="Proto-oncogene">proto-oncogenes</a> or <a href="https://en.wikipedia.org/wiki/Tumor_suppressor_gene" title="Tumor suppressor gene">tumor suppressors</a>, help regulate the <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a> and as such determine how large a cell will get and when it can divide into two daughter cells. One example is the <a href="https://en.wikipedia.org/wiki/Myc" title="Myc">Myc</a> oncogene, which has important roles in <a href="https://en.wikipedia.org/wiki/Cell_growth" title="Cell growth">cell growth</a> and <a href="https://en.wikipedia.org/wiki/Apoptosis" title="Apoptosis">apoptosis</a>.
</p>
<h4><span class="mw-headline" id="Pathogenesis">Pathogenesis</span></h4><p>Transcription
factors can also be used to alter gene expression in a host cell to
promote pathogenesis. A well studied example of this are the
transcription-activator like effectors (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/TAL_effector" title="TAL effector">TAL effectors</a>) secreted by <a href="https://en.wikipedia.org/wiki/Xanthomonas" title="Xanthomonas">Xanthomonas</a>
bacteria. When injected into plants, these proteins can enter the
nucleus of the plant cell, bind plant promoter sequences, and activate
transcription of plant genes that aid in bacterial infection.
TAL effectors contain a central repeat region in which there is a
simple relationship between the identity of two critical residues in
sequential repeats and sequential DNA bases in the TAL effector's target
site.
This property likely makes it easier for these proteins to evolve in
order to better compete with the defense mechanisms of the host cell.
</p>
<h2><span class="mw-headline" id="Regulation">Regulation</span></h2><p>It
is common in biology for important processes to have multiple layers of
regulation and control. This is also true with transcription factors:
Not only do transcription factors control the rates of transcription to
regulate the amounts of gene products (RNA and protein) available to
the cell but transcription factors themselves are regulated (often by
other transcription factors). Below is a brief synopsis of some of the
ways that the activity of transcription factors can be regulated:
</p>
<h3><span class="mw-headline" id="Synthesis">Synthesis</span></h3><p>Transcription
factors (like all proteins) are transcribed from a gene on a chromosome
into RNA, and then the RNA is translated into protein. Any of these
steps can be regulated to affect the production (and thus activity) of a
transcription factor. An implication of this is that transcription
factors can regulate themselves. For example, in a <a href="https://en.wikipedia.org/wiki/Negative_feedback" title="Negative feedback">negative feedback</a>
loop, the transcription factor acts as its own repressor: If the
transcription factor protein binds the DNA of its own gene, it
down-regulates the production of more of itself. This is one mechanism
to maintain low levels of a transcription factor in a cell.
</p>
<h3><span class="mw-headline" id="Nuclear_localization">Nuclear localization</span></h3><p>In <a href="https://en.wikipedia.org/wiki/Eukaryote" title="Eukaryote">eukaryotes</a>, transcription factors (like most proteins) are transcribed in the <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">nucleus</a> but are then translated in the cell's <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a>. Many proteins that are active in the nucleus contain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nuclear_localization_signal" title="Nuclear localization signal">nuclear localization signals</a> that direct them to the nucleus. But, for many transcription factors, this is a key point in their regulation. Important classes of transcription factors such as some <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptors</a> must first bind a <a href="https://en.wikipedia.org/wiki/Ligand_(biochemistry)" title="Ligand (biochemistry)">ligand</a> while in the cytoplasm before they can relocate to the nucleus.
</p>
<h3><span class="mw-headline" id="Activation">Activation</span></h3><p>Transcription factors may be activated (or deactivated) through their <b>signal-sensing domain</b> by a number of mechanisms including:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Ligand_(biochemistry)" title="Ligand (biochemistry)">ligand</a>
binding – Not only is ligand binding able to influence where a
transcription factor is located within a cell but ligand binding can
also affect whether the transcription factor is in an active state and
capable of binding DNA or other cofactors (see, for example, <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptors</a>).</li><li><a href="https://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation">phosphorylation</a> – Many transcription factors such as <a href="https://en.wikipedia.org/wiki/STAT_protein" title="STAT protein">STAT proteins</a> must be <a href="https://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation">phosphorylated</a> before they can bind DNA.</li><li>interaction with other transcription factors (<i>e.g.</i>, homo- or hetero-<a href="https://en.wikipedia.org/wiki/Protein_dimer" title="Protein dimer">dimerization</a>) or <a href="https://en.wikipedia.org/wiki/Transcription_coregulator" title="Transcription coregulator">coregulatory</a> proteins</li></ul>
<h3><span class="mw-headline" id="Accessibility_of_DNA-binding_site">Accessibility of DNA-binding site</span></h3><p>In eukaryotes, DNA is organized with the help of <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histones</a> into compact particles called <a href="https://en.wikipedia.org/wiki/Nucleosome" title="Nucleosome">nucleosomes</a>,
where sequences of about 147 DNA base pairs make ~1.65 turns around
histone protein octamers. DNA within nucleosomes is inaccessible to many
transcription factors. Some transcription factors, so-called <a href="https://en.wikipedia.org/wiki/Pioneer_factor" title="Pioneer factor">pioneer factors</a>
are still able to bind their DNA binding sites on the nucleosomal DNA.
For most other transcription factors, the nucleosome should be actively
unwound by molecular motors such as <a href="https://en.wikipedia.org/wiki/Chromatin_remodeling" title="Chromatin remodeling">chromatin remodelers</a>.
Alternatively, the nucleosome can be partially unwrapped by thermal
fluctuations, allowing temporary access to the transcription factor
binding site. In many cases, a transcription factor needs to <a href="https://en.wikipedia.org/wiki/Competitive_inhibition" title="Competitive inhibition">compete for binding</a> to its DNA binding site with other transcription factors and histones or non-histone chromatin proteins.
Pairs of transcription factors and other proteins can play
antagonistic roles (activator versus repressor) in the regulation of the
same <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">gene</a>.
</p>
<h3><span id="Availability_of_other_cofactors.2Ftranscription_factors"></span><span class="mw-headline" id="Availability_of_other_cofactors/transcription_factors">Availability of other cofactors/transcription factors</span></h3><p>Most
transcription factors do not work alone. Many large TF families form
complex homotypic or heterotypic interactions through dimerization.
For gene transcription to occur, a number of transcription factors must
bind to DNA regulatory sequences. This collection of transcription
factors, in turn, recruit intermediary proteins such as <a href="https://en.wikipedia.org/wiki/Transcription_coregulator" title="Transcription coregulator">cofactors</a> that allow efficient recruitment of the <a href="https://en.wikipedia.org/wiki/Transcription_preinitiation_complex" title="Transcription preinitiation complex">preinitiation complex</a> and <a href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a>.
Thus, for a single transcription factor to initiate transcription, all
of these other proteins must also be present, and the transcription
factor must be in a state where it can bind to them if necessary.
Cofactors are proteins that modulate the effects of transcription
factors. Cofactors are interchangeable between specific gene promoters;
the protein complex that occupies the promoter DNA and the amino acid
sequence of the cofactor determine its spatial conformation. For
example, certain steroid receptors can exchange cofactors with <a href="https://en.wikipedia.org/wiki/NF-%CE%BAB" title="NF-κB">NF-κB</a>,
which is a switch between inflammation and cellular differentiation;
thereby steroids can affect the inflammatory response and function of
certain tissues.
</p>
<h3><span class="mw-headline" id="Interaction_with_methylated_cytosine">Interaction with methylated cytosine</span></h3><p>Transcription
factors and methylated cytosines in DNA both have major roles in
regulating gene expression. (Methylation of cytosine in DNA primarily
occurs where cytosine is followed by guanine in the 5' to 3' DNA
sequence, a <a href="https://en.wikipedia.org/wiki/CpG_site" title="CpG site">CpG site</a>.) Methylation of CpG sites in a promoter region of a gene usually represses gene transcription, while methylation of CpGs in the body of a gene increases expression. <a href="https://en.wikipedia.org/wiki/TET_enzymes" title="TET enzymes">TET enzymes</a>
play a central role in demethylation of methylated cytosines.
Demethylation of CpGs in a gene promoter by TET enzyme activity
increases transcription of the gene.
</p><p>The <a href="https://en.wikipedia.org/wiki/DNA_binding_site" title="DNA binding site">DNA binding sites</a> of 519 transcription factors were evaluated.
Of these, 169 transcription factors (33%) did not have CpG
dinucleotides in their binding sites, and 33 transcription factors (6%)
could bind to a CpG-containing motif but did not display a preference
for a binding site with either a methylated or unmethylated CpG. There
were 117 transcription factors (23%) that were inhibited from binding to
their binding sequence if it contained a methylated CpG site, 175
transcription factors (34%) that had enhanced binding if their binding
sequence had a methylated CpG site, and 25 transcription factors (5%)
were either inhibited or had enhanced binding depending on where in the
binding sequence the methylated CpG was located.
</p><p>TET enzymes do not specifically bind to methylcytosine except when recruited (see <a href="https://en.wikipedia.org/wiki/DNA_demethylation" title="DNA demethylation">DNA demethylation</a>). Multiple transcription factors important in cell differentiation and lineage specification, including <a href="https://en.wikipedia.org/wiki/Homeobox_protein_NANOG" title="Homeobox protein NANOG">NANOG</a>, <a href="https://en.wikipedia.org/wiki/SALL4" title="SALL4">SALL4</a>A, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/WT1" title="WT1">WT1</a>, <a href="https://en.wikipedia.org/wiki/EBF1" title="EBF1">EBF1</a>, <a href="https://en.wikipedia.org/wiki/SPI1" title="SPI1">PU.1</a>, and <a href="https://en.wikipedia.org/wiki/TCF3" title="TCF3">E2A</a>,
have been shown to recruit TET enzymes to specific genomic loci
(primarily enhancers) to act on methylcytosine (mC) and convert it to
hydroxymethylcytosine hmC (and in most cases marking them for subsequent
complete demethylation to cytosine). TET-mediated conversion of mC to hmC appears to disrupt the binding of 5mC-binding proteins including <a href="https://en.wikipedia.org/wiki/MECP2" title="MECP2">MECP2</a> and MBD (<a href="https://en.wikipedia.org/wiki/Methyl-CpG-binding_domain" title="Methyl-CpG-binding domain">Methyl-CpG-binding domain</a>)
proteins, facilitating nucleosome remodeling and the binding of
transcription factors, thereby activating transcription of those genes.
<a href="https://en.wikipedia.org/wiki/EGR1" title="EGR1">EGR1</a> is an important transcription factor in <a href="https://en.wikipedia.org/wiki/Memory" title="Memory">memory</a> formation. It has an essential role in <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuron</a> <a href="https://en.wikipedia.org/wiki/Epigenetics" title="Epigenetics">epigenetic</a> reprogramming. The transcription factor <a href="https://en.wikipedia.org/wiki/EGR1" title="EGR1">EGR1</a> recruits the <a href="https://en.wikipedia.org/wiki/Tet_methylcytosine_dioxygenase_1" title="Tet methylcytosine dioxygenase 1">TET1</a> protein that initiates a pathway of <a href="https://en.wikipedia.org/wiki/DNA_demethylation" title="DNA demethylation">DNA demethylation</a>.
EGR1, together with TET1, is employed in programming the distribution
of methylation sites on brain DNA during brain development and in <a href="https://en.wikipedia.org/wiki/Learning" title="Learning">learning</a> (see <a href="https://en.wikipedia.org/wiki/Epigenetics_in_learning_and_memory" title="Epigenetics in learning and memory">Epigenetics in learning and memory</a>).
</p>
<h2><span class="mw-headline" id="Structure">Structure</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Transcription_factor_schematic_2.png"><img class="mw-file-element" data-file-height="353" data-file-width="2126" height="67" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Transcription_factor_schematic_2.png/390px-Transcription_factor_schematic_2.png" width="400" /></a><figcaption>Schematic
diagram of the amino acid sequence (amino terminus to the left and
carboxylic acid terminus to the right) of a prototypical transcription
factor that contains (1) a DNA-binding domain (DBD), (2) signal-sensing
domain (SSD), and Activation domain (AD). The order of placement and the
number of domains may differ in various types of transcription factors.
In addition, the transactivation and signal-sensing functions are
frequently contained within the same domain.</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:LacI_Dimer_Structure_Annotated.png"><img class="mw-file-element" data-file-height="890" data-file-width="979" height="364" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/cd/LacI_Dimer_Structure_Annotated.png/280px-LacI_Dimer_Structure_Annotated.png" width="400" /></a><figcaption><b>Domain architecture example: <a href="https://en.wikipedia.org/wiki/Lac_repressor" title="Lac repressor">Lactose Repressor (LacI)</a></b>. The N-terminal DNA binding domain (labeled) of the <a href="https://en.wikipedia.org/wiki/Lac_repressor" title="Lac repressor"><i>lac</i> repressor</a> binds its target DNA sequence (gold) in the major groove using a <a href="https://en.wikipedia.org/wiki/Helix-turn-helix" title="Helix-turn-helix">helix-turn-helix</a>
motif. Effector molecule binding (green) occurs in the regulatory
domain (labeled). This triggers an allosteric response mediated by the
linker region (labeled).</figcaption></figure>
<p>Transcription factors are modular in structure and contain the following <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_domains" title="Protein domains">domains</a>:
</p>
<ul><li><b><a href="https://en.wikipedia.org/wiki/DNA-binding_domain" title="DNA-binding domain">DNA-binding domain</a></b> (<b>DBD</b>), which attaches to specific sequences of DNA (<a href="https://en.wikipedia.org/wiki/Enhancer_(genetics)" title="Enhancer (genetics)">enhancer</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Promoter_(biology)" title="Promoter (biology)">promoter</a>. Necessary component for all vectors. Used to drive transcription of the vector's transgene <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Promoter_(biology)" title="Promoter (biology)">promoter</a> sequences) adjacent to regulated genes. DNA sequences that bind transcription factors are often referred to as <b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hormone_response_element" title="Hormone response element">response elements</a></b>.</li><li><b><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Trans-activating_domain" title="Trans-activating domain">Activation domain</a></b> (<b>AD</b>), which contains binding sites for other proteins such as <a href="https://en.wikipedia.org/wiki/Transcription_coregulator" title="Transcription coregulator">transcription coregulators</a>. These binding sites are frequently referred to as <b>activation functions</b> (<b>AFs</b>), <b>Transactivation domain</b> (<b>TAD</b>) or <b>Trans-activating domain</b> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Trans-activating_domain" title="Trans-activating domain">TAD</a>, not to be confused with topologically associating domain (<a href="https://en.wikipedia.org/wiki/Topologically_associating_domain" title="Topologically associating domain">TAD</a>).</li><li>An optional <b>signal-sensing domain</b> (<b>SSD</b>) (<i>e.g.</i>, a
ligand-binding domain), which senses external signals and, in response,
transmits these signals to the rest of the transcription complex,
resulting in up- or down-regulation of gene expression. Also, the DBD
and signal-sensing domains may reside on separate proteins that
associate within the transcription complex to regulate gene expression.</li></ul>
<h3><span class="mw-headline" id="DNA-binding_domain">DNA-binding domain</span></h3><figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Transcription_factors_DNA_binding_sites.svg"><img class="mw-file-element" data-file-height="645" data-file-width="392" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d1/Transcription_factors_DNA_binding_sites.svg/220px-Transcription_factors_DNA_binding_sites.svg.png" width="243" /></a><figcaption>DNA contacts of different types of <a href="https://en.wikipedia.org/wiki/DNA-binding_domain" title="DNA-binding domain">DNA-binding domains</a> of transcription factors</figcaption></figure>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/DNA-binding_domain" title="DNA-binding domain">DNA-binding domain</a></div>
<p>The portion (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein_domains" title="Protein domains">domain</a>)
of the transcription factor that binds DNA is called its DNA-binding
domain. Below is a partial list of some of the major families of
DNA-binding domains/transcription factors:
</p>
<table class="wikitable">
<tbody><tr>
<th style="width: 300pt;">Family
</th>
<th style="width: 100pt;"><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>
</th>
<th style="width: 100pt;"><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a>
</th>
<th style="width: 100pt;"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a>
</th></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_helix-loop-helix" title="Basic helix-loop-helix">basic helix-loop-helix</a>
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR001092" rel="nofollow">IPR001092</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00010" rel="nofollow">PF00010</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=47460" rel="nofollow">47460</a></i>
</td></tr>
<tr>
<td>basic-leucine zipper (<a href="https://en.wikipedia.org/wiki/BZIP_domain" title="BZIP domain">bZIP</a>)
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR004827" rel="nofollow">IPR004827</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00170" rel="nofollow">PF00170</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=57959" rel="nofollow">57959</a></i>
</td></tr>
<tr>
<td>C-terminal effector domain of the bipartite response regulators
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR001789" rel="nofollow">IPR001789</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00072" rel="nofollow">PF00072</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=46894" rel="nofollow">46894</a></i>
</td></tr>
<tr>
<td>AP2/ERF/GCC box
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR001471" rel="nofollow">IPR001471</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00847" rel="nofollow">PF00847</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=54176" rel="nofollow">54176</a></i>
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Helix-turn-helix" title="Helix-turn-helix">helix-turn-helix</a>
</td>
<td>
<br /></td>
<td>
<br /></td>
<td>
<br /></td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Homeodomain_fold" title="Homeodomain fold">homeodomain proteins</a>, which are encoded by <a href="https://en.wikipedia.org/wiki/Homeobox" title="Homeobox">homeobox</a> genes, are transcription factors. Homeodomain proteins play critical roles in the regulation of <a href="https://en.wikipedia.org/wiki/Developmental_biology" title="Developmental biology">development</a>.
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR009057" rel="nofollow">IPR009057</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00046" rel="nofollow">PF00046</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=46689" rel="nofollow">46689</a></i>
</td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/CI_protein" title="CI protein">lambda repressor</a>-like
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR010982" rel="nofollow">IPR010982</a></i>
</td>
<td>
<br /></td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=47413" rel="nofollow">47413</a></i>
</td></tr>
<tr>
<td>srf-like (<a href="https://en.wikipedia.org/wiki/Serum_response_factor" title="Serum response factor">serum response factor</a>)
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR002100" rel="nofollow">IPR002100</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00319" rel="nofollow">PF00319</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=55455" rel="nofollow">55455</a></i>
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Pax_genes" title="Pax genes">paired box</a>
</td>
<td>
<br /></td>
<td>
<br /></td>
<td>
<br /></td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Winged_helix" title="Winged helix">winged helix</a>
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR013196" rel="nofollow">IPR013196</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF08279" rel="nofollow">PF08279</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=46785" rel="nofollow">46785</a></i>
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Zinc_finger" title="Zinc finger">zinc fingers</a>
</td>
<td>
<br /></td>
<td>
<br /></td>
<td>
<br /></td></tr>
<tr>
<td>* multi-domain Cys<sub>2</sub>His<sub>2</sub> zinc fingers
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR007087" rel="nofollow">IPR007087</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00096" rel="nofollow">PF00096</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=57667" rel="nofollow">57667</a></i>
</td></tr>
<tr>
<td>* Zn<sub>2</sub>/Cys<sub>6</sub>
</td>
<td>
<br /></td>
<td>
<br /></td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=57701" rel="nofollow">57701</a></i>
</td></tr>
<tr>
<td>* Zn<sub>2</sub>/Cys<sub>8</sub> <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptor</a> zinc finger
</td>
<td><a href="https://en.wikipedia.org/wiki/InterPro" title="InterPro">InterPro</a>: <i><a class="external text" href="https://www.ebi.ac.uk/interpro/entry/IPR001628" rel="nofollow">IPR001628</a></i>
</td>
<td><a href="https://en.wikipedia.org/wiki/Pfam" title="Pfam">Pfam</a> <a class="external text" href="https://www.ebi.ac.uk/interpro/entry/pfam/PF00105" rel="nofollow">PF00105</a>
</td>
<td><i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Structural_Classification_of_Proteins" title="Structural Classification of Proteins">SCOP</a> <a class="external text" href="http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?sunid=57716" rel="nofollow">57716</a></i>
</td></tr></tbody></table>
<h3><span class="mw-headline" id="Response_elements">Response elements</span></h3><p>The DNA sequence that a transcription factor binds to is called a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_factor-binding_site" title="Transcription factor-binding site">transcription factor-binding site</a> or <a href="https://en.wikipedia.org/wiki/Response_element" title="Response element">response element</a>.
</p><p>Transcription factors interact with their binding sites using a combination of <a href="https://en.wikipedia.org/wiki/Coulomb%27s_law" title="Coulomb's law">electrostatic</a> (of which <a href="https://en.wikipedia.org/wiki/Hydrogen_bond" title="Hydrogen bond">hydrogen bonds</a> are a special case) and <a href="https://en.wikipedia.org/wiki/Van_der_Waals_force" title="Van der Waals force">Van der Waals forces</a>.
Due to the nature of these chemical interactions, most transcription
factors bind DNA in a sequence specific manner. However, not all <a href="https://en.wikipedia.org/wiki/Base_pair" title="Base pair">bases</a>
in the transcription factor-binding site may actually interact with the
transcription factor. In addition, some of these interactions may be
weaker than others. Thus, transcription factors do not bind just one
sequence but are capable of binding a subset of closely related
sequences, each with a different strength of interaction.
</p><p>For example, although the <a href="https://en.wikipedia.org/wiki/Consensus_sequence" title="Consensus sequence">consensus binding site</a> for the <a href="https://en.wikipedia.org/wiki/TATA-binding_protein" title="TATA-binding protein">TATA-binding protein</a> (TBP) is TATAAAA, the TBP transcription factor can also bind similar sequences such as TATATAT or TATATAA.
</p><p>Because transcription factors can bind a set of related sequences
and these sequences tend to be short, potential transcription factor
binding sites can occur by chance if the DNA sequence is long enough.
It is unlikely, however, that a transcription factor will bind all
compatible sequences in the <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> of the <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cell</a>. Other constraints, such as DNA accessibility in the cell or availability of <a href="https://en.wikipedia.org/wiki/Cofactor_(biochemistry)" title="Cofactor (biochemistry)">cofactors</a>
may also help dictate where a transcription factor will actually bind.
Thus, given the genome sequence, it is still difficult to predict where
a transcription factor will actually bind in a living cell.
</p><p>Additional recognition specificity, however, may be obtained
through the use of more than one DNA-binding domain (for example tandem
DBDs in the same transcription factor or through dimerization of two
transcription factors) that bind to two or more adjacent sequences of
DNA.
</p>
<h2><span class="mw-headline" id="Clinical_significance">Clinical significance</span></h2><p>Transcription
factors are of clinical significance for at least two reasons: (1)
mutations can be associated with specific diseases, and (2) they can be
targets of medications.
</p>
<h3><span class="mw-headline" id="Disorders">Disorders</span></h3><p>Due
to their important roles in development, intercellular signaling, and
cell cycle, some human diseases have been associated with <a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">mutations</a> in transcription factors.
</p><p>Many transcription factors are either <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumor_suppressor" title="Tumor suppressor">tumor suppressors</a> or <a href="https://en.wikipedia.org/wiki/Oncogene" title="Oncogene">oncogenes</a>,
and, thus, mutations or aberrant regulation of them is associated with
cancer. Three groups of transcription factors are known to be important
in human cancer: (1) the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/NF-kappaB" title="NF-kappaB">NF-kappaB</a> and <a href="https://en.wikipedia.org/wiki/AP-1_transcription_factor" title="AP-1 transcription factor">AP-1</a> families, (2) the <a href="https://en.wikipedia.org/wiki/STAT_protein" title="STAT protein">STAT</a> family and (3) the <a href="https://en.wikipedia.org/wiki/Steroid_hormone_receptor" title="Steroid hormone receptor">steroid receptors</a>.
</p><p>Below are a few of the better-studied examples:
</p>
<table class="wikitable">
<tbody><tr>
<th>Condition
</th>
<th>Description
</th>
<th>Locus
</th></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Rett_syndrome" title="Rett syndrome">Rett syndrome</a>
</td>
<td>Mutations in the <a href="https://en.wikipedia.org/wiki/MECP2" title="MECP2">MECP2</a> transcription factor are associated with <a href="https://en.wikipedia.org/wiki/Rett_syndrome" title="Rett syndrome">Rett syndrome</a>, a neurodevelopmental disorder.
</td>
<td>Xq28
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">Diabetes</a>
</td>
<td>A rare form of <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a> called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MODY" title="MODY">MODY</a> (Maturity onset diabetes of the young) can be caused by mutations in <a href="https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors" title="Hepatocyte nuclear factors">hepatocyte nuclear factors</a> (HNFs) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pdx1" title="Pdx1">insulin promoter factor-1</a> (IPF1/Pdx1).
</td>
<td>multiple
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Apraxia_of_speech#Childhood_apraxia_of_speech" title="Apraxia of speech">Developmental verbal dyspraxia</a>
</td>
<td>Mutations in the <a href="https://en.wikipedia.org/wiki/FOXP2" title="FOXP2">FOXP2</a> transcription factor are associated with <a href="https://en.wikipedia.org/wiki/Apraxia_of_speech#Childhood_apraxia_of_speech" title="Apraxia of speech">developmental verbal dyspraxia</a>, a disease in which individuals are unable to produce the finely coordinated movements required for speech.
</td>
<td>7q31
</td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autoimmune_diseases" title="Autoimmune diseases">Autoimmune diseases</a>
</td>
<td>Mutations in the <a href="https://en.wikipedia.org/wiki/FOXP3" title="FOXP3">FOXP3</a> transcription factor cause a rare form of <a href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">autoimmune disease</a> called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/IPEX_(syndrome)" title="IPEX (syndrome)">IPEX</a>.
</td>
<td>Xp11.23-q13.3
</td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Li-Fraumeni_syndrome" title="Li-Fraumeni syndrome">Li-Fraumeni syndrome</a>
</td>
<td>Caused by mutations in the tumor suppressor <a class="mw-redirect" href="https://en.wikipedia.org/wiki/P53_(protein)" title="P53 (protein)">p53</a>.
</td>
<td>17p13.1
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Breast_cancer" title="Breast cancer">Breast cancer</a>
</td>
<td>The <a href="https://en.wikipedia.org/wiki/STAT_protein" title="STAT protein">STAT</a> family is relevant to <a href="https://en.wikipedia.org/wiki/Breast_cancer" title="Breast cancer">breast cancer</a>.
</td>
<td>multiple
</td></tr>
<tr>
<td>Multiple cancers
</td>
<td>The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/HOX_gene" title="HOX gene">HOX</a> family are involved in a variety of cancers.
</td>
<td>multiple
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Osteoarthritis" title="Osteoarthritis">Osteoarthritis</a>
</td>
<td><a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">Mutation</a> or reduced activity of <a href="https://en.wikipedia.org/wiki/SOX9" title="SOX9">SOX9</a>
</td>
<td>
<br /></td></tr></tbody></table>
<h3><span class="mw-headline" id="Potential_drug_targets">Potential drug targets</span></h3><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Therapeutic_gene_modulation" title="Therapeutic gene modulation">Therapeutic gene modulation</a></div>
<p>Approximately 10% of currently prescribed drugs directly target the <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptor</a> class of transcription factors. Examples include <a href="https://en.wikipedia.org/wiki/Tamoxifen" title="Tamoxifen">tamoxifen</a> and <a href="https://en.wikipedia.org/wiki/Bicalutamide" title="Bicalutamide">bicalutamide</a> for the treatment of <a href="https://en.wikipedia.org/wiki/Breast_cancer" title="Breast cancer">breast</a> and <a href="https://en.wikipedia.org/wiki/Prostate_cancer" title="Prostate cancer">prostate cancer</a>, respectively, and various types of <a href="https://en.wikipedia.org/wiki/Glucocorticoid#Anti-inflammatory" title="Glucocorticoid">anti-inflammatory</a> and <a href="https://en.wikipedia.org/wiki/Anabolic_steroid" title="Anabolic steroid">anabolic</a> <a href="https://en.wikipedia.org/wiki/Steroid" title="Steroid">steroids</a>. In addition, transcription factors are often indirectly modulated by drugs through <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Signaling_cascade" title="Signaling cascade">signaling cascades</a>. It might be possible to directly target other less-explored transcription factors such as <a href="https://en.wikipedia.org/wiki/NF-%CE%BAB#As_a_drug_target" title="NF-κB">NF-κB</a> with drugs. Transcription factors outside the nuclear receptor family are thought to be more difficult to target with <a href="https://en.wikipedia.org/wiki/Small_molecule" title="Small molecule">small molecule</a> therapeutics since it is not clear that they are <a href="https://en.wikipedia.org/wiki/Drug_design#Rational_drug_discovery" title="Drug design">"drugable"</a> but progress has been made on Pax2 and the <a href="https://en.wikipedia.org/wiki/Notch_signaling_pathway" title="Notch signaling pathway">notch</a> pathway.
</p>
<h2><span class="mw-headline" id="Role_in_evolution">Role in evolution</span></h2><div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Evolutionary_developmental_biology" title="Evolutionary developmental biology">Evolutionary developmental biology</a></div>
<p>Gene duplications have played a crucial role in the <a href="https://en.wikipedia.org/wiki/Evolution" title="Evolution">evolution</a>
of species. This applies particularly to transcription factors. Once
they occur as duplicates, accumulated mutations encoding for one copy
can take place without negatively affecting the regulation of downstream
targets. However, changes of the DNA binding specificities of the
single-copy <a href="https://en.wikipedia.org/wiki/Leafy" title="Leafy">Leafy</a>
transcription factor, which occurs in most land plants, have recently
been elucidated. In that respect, a single-copy transcription factor can
undergo a change of specificity through a promiscuous intermediate
without losing function. Similar mechanisms have been proposed in the
context of all alternative <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phylogenetic" title="Phylogenetic">phylogenetic</a> hypotheses, and the role of transcription factors in the evolution of all species.
</p>
<h2><span class="mw-headline" id="Role_in_biocontrol_activity">Role in biocontrol activity</span></h2><p>The transcription factors have a role in <a href="https://en.wikipedia.org/wiki/Resistance_(ecology)" title="Resistance (ecology)">resistance</a> activity which is important for successful <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biocontrol" title="Biocontrol">biocontrol</a> activity. The resistant to <a href="https://en.wikipedia.org/wiki/Oxidative_stress" title="Oxidative stress">oxidative stress</a> and alkaline pH sensing were contributed from the transcription factor Yap1 and Rim101 of the <i><a href="https://en.wikipedia.org/wiki/Papiliotrema" title="Papiliotrema">Papiliotrema terrestris</a></i> LS28 as molecular tools revealed an understanding of the genetic mechanisms underlying the biocontrol activity which supports <a href="https://en.wikipedia.org/wiki/Disease_management_(agriculture)" title="Disease management (agriculture)">disease management</a> programs based on biological and integrated control.
</p>
<h2><span class="mw-headline" id="Analysis">Analysis</span></h2><p>There are different technologies available to analyze transcription factors. On the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genomic" title="Genomic">genomic</a> level, DNA-<a href="https://en.wikipedia.org/wiki/Sequencing" title="Sequencing">sequencing</a> and database research are commonly used. The protein version of the transcription factor is detectable by using specific <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibodies" title="Antibodies">antibodies</a>. The sample is detected on a <a href="https://en.wikipedia.org/wiki/Western_blot" title="Western blot">western blot</a>. By using <a href="https://en.wikipedia.org/wiki/Electrophoretic_mobility_shift_assay" title="Electrophoretic mobility shift assay">electrophoretic mobility shift assay</a> (EMSA), the activation profile of transcription factors can be detected. A <a href="https://en.wikipedia.org/wiki/Multiplex_(assay)" title="Multiplex (assay)">multiplex</a>
approach for activation profiling is a TF chip system where several
different transcription factors can be detected in parallel.
</p><p>The most commonly used method for identifying transcription factor binding sites is <a href="https://en.wikipedia.org/wiki/Chromatin_immunoprecipitation" title="Chromatin immunoprecipitation">chromatin immunoprecipitation</a> (ChIP). This technique relies on chemical fixation of chromatin with <a href="https://en.wikipedia.org/wiki/Formaldehyde" title="Formaldehyde">formaldehyde</a>, followed by co-precipitation of DNA and the transcription factor of interest using an <a href="https://en.wikipedia.org/wiki/Antibody" title="Antibody">antibody</a> that specifically targets that protein. The DNA sequences can then be identified by microarray or high-throughput sequencing (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/ChIP-sequencing" title="ChIP-sequencing">ChIP-seq</a>) to determine transcription factor binding sites. If no antibody is available for the protein of interest, <a href="https://en.wikipedia.org/wiki/DNA_adenine_methyltransferase_identification" title="DNA adenine methyltransferase identification">DamID</a> may be a convenient alternative.
</p>
<h2><span class="mw-headline" id="Classes">Classes</span></h2><p>As
described in more detail below, transcription factors may be classified
by their (1) mechanism of action, (2) regulatory function, or (3)
sequence homology (and hence structural similarity) in their DNA-binding
domains.
</p>
<h3><span class="mw-headline" id="Mechanistic">Mechanistic</span></h3><p>There are two mechanistic classes of transcription factors:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/General_transcription_factor" title="General transcription factor">General transcription factors</a> are involved in the formation of a <a href="https://en.wikipedia.org/wiki/Transcription_preinitiation_complex" title="Transcription preinitiation complex">preinitiation complex</a>. The most common are abbreviated as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIA" title="TFIIA">TFIIA</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIB" title="TFIIB">TFIIB</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIID" title="TFIID">TFIID</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIE" title="TFIIE">TFIIE</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIF" title="TFIIF">TFIIF</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIH" title="TFIIH">TFIIH</a>. They are ubiquitous and interact with the core promoter region surrounding the transcription start site(s) of all <a href="https://en.wikipedia.org/wiki/Class_II_gene" title="Class II gene">class II genes</a>.</li><li><b>Upstream transcription factors</b> are proteins that bind
somewhere upstream of the initiation site to stimulate or repress
transcription. These are roughly synonymous with <b>specific transcription factors</b>, because they vary considerably depending on what <a href="https://en.wikipedia.org/wiki/Recognition_sequence" title="Recognition sequence">recognition sequences</a> are present in the proximity of the gene.</li></ul>
<table border="1">
<tbody><tr>
<th colspan="4">Examples of specific transcription factors
</th></tr>
<tr>
<th>Factor</th>
<th>Structural type</th>
<th><a href="https://en.wikipedia.org/wiki/Recognition_sequence" title="Recognition sequence">Recognition sequence</a></th>
<th>Binds as
</th></tr>
<tr>
<th><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sp1_transcription_factor" title="Sp1 transcription factor">SP1</a>
</th>
<td><a href="https://en.wikipedia.org/wiki/Zinc_finger" title="Zinc finger">Zinc finger</a></td>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Five_prime_end" title="Five prime end">5'</a>-GGGCGG-<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Three_prime_end" title="Three prime end">3'</a></td>
<td>Monomer
</td></tr>
<tr>
<th><a href="https://en.wikipedia.org/wiki/AP-1_transcription_factor" title="AP-1 transcription factor">AP-1</a>
</th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_zipper" title="Basic zipper">Basic zipper</a></td>
<td>5'-TGA(G/C)TCA-3'</td>
<td>Dimer
</td></tr>
<tr>
<th><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ccaat-enhancer-binding_proteins" title="Ccaat-enhancer-binding proteins">C/EBP</a>
</th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_zipper" title="Basic zipper">Basic zipper</a></td>
<td>5'-ATTGCGCAAT-3'</td>
<td>Dimer
</td></tr>
<tr>
<th><a href="https://en.wikipedia.org/wiki/Heat_shock_factor" title="Heat shock factor">Heat shock factor</a>
</th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_zipper" title="Basic zipper">Basic zipper</a></td>
<td>5'-XGAAX-3'</td>
<td>Trimer
</td></tr>
<tr>
<th><a href="https://en.wikipedia.org/wiki/ATF/CREB" title="ATF/CREB">ATF/CREB</a>
</th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_zipper" title="Basic zipper">Basic zipper</a></td>
<td>5'-TGACGTCA-3'</td>
<td>Dimer
</td></tr>
<tr>
<th><a href="https://en.wikipedia.org/wiki/Myc" title="Myc">c-Myc</a>
</th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Basic_helix-loop-helix" title="Basic helix-loop-helix">Basic helix-loop-helix</a>
</td>
<td>5'-CACGTG-3'</td>
<td>Dimer
</td></tr>
<tr>
<th><a href="https://en.wikipedia.org/wiki/POU2F1" title="POU2F1">Oct-1</a>
</th>
<td><a href="https://en.wikipedia.org/wiki/Helix-turn-helix" title="Helix-turn-helix">Helix-turn-helix</a></td>
<td>5'-ATGCAAAT-3'</td>
<td>Monomer
</td></tr>
<tr>
<th><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nuclear_factor_1" title="Nuclear factor 1">NF-1</a>
</th>
<td>Novel</td>
<td>5'-TTGGCXXXXXGCCAA-3'</td>
<td>Dimer
</td></tr>
<tr>
<td colspan="4">(G/C) = G or C <br /> X = <a href="https://en.wikipedia.org/wiki/Adenine" title="Adenine">A</a>, <a href="https://en.wikipedia.org/wiki/Thymine" title="Thymine">T</a>, <a href="https://en.wikipedia.org/wiki/Guanine" title="Guanine">G</a> or <a href="https://en.wikipedia.org/wiki/Cytosine" title="Cytosine">C</a>
</td></tr></tbody></table>
<h3><span class="mw-headline" id="Functional">Functional</span></h3><p>Transcription factors have been classified according to their regulatory function:
</p>
<ul><li>I. <b>constitutively active</b> – present in all cells at all times – <a href="https://en.wikipedia.org/wiki/General_transcription_factor" title="General transcription factor">general transcription factors</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sp1_transcription_factor" title="Sp1 transcription factor">Sp1</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nuclear_factor_1" title="Nuclear factor 1">NF1</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ccaat-enhancer-binding_proteins" title="Ccaat-enhancer-binding proteins">CCAAT</a></li><li>II. <b>conditionally active</b> – requires activation
<ul><li>II.A <b>developmental</b> (cell specific) – expression is tightly controlled, but, once expressed, require no additional activation – <a href="https://en.wikipedia.org/wiki/GATA_transcription_factor" title="GATA transcription factor">GATA</a>, <a href="https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors" title="Hepatocyte nuclear factors">HNF</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PIT-1" title="PIT-1">PIT-1</a>, <a href="https://en.wikipedia.org/wiki/MyoD" title="MyoD">MyoD</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myf5" title="Myf5">Myf5</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hox_(gene)" title="Hox (gene)">Hox</a>, <a href="https://en.wikipedia.org/wiki/Winged-helix_transcription_factors" title="Winged-helix transcription factors">Winged Helix</a></li><li>II.B <b>signal-dependent</b> – requires external signal for activation
<ul><li>II.B.1 <b>extracellular ligand (<a href="https://en.wikipedia.org/wiki/Endocrine_system" title="Endocrine system">endocrine</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Paracrine_signalling" title="Paracrine signalling">paracrine</a>)-dependent</b> – <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptors</a></li><li>II.B.2 <b>intracellular ligand (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autocrine_signalling" title="Autocrine signalling">autocrine</a>)-dependent</b> – activated by small intracellular molecules – <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sterol_regulatory_element_binding_protein" title="Sterol regulatory element binding protein">SREBP</a>, <a href="https://en.wikipedia.org/wiki/P53" title="P53">p53</a>, orphan nuclear receptors</li><li>II.B.3 <b>cell membrane receptor-dependent</b> – second messenger signaling cascades resulting in the phosphorylation of the transcription factor
<ul><li>II.B.3.a <b>resident nuclear factors</b> – reside in the nucleus regardless of activation state – <a href="https://en.wikipedia.org/wiki/CREB" title="CREB">CREB</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/AP-1_(transcription_factor)" title="AP-1 (transcription factor)">AP-1</a>, <a href="https://en.wikipedia.org/wiki/Mef2" title="Mef2">Mef2</a></li><li>II.B.3.b <b>latent cytoplasmic factors</b> – inactive form reside in the cytoplasm, but, when activated, are translocated into the nucleus – <a href="https://en.wikipedia.org/wiki/STAT_protein" title="STAT protein">STAT</a>, <a href="https://en.wikipedia.org/wiki/R-SMAD" title="R-SMAD">R-SMAD</a>, <a href="https://en.wikipedia.org/wiki/NF-%CE%BAB" title="NF-κB">NF-κB</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Notch_signaling" title="Notch signaling">Notch</a>, <a href="https://en.wikipedia.org/wiki/Tubby_protein" title="Tubby protein">TUBBY</a>, <a href="https://en.wikipedia.org/wiki/NFAT" title="NFAT">NFAT</a></li></ul></li></ul></li></ul></li></ul>
<h3><span class="mw-headline" id="Structural">Structural</span></h3><p>Transcription factors are often classified based on the <a href="https://en.wikipedia.org/wiki/Sequence_homology#Homology_of_sequences_in_genetics" title="Sequence homology">sequence similarity</a> and hence the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tertiary_structure" title="Tertiary structure">tertiary structure</a> of their DNA-binding domains:
</p>
<ul><li>1 Superclass: Basic Domains
<ul><li>1.1 Class: <a href="https://en.wikipedia.org/wiki/Leucine_zipper" title="Leucine zipper">Leucine zipper</a> factors (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/BZIP" title="BZIP">bZIP</a>)
<ul><li>1.1.1 Family: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/AP-1_(transcription_factor)" title="AP-1 (transcription factor)">AP-1</a>(-like) components; includes (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/C-Fos" title="C-Fos">c-Fos</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/C-Jun" title="C-Jun">c-Jun</a>)</li><li>1.1.2 Family: <a href="https://en.wikipedia.org/wiki/CREB" title="CREB">CREB</a></li><li>1.1.3 Family: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ccaat-enhancer-binding_proteins" title="Ccaat-enhancer-binding proteins">C/EBP</a>-like factors</li><li>1.1.4 Family: bZIP / <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PAR_(transcription_factor)" title="PAR (transcription factor)">PAR</a></li><li>1.1.5 Family: Plant G-box binding factors</li><li>1.1.6 Family: ZIP only</li></ul></li><li>1.2 Class: Helix-loop-helix factors (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/BHLH" title="BHLH">bHLH</a>)
<ul><li>1.2.1 Family: Ubiquitous (class A) factors</li><li>1.2.2 Family: Myogenic transcription factors (<a href="https://en.wikipedia.org/wiki/MyoD" title="MyoD">MyoD</a>)</li><li>1.2.3 Family: Achaete-Scute</li><li>1.2.4 Family: Tal/Twist/Atonal/Hen</li></ul></li><li>1.3 Class: Helix-loop-helix / leucine zipper factors (<a href="https://en.wikipedia.org/wiki/Basic_helix-loop-helix_leucine_zipper_transcription_factors" title="Basic helix-loop-helix leucine zipper transcription factors">bHLH-ZIP</a>)
<ul><li>1.3.1 Family: Ubiquitous bHLH-ZIP factors; includes USF (<a href="https://en.wikipedia.org/wiki/USF1" title="USF1">USF1</a>, <a href="https://en.wikipedia.org/wiki/USF2" title="USF2">USF2</a>); SREBP (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sterol_regulatory_element_binding_protein" title="Sterol regulatory element binding protein">SREBP</a>)</li><li>1.3.2 Family: Cell-cycle controlling factors; includes <a href="https://en.wikipedia.org/wiki/Myc" title="Myc">c-Myc</a></li></ul></li><li>1.4 Class: NF-1
<ul><li>1.4.1 Family: NF-1 (<a href="https://en.wikipedia.org/wiki/NFIA" title="NFIA">A</a>, <a href="https://en.wikipedia.org/wiki/NFIB_(gene)" title="NFIB (gene)">B</a>, <a href="https://en.wikipedia.org/wiki/NFIC_(gene)" title="NFIC (gene)">C</a>, <a href="https://en.wikipedia.org/wiki/NFIX" title="NFIX">X</a>)</li></ul></li><li>1.5 Class: RF-X
<ul><li>1.5.1 Family: RF-X (<a href="https://en.wikipedia.org/wiki/RFX1" title="RFX1">1</a>, <a href="https://en.wikipedia.org/wiki/RFX2" title="RFX2">2</a>, <a href="https://en.wikipedia.org/wiki/RFX3" title="RFX3">3</a>, <a href="https://en.wikipedia.org/wiki/RFX4" title="RFX4">4</a>, <a href="https://en.wikipedia.org/wiki/RFX5" title="RFX5">5</a>, <a href="https://en.wikipedia.org/wiki/RFXANK" title="RFXANK">ANK</a>)</li></ul></li><li>1.6 Class: bHSH</li></ul></li><li>2 Superclass: Zinc-coordinating DNA-binding domains
<ul><li>2.1 Class: Cys4 <a href="https://en.wikipedia.org/wiki/Zinc_finger" title="Zinc finger">zinc finger</a> of <a href="https://en.wikipedia.org/wiki/Nuclear_receptor" title="Nuclear receptor">nuclear receptor</a> type
<ul><li>2.1.1 Family: <a href="https://en.wikipedia.org/wiki/Steroid_hormone_receptor" title="Steroid hormone receptor">Steroid hormone receptors</a></li><li>2.1.2 Family: <a href="https://en.wikipedia.org/wiki/Thyroid_hormone_receptor" title="Thyroid hormone receptor">Thyroid hormone receptor</a>-like factors</li></ul></li><li>2.2 Class: diverse Cys4 zinc fingers
<ul><li>2.2.1 Family: <a href="https://en.wikipedia.org/wiki/GATA_transcription_factor" title="GATA transcription factor">GATA-Factors</a></li></ul></li><li>2.3 Class: Cys2His2 zinc finger domain
<ul><li>2.3.1 Family: Ubiquitous factors, includes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TFIIIA" title="TFIIIA">TFIIIA</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sp1_transcription_factor" title="Sp1 transcription factor">Sp1</a></li><li>2.3.2 Family: Developmental / cell cycle regulators; includes <a href="https://en.wikipedia.org/wiki/Kr%C3%BCppel" title="Krüppel">Krüppel</a></li><li>2.3.4 Family: Large factors with NF-6B-like binding properties</li></ul></li><li>2.4 Class: Cys6 cysteine-zinc cluster</li><li>2.5 Class: Zinc fingers of alternating composition</li></ul></li><li>3 Superclass: <a href="https://en.wikipedia.org/wiki/Helix-turn-helix" title="Helix-turn-helix">Helix-turn-helix</a>
<ul><li>3.1 Class: <a href="https://en.wikipedia.org/wiki/Homeobox" title="Homeobox">Homeo domain</a>
<ul><li>3.1.1 Family: Homeo domain only; includes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ubx" title="Ubx">Ubx</a></li><li>3.1.2 Family: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/POU_family" title="POU family">POU domain</a> factors; includes <a href="https://en.wikipedia.org/wiki/Octamer_transcription_factor" title="Octamer transcription factor">Oct</a></li><li>3.1.3 Family: Homeo domain with LIM region</li><li>3.1.4 Family: homeo domain plus zinc finger motifs</li></ul></li><li>3.2 Class: Paired box
<ul><li>3.2.1 Family: Paired plus homeo domain</li><li>3.2.2 Family: Paired domain only</li></ul></li><li>3.3 Class: <a href="https://en.wikipedia.org/wiki/FOX_proteins" title="FOX proteins">Fork head</a> / <a href="https://en.wikipedia.org/wiki/Winged-helix_transcription_factors" title="Winged-helix transcription factors">winged helix</a>
<ul><li>3.3.1 Family: Developmental regulators; includes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Forkhead" title="Forkhead">forkhead</a></li><li>3.3.2 Family: Tissue-specific regulators</li><li>3.3.3 Family: Cell-cycle controlling factors</li><li>3.3.0 Family: Other regulators</li></ul></li><li>3.4 Class: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heat_Shock_Factor" title="Heat Shock Factor">Heat Shock Factors</a>
<ul><li>3.4.1 Family: HSF</li></ul></li><li>3.5 Class: Tryptophan clusters
<ul><li>3.5.1 Family: Myb</li><li>3.5.2 Family: Ets-type</li><li>3.5.3 Family: <a href="https://en.wikipedia.org/wiki/Interferon_regulatory_factors" title="Interferon regulatory factors">Interferon regulatory factors</a></li></ul></li><li>3.6 Class: TEA ( transcriptional enhancer factor) domain
<ul><li>3.6.1 Family: TEA (<a href="https://en.wikipedia.org/wiki/TEAD1" title="TEAD1">TEAD1</a>, <a href="https://en.wikipedia.org/wiki/TEAD2" title="TEAD2">TEAD2</a>, <a href="https://en.wikipedia.org/wiki/TEAD3" title="TEAD3">TEAD3</a>, <a href="https://en.wikipedia.org/wiki/TEAD4" title="TEAD4">TEAD4</a>)</li></ul></li></ul></li><li>4 Superclass: beta-Scaffold Factors with Minor Groove Contacts
<ul><li>4.1 Class: RHR (<a href="https://en.wikipedia.org/wiki/Rel_homology_domain" title="Rel homology domain">Rel homology region</a>)
<ul><li>4.1.1 Family: Rel/<a href="https://en.wikipedia.org/wiki/Ankyrin_repeat" title="Ankyrin repeat">ankyrin</a>; <a href="https://en.wikipedia.org/wiki/NF-%CE%BAB" title="NF-κB">NF-kappaB</a></li><li>4.1.2 Family: ankyrin only</li><li>4.1.3 Family: <a href="https://en.wikipedia.org/wiki/NFAT" title="NFAT">NFAT</a> (<b>N</b>uclear <b>F</b>actor of <b>A</b>ctivated <b>T</b>-cells) (<a href="https://en.wikipedia.org/wiki/NFATC1" title="NFATC1">NFATC1</a>, <a href="https://en.wikipedia.org/wiki/NFATC2" title="NFATC2">NFATC2</a>, <a href="https://en.wikipedia.org/wiki/NFATC3" title="NFATC3">NFATC3</a>)</li></ul></li><li>4.2 Class: STAT
<ul><li>4.2.1 Family: <a href="https://en.wikipedia.org/wiki/STAT_protein" title="STAT protein">STAT</a></li></ul></li><li>4.3 Class: p53
<ul><li>4.3.1 Family: <a href="https://en.wikipedia.org/wiki/P53" title="P53">p53</a></li></ul></li><li>4.4 Class: <a href="https://en.wikipedia.org/wiki/MADS-box" title="MADS-box">MADS box</a>
<ul><li>4.4.1 Family: Regulators of differentiation; includes (<a href="https://en.wikipedia.org/wiki/Mef2" title="Mef2">Mef2</a>)</li><li>4.4.2 Family: Responders to external signals, SRF (<a href="https://en.wikipedia.org/wiki/Serum_response_factor" title="Serum response factor">serum response factor</a>) (<i><a class="external text" href="https://www.genenames.org/tools/search/#!/genes?query=SRF" rel="nofollow">SRF</a></i>)</li><li>4.4.3 Family: Metabolic regulators (ARG80)</li></ul></li><li>4.5 Class: beta-Barrel alpha-helix transcription factors</li><li>4.6 Class: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/TATA_binding_protein" title="TATA binding protein">TATA binding proteins</a>
<ul><li>4.6.1 Family: TBP</li></ul></li><li>4.7 Class: <a href="https://en.wikipedia.org/wiki/HMG-box" title="HMG-box">HMG-box</a>
<ul><li>4.7.1 Family: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SOX_genes" title="SOX genes">SOX genes</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SRY" title="SRY">SRY</a></li><li>4.7.2 Family: TCF-1 (<a href="https://en.wikipedia.org/wiki/HNF1A" title="HNF1A">TCF1</a>)</li><li>4.7.3 Family: HMG2-related, <a href="https://en.wikipedia.org/wiki/Structure_specific_recognition_protein_1" title="Structure specific recognition protein 1">SSRP1</a></li><li>4.7.4 Family: UBF</li><li>4.7.5 Family: MATA</li></ul></li><li>4.8 Class: Heteromeric CCAAT factors
<ul><li>4.8.1 Family: Heteromeric CCAAT factors</li></ul></li><li>4.9 Class: Grainyhead
<ul><li>4.9.1 Family: Grainyhead</li></ul></li><li>4.10 Class: <a href="https://en.wikipedia.org/wiki/Cold-shock_domain" title="Cold-shock domain">Cold-shock domain</a> factors
<ul><li>4.10.1 Family: csd</li></ul></li><li>4.11 Class: Runt
<ul><li>4.11.1 Family: Runt</li></ul></li></ul></li><li>0 Superclass: Other Transcription Factors
<ul><li>0.1 Class: Copper fist proteins</li><li>0.2 Class: HMGI(Y) (<a href="https://en.wikipedia.org/wiki/HMGA1" title="HMGA1">HMGA1</a>)
<ul><li>0.2.1 Family: HMGI(Y)</li></ul></li><li>0.3 Class: Pocket domain</li><li>0.4 Class: E1A-like factors</li><li>0.5 Class: AP2/EREBP-related factors
<ul><li>0.5.1 Family: <a href="https://en.wikipedia.org/wiki/Apetala_2" title="Apetala 2">AP2</a></li><li>0.5.2 Family: EREBP</li><li>0.5.3 Superfamily: <a class="new" href="https://en.wikipedia.org/w/index.php?title=B3_DNA-binding_domain&action=edit&redlink=1" title="B3 DNA-binding domain (page does not exist)">AP2/B3</a>
<ul><li>0.5.3.1 Family: ARF</li><li>0.5.3.2 Family: ABI</li><li>0.5.3.3 Family: RAV</li></ul></li></ul></li></ul></li></ul>
<h2><span class="mw-headline" id="Transcription_factor_databases">Transcription factor databases</span></h2><p>There
are numerous databases cataloging information about transcription
factors, but their scope and utility vary dramatically. Some may contain
only information about the actual proteins, some about their binding
sites, or about their target genes. Examples include the following:
</p>
<ul><li><a class="external text" href="http://floresta.eead.csic.es/footprintdb" rel="nofollow">footprintDB</a>-- a metadatabase of multiple databases, including JASPAR and others</li><li><a href="https://en.wikipedia.org/wiki/JASPAR" title="JASPAR">JASPAR</a>: database of transcription factor binding sites for eukaryotes</li><li><a class="external text" href="http://planttfdb.gao-lab.org" rel="nofollow">PlantTFD</a>: Plant transcription factor database</li><li><a href="https://en.wikipedia.org/wiki/TcoF-DB" title="TcoF-DB">TcoF-DB</a>: Database of transcription co-factors and transcription factor interactions</li><li><a class="external text" href="http://tfcheckpoint.org" rel="nofollow">TFcheckpoint</a>: database of human, mouse and rat TF candidates</li><li><a class="external text" href="http://www.transcriptionfactor.org" rel="nofollow">transcriptionfactor.org</a> (now commercial, selling reagents)</li><li><a class="external text" href="https://methmotif.org" rel="nofollow">MethMotif.org</a>: An integrative cell-specific database of transcription factor binding motifs coupled with DNA methylation profiles.</li></ul>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-8705176791373857682024-03-28T20:45:00.007-04:002024-03-28T20:45:43.791-04:00Induced stem cells<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia<br /><a href="https://en.wikipedia.org/wiki/Induced_stem_cells">https://en.wikipedia.org/wiki/Induced_stem_cells</a><br /></div>
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<p><b>Induced stem cells</b> (<b>iSC</b>) are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cells" title="Stem cells">stem cells</a> derived from <a href="https://en.wikipedia.org/wiki/Somatic_cell" title="Somatic cell">somatic</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Reproductive_cells" title="Reproductive cells">reproductive</a>, <a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">pluripotent</a> or other cell types by deliberate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epigenetic" title="Epigenetic">epigenetic</a> reprogramming. They are classified as either <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Totipotency" title="Totipotency">totipotent</a> (iTC), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells" title="Induced pluripotent stem cells">pluripotent</a> (iPSC) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Progenitor_cells" title="Progenitor cells">progenitor</a> (multipotent – iMSC, also called an induced multipotent progenitor cell – iMPC) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Unipotency" title="Unipotency">unipotent</a> – (iUSC) according to their <a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">developmental potential and degree of dedifferentiation</a>. Progenitors are obtained by so-called <a href="https://en.wikipedia.org/wiki/Induced_stem_cells#Induced_progenitor_stem_cells">direct reprogramming</a> or directed <a href="https://en.wikipedia.org/wiki/Transdifferentiation" title="Transdifferentiation">differentiation</a> and are also called induced <a href="https://en.wikipedia.org/wiki/Adult_stem_cell" title="Adult stem cell">somatic stem cells</a>.
</p><p>Three techniques are widely recognized: <a href="https://en.wikipedia.org/wiki/Nuclear_transfer" title="Nuclear transfer">Transplantation of nuclei</a> taken from somatic cells into an oocyte (egg cell) lacking its own nucleus (removed in lab)</p><ul><li><a href="https://en.wikipedia.org/wiki/Cell_fusion" title="Cell fusion">Fusion</a> of somatic cells with pluripotent stem cells and</li><li>Transformation of somatic cells into stem cells, using the genetic material encoding <a href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell#Genes_used_to_produce_iPSCs" title="Induced pluripotent stem cell">reprogramming protein factors</a>, recombinant proteins; microRNA, a synthetic, self-replicating polycistronic RNA and low-molecular weight biologically active substances.</li></ul>
<div class="toclimit-3"></div>
<h2><span class="mw-headline" id="Natural_processes">Natural processes</span></h2></div></div></div><p>In 1895 <a href="https://en.wikipedia.org/wiki/Thomas_Hunt_Morgan" title="Thomas Hunt Morgan">Thomas Morgan</a> removed one of a <a href="https://en.wikipedia.org/wiki/Frog" title="Frog">frog</a>'s two <a href="https://en.wikipedia.org/wiki/Blastomere" title="Blastomere">blastomeres</a> and found that <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Amphibians" title="Amphibians">amphibians</a> are able to form whole <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryos</a> from the remaining part. This meant that the cells can change their differentiation pathway. In 1924 <a href="https://en.wikipedia.org/wiki/Hans_Spemann" title="Hans Spemann">Hans Spemann</a> and <a href="https://en.wikipedia.org/wiki/Hilde_Mangold" title="Hilde Mangold">Hilde Mangold</a> demonstrated the key importance of cell–cell inductions during animal development. The reversible transformation of cells of one differentiated cell type to another is called <a href="https://en.wikipedia.org/wiki/Metaplasia" title="Metaplasia">metaplasia</a>. This transition can be a part of the normal maturation process, or caused by an inducement.
</p><p>One example is the transformation of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Iris_(eye)" title="Iris (eye)">iris</a> cells to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lens_(eye)" title="Lens (eye)">lens</a> cells in the process of maturation and transformation of <a href="https://en.wikipedia.org/wiki/Retinal_pigment_epithelium" title="Retinal pigment epithelium">retinal pigment epithelium</a> cells into the neural retina during regeneration in adult <a href="https://en.wikipedia.org/wiki/Newt" title="Newt">newt</a> eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In <a href="https://en.wikipedia.org/wiki/Drosophila" title="Drosophila">Drosophila</a>
imaginal discs, cells have to choose from a limited number of standard
discrete differentiation states. The fact that transdetermination
(change of the path of differentiation) often occurs for a group of
cells rather than single cells shows that it is induced rather than part
of maturation.
</p><p>The researchers were able to identify the minimal conditions and
factors that would be sufficient for starting the cascade of molecular
and cellular processes to instruct pluripotent cells to organize the <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryo</a>. They showed that <a href="https://en.wikipedia.org/wiki/Chemotaxis" title="Chemotaxis">opposing gradients</a> of <a href="https://en.wikipedia.org/wiki/Bone_morphogenetic_protein" title="Bone morphogenetic protein">bone morphogenetic protein</a> (BMP) and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/NODAL" title="NODAL">Nodal</a>, two <a href="https://en.wikipedia.org/wiki/Transforming_growth_factor" title="Transforming growth factor">transforming growth factor</a> family members that act as <a href="https://en.wikipedia.org/wiki/Morphogen" title="Morphogen">morphogens</a>, are sufficient to induce molecular and cellular mechanisms required to organize, <i><a href="https://en.wikipedia.org/wiki/In_vivo" title="In vivo">in vivo</a></i> or <i><a href="https://en.wikipedia.org/wiki/In_vitro" title="In vitro">in vitro</a></i>, <a href="https://en.wikipedia.org/wiki/Cell_fate_determination" title="Cell fate determination">uncommitted cells</a> of the <a href="https://en.wikipedia.org/wiki/Zebrafish" title="Zebrafish">zebrafish</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Blastula" title="Blastula">blastula</a> animal pole into a well-developed <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryo</a>.
</p><p>Some types of mature, specialized adult cells can naturally
revert to stem cells. For example, "chief" cells express the stem cell
marker Troy. While they normally produce digestive fluids for the
stomach, they can revert into stem cells to make temporary repairs to
stomach injuries, such as a cut or damage from infection. Moreover, they
can make this transition even in the absence of noticeable injuries and
are capable of replenishing entire gastric units, in essence serving as
quiescent "reserve" stem cells. Differentiated airway epithelial cells can revert into stable and functional stem cells <a href="https://en.wikipedia.org/wiki/In_vivo" title="In vivo">in vivo</a>.
After injury, mature terminally differentiated kidney cells
dedifferentiate into more primordial versions of themselves and then
differentiate into the cell types needing replacement in the damaged
tissue Macrophages can self-renew by local proliferation of mature differentiated cells.
In newts, muscle tissue is regenerated from specialized muscle cells
that dedifferentiate and forget the type of cell they had been. This
capacity to regenerate does not decline with age and may be linked to
their ability to make new stem cells from muscle cells on demand.
</p><p>A variety of nontumorigenic stem cells display the ability to
generate multiple cell types. For instance, multilineage-differentiating
stress-enduring <a href="https://en.wikipedia.org/wiki/Muse_cell" title="Muse cell">(Muse)</a>
cells are stress-tolerant adult human stem cells that can self-renew.
They form characteristic cell clusters in suspension culture that
express a set of genes associated with pluripotency and can
differentiate into <a href="https://en.wikipedia.org/wiki/Endoderm" title="Endoderm">endodermal</a>, <a href="https://en.wikipedia.org/wiki/Ectoderm" title="Ectoderm">ectodermal</a> and mesodermal cells both in vitro and in vivo.
</p><p>Other well-documented examples of <a href="https://en.wikipedia.org/wiki/Transdifferentiation" title="Transdifferentiation">transdifferentiation</a> and their significance in development and regeneration were described in detail.
</p>
<figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Cloning_diagram_english.svg"><img class="mw-file-element" data-file-height="475" data-file-width="721" height="264" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/ec/Cloning_diagram_english.svg/300px-Cloning_diagram_english.svg.png" width="400" /></a><figcaption>Induced totipotent cells usually can be obtained by reprogramming somatic cells by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Somatic-cell_nuclear_transfer" title="Somatic-cell nuclear transfer">somatic-cell nuclear transfer</a> (SCNT).</figcaption></figure>
<h2><span class="mw-headline" id="Induced_totipotent_cells">Induced totipotent cells</span></h2><h3><span class="mw-headline" id="SCNT-mediated">SCNT-mediated</span></h3><p>Induced totipotent cells can be obtained by reprogramming somatic cells with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Somatic-cell_nuclear_transfer" title="Somatic-cell nuclear transfer">somatic-cell nuclear transfer</a>
(SCNT). The process involves sucking out the nucleus of a somatic
(body) cell and injecting it into an oocyte that has had its nucleus
removed.
</p><p>Using an approach based on the protocol outlined by Tachibana et al.,
hESCs can be generated by SCNT using dermal fibroblasts nuclei from
both a middle-aged 35-year-old male and an elderly, 75-year-old male,
suggesting that age-associated changes are not necessarily an impediment
to SCNT-based nuclear reprogramming of human cells. Such reprogramming of somatic cells to a pluripotent state holds huge potentials for <a href="https://en.wikipedia.org/wiki/Regenerative_medicine" title="Regenerative medicine">regenerative medicine</a>. Unfortunately, the cells generated by this technology are potentially not completely protected from the <a href="https://en.wikipedia.org/wiki/Immune_system" title="Immune system">immune system</a> of the patient (donor of nuclei), because they have the same <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria">mitochondrial</a> DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autologous_stem_cell_transplantation" title="Autologous stem cell transplantation">autologous stem cell transplantation</a> therapy; as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.
</p><p>Induced androgenetic haploid embryonic stem cells can be used
instead of sperm for cloning. These cells, synchronized in M phase and
injected into the oocyte, can produce viable offspring.
</p><p>These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,
offer the possibility of industrial production of transgenic farm
animals. Repeated recloning of viable mice through a SCNT method that
includes a <a href="https://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" title="Histone deacetylase inhibitor">histone deacetylase inhibitor</a>, trichostatin, added to the cell culture medium, show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors. However, research into technologies to develop sperm and egg cells from stem cells raises <a href="https://en.wikipedia.org/wiki/Bioethics" title="Bioethics">bioethical</a> issues.
</p><p>Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes. For example, the technology could prevent inherited <a href="https://en.wikipedia.org/wiki/Mitochondrial_disease" title="Mitochondrial disease">mitochondrial disease</a>
from passing to future generations. Mitochondrial genetic material is
passed from mother to child. Mutations can cause diabetes, deafness, eye
disorders, gastrointestinal disorders, heart disease, dementia, and
other neurological diseases. The nucleus from one human egg has been
transferred to another, including its mitochondria, creating a cell that
could be regarded as having two mothers. The eggs were then fertilised
and the resulting embryonic stem cells carried the swapped mitochondrial
DNA.
As evidence that the technique is safe, the author of this method points
to the existence of the healthy monkeys that are now more than four
years old – and are the product of mitochondrial transplants across
different genetic backgrounds.
</p><p>In late-generation <a href="https://en.wikipedia.org/wiki/Telomerase" title="Telomerase">telomerase</a>-deficient
(Terc−/−) mice, SCNT-mediated reprogramming mitigates telomere
dysfunction and mitochondrial defects to a greater extent than
iPSC-based reprogramming.
</p><p>Other cloning and totipotent transformation achievements have been described.
</p>
<h3><span class="mw-headline" id="Obtained_without_SCNT">Obtained without SCNT</span></h3><p>Recently,
some researchers succeeded in getting totipotent cells without the aid
of SCNT. Totipotent cells were obtained using epigenetic factors such as
oocyte germinal isoform of histone.
Reprogramming in vivo, by transitory induction of the four factors Oct4,
Sox2, Klf4 and c-Myc in mice, confers totipotency features.
Intraperitoneal injection of such in vivo iPS cells generates
embryo-like structures that express embryonic and extraembryonic (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Trophectoderm" title="Trophectoderm">trophectodermal</a>) markers.
The developmental potential of mouse pluripotent stem cells to yield
both embryonic and extra-embryonic lineages also can be expanded by
microRNA <a href="https://en.wikipedia.org/wiki/MIR34A" title="MIR34A">miR-34a</a> deficiency, leading to strong induction of endogenous <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retroviruses</a> MuERV-L (MERVL).
</p>
<h2><span class="mw-headline" id="Rejuvenation_to_iPSCs">Rejuvenation to iPSCs</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells" title="Induced pluripotent stem cells">Induced pluripotent stem cells</a></div>
<p>Transplantation of pluripotent/embryonic stem cells into the body of adult mammals usually leads to the formation of <a href="https://en.wikipedia.org/wiki/Teratoma" title="Teratoma">teratomas</a>,
which can then turn into a malignant tumor teratocarcinoma. However,
putting embryonic stem cells or teratocarcinoma cells into the embryo at
the blastocyst stage caused them to become incorporated in the cell
mass and often produced a normal healthy chimeric (i.e. composed of
cells from different organisms) animal.
iPSc were first obtained in the form of transplantable <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Teratocarcinoma" title="Teratocarcinoma">teratocarcinoma</a> induced by grafts taken from mouse embryos. Teratocarcinoma formed from somatic cells. <a href="https://en.wikipedia.org/wiki/Chimera_(genetics)" title="Chimera (genetics)">Genetically mosaic mice</a> were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency. It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">embryonic stem cell</a> in an undifferentiated state, by supplying the culture medium with various factors.
In the 1980s, it became clear that transplanting pluripotent/embryonic
stem cells into the body of adult mammals, usually leads to the
formation of <a href="https://en.wikipedia.org/wiki/Teratoma" title="Teratoma">teratomas</a>, which can then turn into a malignant tumor teratocarcinoma. However, putting teratocarcinoma cells into the embryo at the blastocyst stage caused them to become incorporated in the <a href="https://en.wikipedia.org/wiki/Inner_cell_mass" title="Inner cell mass">inner cell mass</a> and often produced a normal chimeric (i.e. composed of cells from different organisms) animal. This indicated that the cause of the teratoma is a dissonance - mutual
miscommunication between young donor cells and surrounding adult cells
(the recipient's so-called "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cell_niche" title="Stem cell niche">niche</a>").
</p><p>In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic <a href="https://en.wikipedia.org/wiki/Fibroblast" title="Fibroblast">fibroblasts</a> into pluripotent stem cells via the ectopic expression of four <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factors</a>, namely <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oct4" title="Oct4">Oct4</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sox2" title="Sox2">Sox2</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Klf4" title="Klf4">Klf4</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/C-Myc" title="C-Myc">c-Myc</a>,
they proved that the overexpression of a small number of factors can
push the cell to transition to a new stable state that is associated
with changes in the activity of thousands of genes.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Overview_of_iPS_cells.png"><img class="mw-file-element" data-file-height="361" data-file-width="478" height="302" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/28/Overview_of_iPS_cells.png/220px-Overview_of_iPS_cells.png" width="400" /></a><figcaption>Human
somatic cells are made pluripotent by transducing them with factors
that induce pluripotency (OCT 3/4, SOX2, Klf4, c-Myc, NANOG and LIN28).
This results in the production of IPS cells, which can differentiate
into any cell of the three embryonic germ layers (Mesoderm, Endoderm,
Ectoderm).</figcaption></figure>
<p>Reprogramming mechanisms are thus linked, rather than independent, and are centered on a small number of genes.
IPSC properties are very similar to ESCs. iPSCs have been shown to support the development of all-iPSC mice using a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tetraploid" title="Tetraploid">tetraploid</a> (4n) embryo,
the most stringent assay for developmental potential. However, some
genetically normal iPSCs failed to produce all-iPSC mice because of
aberrant epigenetic silencing of the imprinted <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dio3_Gene" title="Dio3 Gene">Dlk1-Dio3 gene</a> cluster.
A team headed by Hans Schöler (who discovered the Oct4 gene back in
1989) showed that Oct4 overexpression drives massive off-target gene
activation during reprogramming deteriorating the quality of iPSCs.
Compared to OSKM (Oct4, Sox2, Klf4 and c-Myc) that show abnormal
imprinting and differentiation patterns, SKM (Sox2, Klf4 and c-Myc)
reprogramming generates iPSCs with high developmental potential (nearly
20-fold higher than that of OSKM) equivalent to <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">embryonic stem cell</a>, as determined by their ability to generate all-iPSC mice through tetraploid embryo complementation.
</p><p>An important advantage of iPSC over ESC is that they can be
derived from adult cells, rather than from embryos. Therefore, it
becomes possible to obtain iPSC from adult and even elderly patients.
</p><p>Reprogramming somatic cells into iPSCs leads to rejuvenation. It
was found that reprogramming leads to telomere lengthening and
subsequent shortening after their differentiation back into
fibroblast-like derivatives. Thus, reprogramming leads to the restoration of embryonic telomere length, and hence increases the potential number of cell divisions otherwise limited by the <a href="https://en.wikipedia.org/wiki/Hayflick_limit" title="Hayflick limit">Hayflick limit</a>.
</p><p>However, because of the dissonance between rejuvenated cells and
the surrounding niche of the recipient's older cells, the injection of
his own iPSC usually leads to an <a href="https://en.wikipedia.org/wiki/Immune_response" title="Immune response">immune response</a>, which can be used for medical purposes, or the formation of tumors such as teratoma. A hypothesized reason is that some cells differentiated from ESCs and iPSCs in vivo continue to synthesize embryonic <a href="https://en.wikipedia.org/wiki/Protein_isoform" title="Protein isoform">protein isoforms</a>. So, the immune system might detect and attack cells that are not cooperating properly.
</p><p>A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering <a href="https://en.wikipedia.org/wiki/Apoptosis" title="Apoptosis">apoptosis</a> (via <a href="https://en.wikipedia.org/wiki/Cytochrome_c" title="Cytochrome c">cytochrome c</a> release across the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria">mitochondrial</a>
outer membrane) in human pluripotent stem cells, but not in
differentiated cells. Shortly after differentiation, daughter cells
became resistant to death. When MitoBloCK-6 was introduced to
differentiated cell lines, the cells remained healthy. The key to their
survival was hypothesized to be due to the changes undergone by
pluripotent stem cell mitochondria in the process of cell
differentiation. This ability of MitoBloCK-6 to separate the pluripotent
and differentiated cell lines has the potential to reduce the risk of
teratomas and other problems in regenerative medicine.
</p><p>In 2012, other <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Small_molecules" title="Small molecules">small molecules</a>
(selective cytotoxic inhibitors of human pluripotent stem cells –
hPSCs) were identified that prevented human pluripotent stem cells from
forming teratomas in mice. The most potent and selective compound of
them (PluriSIn #1) inhibits <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1" title="Stearoyl-CoA desaturase-1">stearoyl-coA desaturase</a> (the key enzyme in <a href="https://en.wikipedia.org/wiki/Oleic_acid" title="Oleic acid">oleic acid</a>
biosynthesis), which finally results in apoptosis. With the help of
this molecule, the undifferentiated cells can be selectively removed
from culture.
An efficient strategy to selectively eliminate pluripotent cells with
teratoma potential is targeting pluripotent stem cell-specific <a href="https://en.wikipedia.org/wiki/Inhibitor_of_apoptosis" title="Inhibitor of apoptosis">antiapoptotic factor(s)</a> (i.e., <a href="https://en.wikipedia.org/wiki/Survivin" title="Survivin">survivin</a> or Bcl10). A single treatment with chemical survivin inhibitors (e.g., <a href="https://en.wikipedia.org/wiki/Quercetin" title="Quercetin">quercetin</a>
or YM155) can induce selective and complete cell death of
undifferentiated hPSCs and is claimed to be sufficient to prevent
teratoma formation after transplantation.
However, it is unlikely that any kind of preliminary clearance is able
to secure the replanting of iPSCs or ESCs. After the selective removal
of pluripotent cells, they re-emerge quickly by reverting differentiated
cells into stem cells, which leads to tumors. This may be due to the disorder of <a href="https://en.wikipedia.org/wiki/Let-7_microRNA_precursor" title="Let-7 microRNA precursor">let-7</a> regulation of its target Nr6a1 (also known as <a href="https://en.wikipedia.org/wiki/Germ_cell_nuclear_factor" title="Germ cell nuclear factor">Germ cell nuclear factor</a>
- GCNF), an embryonic transcriptional repressor of pluripotency genes
that regulates gene expression in adult fibroblasts following <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Micro-RNA" title="Micro-RNA">micro-RNA</a> miRNA loss.
</p><p>Teratoma formation by pluripotent stem cells may be caused by low activity of <a href="https://en.wikipedia.org/wiki/PTEN_(gene)" title="PTEN (gene)">PTEN enzyme</a>,
reported to promote the survival of a small population (0.1–5% of total
population) of highly tumorigenic, aggressive, teratoma-initiating
embryonic-like carcinoma cells during differentiation. The survival of
these teratoma-initiating cells is associated with failed repression of <a href="https://en.wikipedia.org/wiki/Homeobox_protein_NANOG" title="Homeobox protein NANOG">Nanog</a>, as well as a propensity for increased glucose and cholesterol metabolism. These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.
In connection with the above safety problems, the use of iPSCs for cell therapy is still limited. However, they can be used for a variety of other purposes, including the modeling of disease, screening (selective selection) of drugs, and toxicity testing of various drugs.
</p>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Stem_cell_modulators.svg"><img class="mw-file-element" data-file-height="639" data-file-width="512" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/eb/Stem_cell_modulators.svg/275px-Stem_cell_modulators.svg.png" width="321" /></a><figcaption>Small molecule modulators of stem-cell fate</figcaption></figure>
<p>The tissue grown from iPSCs, placed in the "chimeric" embryos in the
early stages of mouse development, practically do not cause an immune
response (after the embryos have grown into adult mice) and are suitable
for <a href="https://en.wikipedia.org/wiki/Autotransplantation" title="Autotransplantation">autologous transplantation</a>
At the same time, full reprogramming of adult cells in vivo within
tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and
c-Myc in mice results in teratomas emerging from multiple organs.
Furthermore, partial reprogramming of cells toward pluripotency in vivo
in mice demonstrates that incomplete reprogramming entails epigenetic
changes (failed repression of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Polycomb" title="Polycomb">Polycomb</a> targets and altered <a href="https://en.wikipedia.org/wiki/DNA_methylation" title="DNA methylation">DNA methylation</a>) in cells that drive cancer development. However, a number of researchers later managed to carry out cyclical partial reprogramming <i>in vivo</i>
by expression of the Yamanaka factors for a short period of time
without subsequent carcinogenesis, thus partially rejuvenating and
extending lifespan in
physiologically aging wild-type mice and progeroid mice. With <i>in vitro</i>
method employing slightly longer periods of reprogramming (to
substantially rejuvenate) cells temporarily lose their cell identity but "reacquire their initial somatic fate when the reprogramming factors are withdrawn".
</p>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Regen2.svg"><img class="mw-file-element" data-file-height="250" data-file-width="231" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e7/Regen2.svg/200px-Regen2.svg.png" width="370" /></a><figcaption>Cell culture example of a small molecule as a tool instead of a protein. In <a href="https://en.wikipedia.org/wiki/Cell_culture" title="Cell culture">cell culture</a> to obtain a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Islets_of_Langerhans" title="Islets of Langerhans">pancreatic lineage</a> from <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesodermal</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cells" title="Stem cells">stem cells</a> the <a href="https://en.wikipedia.org/wiki/Retinoic_acid" title="Retinoic acid">retinoic acid</a> signalling pathway must be activated while the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sonic_hedgehog" title="Sonic hedgehog">sonic hedgehog</a> pathway is inhibited, which can be done by adding to the <a href="https://en.wikipedia.org/wiki/Growth_medium" title="Growth medium">media</a> anti-shh <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibodies" title="Antibodies">antibodies</a>, <a href="https://en.wikipedia.org/wiki/HHIP" title="HHIP">Hedgehog interacting protein</a> or <a href="https://en.wikipedia.org/wiki/Cyclopamine" title="Cyclopamine">cyclopamine</a>- the first two are proteins and the last a small molecule.</figcaption></figure>
<h3><span class="mw-headline" id="Chemical_inducement">Chemical inducement</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Chemical_biology#Chemical_approaches_to_stem-cell_biology" title="Chemical biology">Chemical biology § Chemical approaches to stem-cell biology</a></div>
<p>By using solely <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Small_molecules" title="Small molecules">small molecules</a>,
Deng Hongkui and colleagues demonstrated that endogenous "master genes"
are enough for cell fate reprogramming. They induced a pluripotent
state in adult cells from mice using seven small-molecule compounds.
The method's effectiveness is quite high: it was able to convert 0.02%
of the adult tissue cells into iPSCs, which is comparable to the gene
insertion conversion rate.
The authors note that the mice generated from CiPSCs were "100% viable
and apparently healthy for up to 6 months". So, this chemical
reprogramming strategy has potential use in generating functional
desirable cell types for clinical applications.
</p><p>In 2015 a robust chemical reprogramming system was established
with a yield up to 1,000-fold greater than that of the previously
reported protocol. So, chemical reprogramming became a promising
approach to manipulate cell fates.
</p>
<h3><span class="mw-headline" id="Differentiation_from_induced_teratoma">Differentiation from induced teratoma</span></h3><p>The
fact that human iPSCs are capable of forming teratomas not only in
humans but also in some animal body, in particular mice or pigs, allowed
researchers to develop a method for differentiation of iPSCs in vivo.
For this purpose, iPSCs with an agent for inducing differentiation into
target cells are injected to a <a href="https://en.wikipedia.org/wiki/Genetically_modified_mammal" title="Genetically modified mammal">genetically modified</a> pig or mouse that has suppressed immune system activation on human cells.
The formed teratoma is cut out and used for the isolation of the necessary differentiated human cells by means of <a href="https://en.wikipedia.org/wiki/Monoclonal_antibody" title="Monoclonal antibody">monoclonal antibody</a>
to tissue-specific markers on the surface of these cells. This method
has been successfully used for the production of functional myeloid,
erythroid, and lymphoid human cells suitable for transplantation (yet
only to mice).
Mice engrafted with human iPSC teratoma-derived hematopoietic cells
produced human B and T cells capable of functional immune responses.
These results offer hope that in vivo generation of patient customized
cells is feasible, providing materials that could be useful for
transplantation, human antibody generation, and drug screening
applications.
Using MitoBloCK-6
and/or PluriSIn # 1 the differentiated progenitor cells can be further
purified from teratoma forming pluripotent cells. The fact that the
differentiation takes place even in the teratoma niche offers hope that
the resulting cells are sufficiently stable to stimuli able to cause
their transition back to the dedifferentiated (pluripotent) state and
therefore safe. A similar in vivo differentiation system, yielding
engraftable hematopoietic stem cells from mouse and human iPSCs in
teratoma-bearing animals in combination with a maneuver to facilitate
hematopoiesis, was described by Suzuki et al.
They noted that neither leukemia nor tumors were observed in recipients
after intravenous injection of iPSC-derived hematopoietic stem cells
into irradiated recipients. Moreover, this injection resulted in
multilineage and long-term reconstitution of the hematolymphopoietic
system in serial transfers. Such a system provides a useful tool for
practical application of iPSCs in the treatment of hematologic and
immunologic diseases.
</p><p>For further development of this method, animals (such as a mice)
in which the human cell graft is grown must have modified genome such
that all its cells express and have on its surface human <a href="https://en.wikipedia.org/wiki/Signal-regulatory_protein_alpha" title="Signal-regulatory protein alpha">SIRPα</a>.
To prevent rejection after transplantation to the patient of the
allogenic organ or tissue, grown from the pluripotent stem cells in vivo
in the animal, these cells should express two molecules: <a href="https://en.wikipedia.org/wiki/Belatacept" title="Belatacept">CTLA4-Ig</a>, which disrupts T cell costimulatory pathways and <a href="https://en.wikipedia.org/wiki/PD-L1" title="PD-L1">PD-L1</a>, which activates T cell inhibitory pathway.
</p><p>See also: <span class="citation patent"><a class="external text" href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US20130058900" rel="nofollow">US 20130058900</a></span><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Apatent&rft.number=20130058900&rft.cc=US&rft.title="></span> patent.
</p>
<h3><span class="mw-headline" id="Differentiated_cell_types">Differentiated cell types</span></h3><h4><span class="mw-headline" id="Retinal_cells">Retinal cells</span></h4><p>In
the near-future, clinical trials designed to demonstrate the safety of
the use of iPSCs for cell therapy of people with age-related macular
degeneration, a disease causing blindness through retina damaging, will
begin. There are several articles describing methods for producing
retinal cells from iPSCs
and how to use them for cell therapy. Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced
visual-guided behaviors of experimental animals for 6 weeks after transplantation.
However, clinical trials have been successful: ten patients with
retinitis pigmentosa have had eyesight restored, including a woman who
had only 17 percent of her vision left.
</p>
<h4><span class="mw-headline" id="Lung_and_airway_epithelial_cells">Lung and airway epithelial cells</span></h4><p>Chronic lung diseases, such as idiopathic pulmonary fibrosis and cystic fibrosis or <a href="https://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_disease" title="Chronic obstructive pulmonary disease">chronic obstructive pulmonary disease</a> and <a href="https://en.wikipedia.org/wiki/Asthma" title="Asthma">asthma</a>,
are leading causes of morbidity and mortality worldwide, with a
considerable human, societal, and financial burden. Therefore, there is
an urgent need for effective cell therapy and <a href="https://en.wikipedia.org/wiki/Lung" title="Lung">lung</a> <a href="https://en.wikipedia.org/wiki/Tissue_engineering" title="Tissue engineering">tissue engineering</a>. Several protocols have been developed for generation of most cell types of the <a href="https://en.wikipedia.org/wiki/Respiratory_system" title="Respiratory system">respiratory system</a>, which may be useful for deriving patient-specific therapeutic cells.
</p>
<h4><span class="mw-headline" id="Reproductive_cells">Reproductive cells</span></h4><p>Some
lines of iPSCs have the potential to differentiate into male germ cells
and oocyte-like cells in an appropriate niche (by culturing in retinoic
acid and porcine follicular fluid differentiation medium or
seminiferous tubule transplantation). Moreover, iPSC transplantation
contributes to repairing the testis of infertile mice, demonstrating the
potential of gamete derivation from iPSCs in vivo and in vitro.
</p>
<h2><span class="mw-headline" id="Induced_progenitor_stem_cells">Induced progenitor stem cells</span></h2><h3><span class="mw-headline" id="Direct_transdifferentiation">Direct transdifferentiation</span></h3><p>The
risk of cancer and tumors creates the need to develop methods for safer
cell lines suitable for clinical use. An alternative approach is
so-called "direct reprogramming" – transdifferentiation of cells without
passing through the pluripotent state. The basis for this approach was that <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5-azacytidine" title="5-azacytidine">5-azacytidine</a> – a DNA demethylation reagent – can cause the formation of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myogenic" title="Myogenic">myogenic</a>, chondrogenic, and adipogeni clones in an immortal cell line of mouse embryonic fibroblasts and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.
Compared with iPSCs whose reprogramming requires at least two weeks,
the formation of induced progenitor cells sometimes occurs within a few
days and the efficiency of reprogramming is usually many times higher.
This reprogramming does not always require cell division. The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.
For example, Chandrakanthan et al., & Pimanda describe the
generation of tissue-regenerative multipotent stem cells (iMS cells) by
treating mature bone and fat cells transiently with a growth factor (<a href="https://en.wikipedia.org/wiki/Platelet-derived_growth_factor" title="Platelet-derived growth factor">platelet-derived growth factor</a>–AB
(PDGF-AB)) and 5-Azacytidine. These authors state that "Unlike primary
mesenchymal stem cells, which are used with little objective evidence in
clinical practice to promote tissue repair, iMS cells contribute
directly to in vivo tissue regeneration in a context-dependent manner
without forming tumors" and thus "has significant scope for application
in tissue regeneration".
</p>
<h4><span class="mw-headline" id="Single_transcription_factor_transdifferentiation">Single transcription factor transdifferentiation</span></h4><p>Originally,
only early embryonic cells could be coaxed into changing their
identity. Mature cells are resistant to changing their identity once
they've committed to a specific kind. However, brief expression of a
single transcription factor, the ELT-7 GATA factor, can convert the
identity of fully differentiated, specialized non-endodermal cells of
the <a href="https://en.wikipedia.org/wiki/Pharynx" title="Pharynx">pharynx</a> into fully differentiated intestinal cells in intact <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Larvae" title="Larvae">larvae</a> and adult roundworm <i><a href="https://en.wikipedia.org/wiki/Caenorhabditis_elegans" title="Caenorhabditis elegans">Caenorhabditis elegans</a></i> with no requirement for a dedifferentiated intermediate.
</p>
<h4><span class="mw-headline" id="Transdifferentiation_with_CRISPR-mediated_activator">Transdifferentiation with CRISPR-mediated activator</span></h4><p>The cell fate can be effectively manipulated by <a href="https://en.wikipedia.org/wiki/Epigenome_editing" title="Epigenome editing">epigenome editing</a>, in particular via the direct activation of specific endogenous gene expression with <a href="https://en.wikipedia.org/wiki/CRISPR" title="CRISPR">CRISPR</a>-mediated activator. When <a href="https://en.wikipedia.org/wiki/Cas9#Applications_of_Cas9_to_transcription_tuning" title="Cas9">dCas9</a>
(which has been modified so that it no longer cuts DNA, but still can
be guided to specific sequences and to bind to them) is combined with
transcription activators, it can precisely manipulate endogenous gene
expression. Using this method, Wei et al., enhanced the expression of
endogenous <a href="https://en.wikipedia.org/wiki/CDX2" title="CDX2">Cdx2</a> and <a href="https://en.wikipedia.org/wiki/GATA6" title="GATA6">Gata6</a>
genes by CRISPR-mediated activators, thus directly converting mouse
embryonic stem cells into two extraembryonic lineages, i.e., typical
trophoblast stem cells and extraembryonic endoderm cells.
An analogous approach was used to induce activation of the endogenous
Brn2, Ascl1, and Myt1l genes to convert mouse embryonic fibroblasts to
induced neuronal cells.
Thus, transcriptional activation and epigenetic remodeling of
endogenous master transcription factors are sufficient for conversion
between cell types. The rapid and sustained activation of endogenous
genes in their native chromatin context by this approach may facilitate
reprogramming with transient methods that avoid genomic integration and
provides a new strategy for overcoming epigenetic barriers to cell fate
specification.
</p>
<h3><span class="mw-headline" id="Phased_process_modeling_regeneration">Phased process modeling regeneration</span></h3><p>Another way of reprogramming is the simulation of processes that occur during <a href="https://en.wikipedia.org/wiki/Amphibian" title="Amphibian">amphibian</a> limb regeneration. In <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urodele" title="Urodele">urodele</a>
amphibians, an early step in limb regeneration is skeletal muscle fiber
dedifferentiation into a cellulate that proliferates into limb tissue.
However, sequential small molecule treatment of the muscle fiber with
myoseverin, <a href="https://en.wikipedia.org/wiki/Reversine" title="Reversine">reversine</a> (the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aurora_B_kinase" title="Aurora B kinase">aurora B kinase</a> inhibitor), and some other chemicals (BIO (glycogen synthase-3 kinase inhibitor), <a href="https://en.wikipedia.org/wiki/Lysophosphatidic_acid" title="Lysophosphatidic acid">lysophosphatidic acid</a> (pleiotropic activator of G-protein-coupled receptors), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SB203580" title="SB203580">SB203580</a> (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/P38_MAP_kinase" title="P38 MAP kinase">p38 MAP kinase</a> inhibitor), or <a class="new" href="https://en.wikipedia.org/w/index.php?title=SQ22536&action=edit&redlink=1" title="SQ22536 (page does not exist)">SQ22536</a>
(adenylyl cyclase inhibitor)) causes the formation of new muscle cell
types as well as other cell types such as precursors to fat, bone, and
nervous system cells.
</p>
<h3><span class="mw-headline" id="Antibody-based_transdifferentiation">Antibody-based transdifferentiation</span></h3><p>The researchers discovered that <a href="https://en.wikipedia.org/wiki/Granulocyte_colony-stimulating_factor" title="Granulocyte colony-stimulating factor">GCSF</a>-mimicking <a href="https://en.wikipedia.org/wiki/Antibody" title="Antibody">antibody</a> can activate a growth-stimulating receptor on <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">marrow</a>
cells in a way that induces marrow stem cells which normally develop
into white blood cells to become neural progenitor cells. The technique enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.
</p>
<h3><span class="mw-headline" id="Reprograming_by_bacteria">Reprograming by bacteria</span></h3><p>The
human gastrointestinal tract is colonized by a vast community of
symbionts and commensals. The researchers demonstrate the phenomenon of
somatic cell reprograming by bacteria and generation of multipotential
cells from adult human dermal fibroblast cells by incorporating Lactic
acid bacteria.
This cellular transdifferentiation is caused by ribosomes and "can
occur via donor bacteria that are swallowed and digested by host cells,
which may induce ribosomal stress and stimulate cellular developmental
plasticity".
</p>
<h3><span id="Conditionally_reprogrammed_cells_.28CRC.29"></span><span class="mw-headline" id="Conditionally_reprogrammed_cells_(CRC)">Conditionally reprogrammed cells (CRC)</span></h3><p><a href="https://en.wikipedia.org/wiki/Richard_Schlegel" title="Richard Schlegel">Schlegel</a> and Liu demonstrated that the combination of feeder cells and a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rho_kinase" title="Rho kinase">Rho kinase</a> inhibitor (Y-27632) induces normal and tumor epithelial cells from many tissues <a href="https://en.wikipedia.org/wiki/Immortalised_cell_line" title="Immortalised cell line">to proliferate indefinitely <i>in vitro</i></a>.
This process occurs without the need for transduction of exogenous
viral or cellular genes. These cells have been termed "conditionally
reprogrammed cells" (CRC).
The induction of CRCs is rapid and results from reprogramming of the
entire cell population. CRCs do not express high levels of proteins
characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2,
Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal
of Y-27632 and feeders allows the cells to differentiate normally. CRC technology can generate 2<span style="margin: 0 .15em 0 .25em;">×</span>10<sup><span class="nowrap"><span data-sort-value="7000600000000000000♠"></span>6</span></sup>
cells in 5 to 6 days from needle biopsies and can generate cultures
from cryopreserved tissue and from fewer than four viable cells. CRCs
retain a normal <a href="https://en.wikipedia.org/wiki/Karyotype" title="Karyotype">karyotype</a> and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors.
</p><p>The ability to rapidly generate many tumor cells from small
biopsy specimens and frozen tissue provides significant opportunities
for cell-based diagnostics and therapeutics (including chemosensitivity
testing) and greatly expands the value of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biobanking" title="Biobanking">biobanking</a>. Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor. Engleman's group describes a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pharmacogenomic" title="Pharmacogenomic">pharmacogenomics</a>
platform that facilitates fast discovery of drug combinations which can
overcome resistance using CRC system. In addition, the CRC method
allows for the genetic manipulation of epithelial cells ex vivo and
their subsequent evaluation in vivo in the same host. While initial
studies revealed that co-culturing epithelial cells with Swiss 3T3 cells
J2 was essential for CRC induction, with transwell culture plates,
physical contact between feeders and epithelial cells isn't required for
inducing CRCs, and more importantly, irradiation of the feeder cells is
required for this induction. Consistent with the transwell experiments,
conditioned medium induces and maintains CRCs, which is accompanied by a
concomitant increase of cellular telomerase activity. The activity of
the conditioned medium correlates directly with radiation-induced feeder
cell apoptosis. Thus, conditional reprogramming of epithelial cells is
mediated by a combination of Y-27632 and a soluble factor(s) released by
apoptotic feeder cells.
</p><p>Riegel et al.
demonstrate that mouse ME cells, isolated from normal mammary glands or
from mouse mammary tumor virus (MMTV)-Neu–induced mammary tumors, can
be cultured indefinitely as conditionally reprogrammed cells (CRCs).
Cell surface progenitor-associated markers are rapidly induced in normal
mouse ME-CRCs relative to ME cells. However, the expression of certain
mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops
significantly in later passages. Nevertheless, mouse ME-CRCs grown in a
three-dimensional extracellular matrix gave rise to mammary acinar
structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary
tumors express high levels of HER2/neu, as well as tumor-initiating cell
markers, such as CD44+, CD49f+, and ESA+ (EpCam). These patterns of
expression are sustained in later CRC passages. Early and late passage
ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads
of syngeneic or nude mice developed vascular tumors that metastasized
within 6 weeks of transplantation. Importantly, the histopathology of
these tumors was indistinguishable from that of the parental tumors that
develop in the MMTV-Neu mice. Application of the CRC system to mouse
mammary epithelial cells provides an attractive model system to study
genetics and phenotype of normal and transformed mouse epithelium in a
defined culture environment and for in vivo transplant studies.
</p><p>A different approach to CRC is to inhibit <a href="https://en.wikipedia.org/wiki/CD47" title="CD47">CD47</a> – a <a href="https://en.wikipedia.org/wiki/Membrane_protein" title="Membrane protein">membrane protein</a> that is the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thrombospondin-1" title="Thrombospondin-1">thrombospondin-1</a> receptor. Loss of CD47 permits sustained proliferation of primary <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Murine" title="Murine">murine</a> endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent <a href="https://en.wikipedia.org/wiki/Embryoid_body" title="Embryoid body">embryoid body</a>-like clusters. CD47 knockdown acutely increases <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRNA" title="MRNA">mRNA</a>
levels of c-Myc and other stem cell transcription factors in cells in
vitro and in vivo. Thrombospondin-1 is a key environmental signal that
inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable
cell self-renewal and reprogramming by overcoming negative regulation of
c-Myc and other stem cell transcription factors. In vivo blockade of CD47 using an antisense <a href="https://en.wikipedia.org/wiki/Morpholino" title="Morpholino">morpholino</a>
increases survival of mice exposed to lethal total body irradiation due
to increased proliferative capacity of bone marrow-derived cells and
radioprotection of radiosensitive gastrointestinal tissues.
</p>
<h4><span class="mw-headline" id="Lineage-specific_enhancers">Lineage-specific enhancers</span></h4><p>Differentiated <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Macrophages" title="Macrophages">macrophages</a> can self-renew in tissues and expand long-term in culture. Under certain conditions, macrophages can divide without losing features they have acquired while specializing into <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Immune_cells" title="Immune cells">immune cells</a> – which is usually not possible with <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">differentiated cells</a>. The macrophages achieve this by activating a <a href="https://en.wikipedia.org/wiki/Gene_regulatory_network" title="Gene regulatory network">gene network</a> similar to one found in embryonic stem cells. <a href="https://en.wikipedia.org/wiki/Single-cell_analysis" title="Single-cell analysis">Single-cell analysis</a> revealed that, <i>in vivo</i>,
proliferating macrophages can derepress a macrophage-specific enhancer
repertoire associated with a gene network controlling self-renewal. This
happened when concentrations of two transcription factors named <a href="https://en.wikipedia.org/wiki/MAFB_(gene)" title="MAFB (gene)">MafB</a> and <a href="https://en.wikipedia.org/wiki/MAF_(gene)" title="MAF (gene)">c-Maf</a>
were naturally low or were inhibited for a short time. Genetic
manipulations that turned off MafB and c-Maf in the macrophages caused
the cells to start a self-renewal program. The similar network also
controls embryonic stem cell self-renewal but is associated with
distinct embryonic stem cell-specific enhancers.
</p><p>Hence macrophages isolated from MafB- and c-Maf-double deficient mice divide indefinitely; the self-renewal depends on <a href="https://en.wikipedia.org/wiki/Myc" title="Myc">c-Myc</a> and <a href="https://en.wikipedia.org/wiki/KLF4" title="KLF4">Klf4</a>.
</p>
<h3><span class="mw-headline" id="Indirect_lineage_conversion">Indirect lineage conversion</span></h3><p>Indirect
lineage conversion is a reprogramming methodology in which somatic
cells transition through a plastic intermediate state of partially
reprogrammed cells (pre-iPSC), induced by brief exposure to
reprogramming factors, followed by differentiation in a specially
developed chemical environment (artificial niche).
</p><p>This method could be both more efficient and safer, since it does
not seem to produce tumors or other undesirable genetic changes and
results in much greater yield than other methods. However, the safety of
these cells remains questionable. Since lineage conversion from
pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction
of the cells could acquire pluripotent properties if they do not stop
the de-differentation process in vitro or due to further
de-differentiation in vivo.
</p>
<h3><span class="mw-headline" id="Outer_membrane_glycoprotein">Outer membrane glycoprotein</span></h3><p>A common feature of pluripotent stem cells is the specific nature of protein <a href="https://en.wikipedia.org/wiki/Glycosylation" title="Glycosylation">glycosylation</a> of their outer membrane. That distinguishes them from most nonpluripotent cells, although not from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/White_blood_cells" title="White blood cells">white blood cells</a>. The <a href="https://en.wikipedia.org/wiki/Glycan" title="Glycan">glycans</a>
on the stem cell surface respond rapidly to alterations in cellular
state and signaling and are therefore ideal for identifying even minor
changes in cell populations. Many <a href="https://en.wikipedia.org/wiki/Stem_cell_marker" title="Stem cell marker">stem cell markers</a> are based on cell surface glycan epitopes, including the widely used markers <a href="https://en.wikipedia.org/wiki/Stage_specific_embryonic_antigen_3" title="Stage specific embryonic antigen 3">SSEA-3</a>, SSEA-4, Tra 1-60 and Tra 1-81. Suila Heli et al.
speculate that in human stem cells, extracellular O-GlcNAc and
extracellular O-LacNAc play a crucial role in the fine tuning of <a href="https://en.wikipedia.org/wiki/Notch_signaling_pathway" title="Notch signaling pathway">Notch signaling pathway</a>
- a highly conserved cell signaling system that regulates cell fate
specification, differentiation, left–right asymmetry, apoptosis,
somitogenesis, and angiogenesis, and plays a key role in stem cell
proliferation (reviewed by Perdigoto and Bardin and Jafar-Nejad et al.)
</p><p>Changes in outer membrane protein glycosylation are markers of
cell states connected in some way with pluripotency and differentiation.
The glycosylation change is apparently not just the result of the
initialization of gene expression, but also performs as an important
gene regulator involved in the acquisition and maintenance of the
undifferentiated state.
</p><p>For example, activation of <a href="https://en.wikipedia.org/wiki/Glycoprotein" title="Glycoprotein">glycoprotein</a> ACA,
linking glycosylphosphatidylinositol on the surface of the progenitor
cells in human peripheral blood induces increased expression of genes <a href="https://en.wikipedia.org/wiki/Wnt_signaling_pathway" title="Wnt signaling pathway">Wnt</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Notch-1" title="Notch-1">Notch-1</a>, <a href="https://en.wikipedia.org/wiki/BMI1" title="BMI1">BMI1</a> and <a href="https://en.wikipedia.org/wiki/HOXB4" title="HOXB4">HOXB4</a> through a signaling cascade <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PI3K" title="PI3K">PI3K</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Akt" title="Akt">Akt</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin" title="Mammalian target of rapamycin">mTor</a>/<a href="https://en.wikipedia.org/wiki/PTEN_(gene)" title="PTEN (gene)">PTEN</a> and promotes the formation of a self-renewing population of hematopoietic stem cells.
</p><p>Furthermore, dedifferentiation of progenitor cells induced by
ACA-dependent signaling pathway leads to ACA-induced pluripotent stem
cells, capable of differentiating in vitro into cells of all three <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Germ_layers" title="Germ layers">germ layers</a>. The study of <a href="https://en.wikipedia.org/wiki/Lectin" title="Lectin">lectins</a>' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin <a href="https://en.wikipedia.org/wiki/Erythrina_crista-galli" title="Erythrina crista-galli">Erythrina crista-galli</a> (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.
</p>
<h4><span class="mw-headline" id="Reprogramming_with_a_proteoglycan">Reprogramming with a proteoglycan</span></h4><p>An alternative strategy to convert somatic cells to pluripotent states may be continuous stimulation of fibroblasts by a single <a href="https://en.wikipedia.org/wiki/Extracellular_matrix" title="Extracellular matrix">ECM</a> <a href="https://en.wikipedia.org/wiki/Proteoglycan" title="Proteoglycan">proteoglycan</a>, <a href="https://en.wikipedia.org/wiki/Fibromodulin" title="Fibromodulin">fibromodulin</a>. Such cells exhibit capability for skeletal muscle regeneration with markedly lower tumorigenic risk when compared to iPSCs.
The decreased tumorigenicity of such cells is related to CDKN2B
upregulation during the recombinant human fibromodulin reprogramming
process
</p>
<h3><span class="mw-headline" id="Reprogramming_through_a_physical_approach">Reprogramming through a physical approach</span></h3><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cell_adhesion_protein" title="Cell adhesion protein">Cell adhesion protein</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/CDH1_(gene)" title="CDH1 (gene)">E-cadherin</a> is indispensable for a robust pluripotent <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">phenotype</a>. During reprogramming for iPS cell generation, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/CDH2" title="CDH2">N-cadherin</a> can replace function of E-cadherin.
These functions of cadherins are not directly related to adhesion
because sphere morphology helps maintaining the "stemness" of stem
cells.
Moreover, sphere formation, due to forced growth of cells on a low
attachment surface, sometimes induces reprogramming. For example, neural
progenitor cells can be generated from fibroblasts directly through a
physical approach without introducing exogenous reprogramming factors.
</p><p>Physical cues, in the form of parallel microgrooves on the
surface of cell-adhesive substrates, can replace the effects of
small-molecule epigenetic modifiers and significantly improve
reprogramming efficiency. The mechanism relies on the mechanomodulation
of the cells' epigenetic state. Specifically, "decreased histone
deacetylase activity and upregulation of the expression of WD repeat
domain 5 (WDR5) – a subunit of H3 methyltranferase – by microgrooved
surfaces lead to increased histone H3 acetylation and methylation".
Nanofibrous scaffolds with aligned fibre orientation produce effects
similar to those produced by microgrooves, suggesting that changes in
cell morphology may be responsible for modulation of the epigenetic
state.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Adhesion_diagram.jpg"><img alt="A" class="mw-file-element" data-file-height="252" data-file-width="359" height="280" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/5d/Adhesion_diagram.jpg/220px-Adhesion_diagram.jpg" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Role_of_cell_adhesions_in_neural_development" title="Role of cell adhesions in neural development">Role of cell adhesions in neural development</a>. Image courtesy of Wikipedia user JWSchmidt under the GNU Free Documentation License</figcaption></figure>
<p>Substrate rigidity is an important biophysical cue influencing neural
induction and subtype specification. For example, soft substrates
promote neuroepithelial conversion while inhibiting <a href="https://en.wikipedia.org/wiki/Neural_crest" title="Neural crest">neural crest</a> differentiation of hESCs in a <a href="https://en.wikipedia.org/wiki/Bone_morphogenetic_protein_4" title="Bone morphogenetic protein 4">BMP4</a>-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive <a href="https://en.wikipedia.org/wiki/SMAD_(protein)" title="SMAD (protein)">Smad</a> <a href="https://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation">phosphorylation</a> and nucleocytoplasmic shuttling, regulated by rigidity-dependent <a href="https://en.wikipedia.org/wiki/Hippo_signaling_pathway" title="Hippo signaling pathway">Hippo</a>/<a href="https://en.wikipedia.org/wiki/YAP1" title="YAP1">YAP</a> activities and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Actomyosin" title="Actomyosin">actomyosin</a> <a href="https://en.wikipedia.org/wiki/Cytoskeleton" title="Cytoskeleton">cytoskeleton</a> integrity and <a href="https://en.wikipedia.org/wiki/Contractility" title="Contractility">contractility</a>.
</p><p>Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the <a href="https://en.wikipedia.org/wiki/Cytokine" title="Cytokine">cytokine</a> <a href="https://en.wikipedia.org/wiki/Leukemia_inhibitory_factor" title="Leukemia inhibitory factor">leukemia inhibitory factor</a> (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cell–substratum <a href="https://en.wikipedia.org/wiki/Adhesion" title="Adhesion">adhesion</a>
and cell spreading. Restricted cell spreading in the absence of LIF by
either culturing mESCs on chemically defined, weakly adhesive
biosubstrates, or by manipulating the <a href="https://en.wikipedia.org/wiki/Cytoskeleton" title="Cytoskeleton">cytoskeleton</a>,
allowed the cells to remain in an undifferentiated and pluripotent
state. The effect of restricted cell spreading on mESC self-renewal is
not mediated by increased intercellular adhesion, as inhibition of mESC
adhesion using a function blocking anti E-cadherin antibody or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SiRNA" title="SiRNA">siRNA</a> does not promote differentiation.
Possible mechanisms of stem cell fate predetermination by physical
interactions with the extracellular matrix have been described.
</p><p>A new method has been developed that turns cells into stem cells
faster and more efficiently by 'squeezing' them using 3D
microenvironment stiffness and density of the surrounding gel. The
technique can be applied to a large number of cells to produce stem
cells for medical purposes on an industrial scale.
</p><p>Cells involved in the reprogramming process change
morphologically as the process proceeds. This results in physical
differences in adhesive forces among cells. Substantial differences in
'adhesive signature' between pluripotent stem cells, partially
reprogrammed cells, differentiated progeny and somatic cells allowed the
development of separation process for isolation of pluripotent stem
cells in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Microfluidic_device" title="Microfluidic device">microfluidic devices</a>, which is:
</p>
<ol><li>fast (separation takes less than 10 minutes);</li><li>efficient (separation results in a greater than 95 percent pure iPS cell culture);</li><li>innocuous (cell survival rate is greater than 80 percent and the
resulting cells retain normal transcriptional profiles, differentiation
potential and karyotype).</li></ol>
<p>Stem cells possess mechanical memory (they remember past physical signals) – with the <a href="https://en.wikipedia.org/wiki/Hippo_signaling_pathway" title="Hippo signaling pathway">Hippo signaling pathway</a> factors. Yes-associated protein (YAP) and <a href="https://en.wikipedia.org/wiki/Coactivator_(genetics)" title="Coactivator (genetics)">transcriptional coactivator</a>
with PDZ-binding domain (TAZ) acting as an intracellular mechanical
rheostat—that stores information from past physical environments and
influences the cells' fate.
</p>
<h3><span class="mw-headline" id="Neural_stem_cells">Neural stem cells</span></h3><p>Stroke
and many neurodegenerative disorders, such as Parkinson's disease,
Alzheimer's disease, and amyotrophic lateral sclerosis, need cell
replacement therapies. The successful use of converted neural cells
(cNs) in transplantations opens a new avenue to treat such diseases.
Nevertheless, induced neurons (iNs) directly converted from fibroblasts
are terminally committed and exhibit very limited proliferative ability
that may not provide enough <a href="https://en.wikipedia.org/wiki/Autotransplantation" title="Autotransplantation">autologous donor</a> cells for transplantation.
Self-renewing induced neural stem cells (iNSCs) provide additional
advantages over iNs for both basic research and clinical applications.
</p><p>For example, under specific growth conditions, mouse fibroblasts
can be reprogrammed with a single factor, Sox2, to form iNSCs that
self-renew in culture and after transplantation and can survive and
integrate without forming tumors in mouse brains.
INSCs can be derived from adult human fibroblasts by non-viral
techniques, thus offering a safe method for autologous transplantation
or for the development of cell-based disease models.
</p><p>Neural chemically induced progenitor cells (ciNPCs) can be
generated from mouse tail-tip fibroblasts and human urinary somatic
cells without introducing exogenous factors, but - by a chemical
cocktail, namely VCR (V, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Valproic_acid" title="Valproic acid">VPA</a>, an <a href="https://en.wikipedia.org/wiki/Histone_deacetylase#HDAC_inhibitors" title="Histone deacetylase">inhibitor of HDACs</a>; C, CHIR99021, an <a href="https://en.wikipedia.org/wiki/GSK-3#Inhibitors" title="GSK-3">inhibitor of GSK-3 kinases</a> and R, <a class="external text" href="https://web.archive.org/web/20140328213812/http://xcessbio.com/index.php/small-molecules/tgf/repsox.html" rel="nofollow">RepSox</a>, an inhibitor of <a href="https://en.wikipedia.org/wiki/TGF_beta_signaling_pathway" title="TGF beta signaling pathway">TGF beta signaling pathways</a>), under a physiological <a href="https://en.wikipedia.org/wiki/Hypoxia_(environmental)" title="Hypoxia (environmental)">hypoxic condition</a>. Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase and TGF-β pathways (where: <a href="https://en.wikipedia.org/wiki/Sodium_butyrate" title="Sodium butyrate">sodium butyrate</a> (NaB) or <a href="https://en.wikipedia.org/wiki/Trichostatin_A" title="Trichostatin A">Trichostatin A</a> (TSA) could replace VPA, <a href="https://en.wikipedia.org/wiki/Lithium_chloride" title="Lithium chloride">Lithium chloride</a> (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with <a href="https://en.wikipedia.org/wiki/SB-431542" title="SB-431542">SB-431542</a> or <a href="https://en.wikipedia.org/wiki/Tranilast" title="Tranilast">Tranilast</a>) show similar efficacies for ciNPC induction.
Zhang, et al.,
also report highly efficient reprogramming of mouse fibroblasts into
induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine
components.
</p><p>Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.
</p><p>Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a>
directly in the brain that are engineered to express inducible forms of
neural reprogramming genes, into neurons, when reprogramming genes (<a href="https://en.wikipedia.org/wiki/ASCL1" title="ASCL1">Ascl1</a>, <a href="https://en.wikipedia.org/wiki/POU3F2" title="POU3F2">Brn2a</a> and <a class="new" href="https://en.wikipedia.org/w/index.php?title=Myt1l&action=edit&redlink=1" title="Myt1l (page does not exist)">Myt1l</a>) are activated after transplantation using a drug.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Astrocytes" title="Astrocytes">Astrocytes</a> – the most common <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neuroglia" title="Neuroglia">neuroglial</a> brain cells, which contribute to <a href="https://en.wikipedia.org/wiki/Scar" title="Scar">scar</a>
formation in response to injury – can be directly reprogrammed in vivo
to become functional neurons that form networks in mice without the need
for cell transplantation.
The researchers followed the mice for nearly a year to look for signs
of tumor formation and reported finding none. The same researchers have
turned scar-forming astrocytes into progenitor cells, called
neuroblasts, that regenerated into neurons in the injured adult spinal
cord.
</p>
<h3><span class="mw-headline" id="Oligodendrocyte_precursor_cells">Oligodendrocyte precursor cells</span></h3><p>Without <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a>
to insulate neurons, nerve signals quickly lose power. Diseases that
attack myelin, such as multiple sclerosis, result in nerve signals that
cannot propagate to nerve endings and as a consequence lead to
cognitive, motor and sensory problems. Transplantation of <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocyte</a>
precursor cells (OPCs), which can successfully create myelin sheaths
around nerve cells, is a promising potential therapeutic response.
Direct lineage conversion of mouse and rat fibroblasts into
oligodendroglial cells provides a potential source of OPCs. Conversion
by forced expression of both eight or of the three transcription factors Sox10, Olig2 and Zfp536, may provide such cells.
</p>
<h3><span class="mw-headline" id="Cardiomyocytes">Cardiomyocytes</span></h3><p>Cell-based
in vivo therapies may provide a transformative approach to augment
vascular and muscle growth and to prevent non-contractile scar formation
by delivering transcription factors or microRNAs to the heart. Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into <a href="https://en.wikipedia.org/wiki/Cardiac_muscle" title="Cardiac muscle">cardiomyocyte</a>-like
cells in vivo by local delivery of cardiac core transcription factors (
GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1,
Myocardin and ZFPM2) after coronary <a href="https://en.wikipedia.org/wiki/Ligature_(medicine)" title="Ligature (medicine)">ligation</a>.
These results implicated therapies that can directly remuscularize the
heart without cell transplantation. However, the efficiency of such
reprogramming turned out to be very low and the phenotype of received
cardiomyocyte-like cells does not resemble those of a mature normal
cardiomyocyte. Furthermore, transplantation of cardiac transcription
factors into injured murine hearts resulted in poor cell survival and
minimal expression of cardiac genes.
</p><p>Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.
Efficient cardiac differentiation of human iPS cells gave rise to
progenitors that were retained within infarcted rat hearts and reduced
remodeling of the heart after ischemic damage.
</p><p>The team of scientists, led by Sheng Ding, used a cocktail of
nine chemicals (9C) for transdifferentiation of human skin cells into
beating heart cells. With this method, more than 97% of the cells began
beating, a characteristic of fully developed, healthy heart cells. The
chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted
and resembled human cardiomyocytes in their transcriptome, epigenetic,
and electrophysiological properties. When transplanted into infarcted
mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs
and developed into healthy-looking heart muscle cells within the organ.
This chemical reprogramming approach, after further optimization, may
offer an easy way to provide the cues that induce heart muscle to
regenerate locally.
</p><p>In another study, <a href="https://en.wikipedia.org/wiki/Ischemic_cardiomyopathy" title="Ischemic cardiomyopathy">ischemic cardiomyopathy</a>
in the murine infarction model was targeted by iPS cell
transplantation. It synchronized failing ventricles, offering a
regenerative strategy to achieve resynchronization and protection from <a href="https://en.wikipedia.org/wiki/Decompensation" title="Decompensation">decompensation</a> by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.
One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical <a href="https://en.wikipedia.org/wiki/Wnt_signaling_pathway" title="Wnt signaling pathway">Wnt signaling pathway</a> at defined time points in during differentiation, using readily accessible small molecule compounds.
</p><p>Discovery of the mechanisms controlling the formation of
cardiomyocytes led to the development of the drug ITD-1, which
effectively clears the cell surface from <a href="https://en.wikipedia.org/wiki/Transforming_growth_factor_beta" title="Transforming growth factor beta">TGF-β</a>
receptor type II and selectively inhibits intracellular TGF-β
signaling. It thus selectively enhances the differentiation of
uncommitted <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesoderm</a> to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.
</p><p>One project seeded decellularized mouse hearts with human
iPSC-derived multipotential cardiovascular progenitor cells. The
introduced cells migrated, proliferated and differentiated in situ into
cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct
the hearts. In addition, the heart's extracellular matrix (the
substrate of heart scaffold) signalled the human cells into becoming the
specialised cells needed for proper heart function. After 20 days of
perfusion with growth factors, the engineered heart tissues started to
beat again and were responsive to drugs.
</p><p>Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) <i>in situ</i> represents a promising strategy for cardiac regeneration. Mice exposed <i>in vivo</i>, to three cardiac transcription factors GMT (Gata4, Mef2c, Tbx5) and the small-molecules: <a href="https://en.wikipedia.org/wiki/SB-431542" title="SB-431542">SB-431542</a>
(the transforming growth factor (TGF)-β inhibitor), and XAV939 (the WNT
inhibitor) for 2 weeks after myocardial infarction showed significantly
improved reprogramming (reprogramming efficiency increased eight-fold)
and cardiac function compared to those exposed to only GMT.
</p>
<h3><span class="mw-headline" id="Rejuvenation_of_the_muscle_stem_cell">Rejuvenation of the muscle stem cell</span></h3><p>The elderly often with progressive <a href="https://en.wikipedia.org/wiki/Muscle_weakness" title="Muscle weakness">muscle weakness</a> and regenerative failure owing in part to elevated activity of the <a href="https://en.wikipedia.org/wiki/P38_mitogen-activated_protein_kinases" title="P38 mitogen-activated protein kinases">p38α and p38β mitogen-activated kinase</a>
pathway in senescent skeletal muscle stem cells. Subjecting such stem
cells to transient inhibition of p38α and p38β in conjunction with
culture on soft <a href="https://en.wikipedia.org/wiki/Hydrogel" title="Hydrogel">hydrogel</a> substrates rapidly expands and rejuvenates them that result in the return of their strength.
</p><p>In geriatric mice, resting satellite cells lose reversible
quiescence by switching to an irreversible pre-senescence state, caused
by derepression of <a href="https://en.wikipedia.org/wiki/P16" title="P16">p16</a>INK4a
(also called Cdkn2a).
On injury, these cells fail to activate and expand, even in a youthful
environment. p16INK4a silencing in geriatric satellite cells restores
quiescence and muscle regenerative functions.
</p><p>Myogenic progenitors for potential use in disease modeling or
cell-based therapies targeting skeletal muscle could also be generated
directly from induced pluripotent stem cells using <a href="https://en.wikipedia.org/wiki/3D_cell_culture" title="3D cell culture">free-floating spherical culture</a> (EZ spheres) in a culture medium supplemented with high concentrations (100 ng/ml) of fibroblast growth factor-2 (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/FGF-2" title="FGF-2">FGF-2</a>) and <a href="https://en.wikipedia.org/wiki/Epidermal_growth_factor" title="Epidermal growth factor">epidermal growth factor</a>.
</p>
<h3><span class="mw-headline" id="Hepatocytes">Hepatocytes</span></h3><p>Unlike current protocols for deriving <a href="https://en.wikipedia.org/wiki/Hepatocyte" title="Hepatocyte">hepatocytes</a> from human fibroblasts, Saiyong Zhu et al., (2014)
did not generate iPSCs but, using small molecules, cut short
reprogramming to pluripotency to generate an induced multipotent
progenitor cell (iMPC) state from which endoderm progenitor cells and
subsequently hepatocytes (iMPC-Heps) were efficiently differentiated.
After transplantation into an immune-deficient mouse model of human
liver failure, iMPC-Heps proliferated extensively and acquired levels of
hepatocyte function similar to those of human primary adult
hepatocytes. iMPC-Heps did not form tumours, most probably because they
never entered a pluripotent state.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gray1062.png"><img class="mw-file-element" data-file-height="400" data-file-width="159" height="400" src="https://upload.wikimedia.org/wikipedia/commons/e/e5/Gray1062.png" width="159" /></a><figcaption>An intestinal crypt - an accessible and abundant source of intestinal epithelial cells for conversion into β-like cells</figcaption></figure>
<p>These results establish the feasibility of significant liver
repopulation of mice with human hepatocytes generated in vitro, which
removes a long-standing roadblock on the path to autologous liver cell
therapy.
</p><p>A cocktail of small molecules, <a href="https://en.wikipedia.org/wiki/Y-27632" title="Y-27632">Y-27632</a>, A-83-01 (a TGFβ kinase/activin receptor like kinase (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/ALK5" title="ALK5">ALK5</a>) inhibitor), and CHIR99021 (potent inhibitor of <a href="https://en.wikipedia.org/wiki/GSK-3" title="GSK-3">GSK-3</a>),
can convert rat and mouse mature hepatocytes in vitro into
proliferative bipotent cells – CLiPs (chemically induced liver
progenitors). CLiPs can differentiate into both mature hepatocytes and
biliary epithelial cells that can form functional ductal structures. In
long-term culture CLiPs did not lose their proliferative capacity and
their hepatic differentiation ability, and can repopulate chronically
injured liver tissue.
</p>
<h3><span class="mw-headline" id="Insulin-producing_cells">Insulin-producing cells</span></h3><p>Complications of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">Diabetes mellitus</a> such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular_diseases" title="Cardiovascular diseases">cardiovascular diseases</a>, <a href="https://en.wikipedia.org/wiki/Diabetic_retinopathy" title="Diabetic retinopathy">retinopathy</a>, <a href="https://en.wikipedia.org/wiki/Diabetic_neuropathy" title="Diabetic neuropathy">neuropathy</a>, <a href="https://en.wikipedia.org/wiki/Diabetic_nephropathy" title="Diabetic nephropathy">nephropathy</a>, and peripheral circulatory diseases depend on <a href="https://en.wikipedia.org/wiki/Blood_sugar_regulation" title="Blood sugar regulation">sugar dysregulation</a> due to lack of <a href="https://en.wikipedia.org/wiki/Insulin" title="Insulin">insulin</a> from pancreatic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beta_cells" title="Beta cells">beta cells</a>
and can be lethal if they are not treated. One of the promising
approaches to understand and cure diabetes is to use pluripotent stem
cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs
(iPSCs).
Unfortunately, human PSC-derived insulin-expressing cells resemble human
fetal β cells rather than adult β cells. In contrast to adult β cells,
fetal β cells seem functionally immature, as indicated by increased <a href="https://en.wikipedia.org/wiki/Basal_rate" title="Basal rate">basal</a> <a href="https://en.wikipedia.org/wiki/Glucose" title="Glucose">glucose</a> secretion and lack of glucose stimulation and confirmed by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/RNA-seq" title="RNA-seq">RNA-seq</a> of whose <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)">transcripts</a>. An alternative strategy is the conversion of fibroblasts towards
distinct endodermal progenitor cell populations and, using cocktails of
signalling factors, successful differentiation of these endodermal
progenitor cells into functional beta-like cells both in vitro and in
vivo.
</p><p>Overexpression of the three <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factors</a>, <b><a href="https://en.wikipedia.org/wiki/PDX1" title="PDX1">PDX1</a></b> (required for <a href="https://en.wikipedia.org/wiki/Pancreas" title="Pancreas">pancreatic bud outgrowth</a> and beta-cell maturation), <b><a href="https://en.wikipedia.org/wiki/Neurogenins#Neurogenin-3" title="Neurogenins">NGN3</a></b> (required for endocrine precursor cell formation) and <b><a href="https://en.wikipedia.org/wiki/MAF_(gene)" title="MAF (gene)">MAFA</a></b>
(for beta-cell maturation) combination (called PNM) can lead to the
transformation of some cell types into a beta cell-like state.
An accessible and abundant source of functional insulin-producing cells is <a href="https://en.wikipedia.org/wiki/Gastrointestinal_wall" title="Gastrointestinal wall">intestine</a>. PMN expression in human intestinal "<a href="https://en.wikipedia.org/wiki/Organoid" title="Organoid">organoids</a>" stimulates the conversion of intestinal epithelial cells into β-like cells possibly acceptable for <a href="https://en.wikipedia.org/wiki/Islet_cell_transplantation" title="Islet cell transplantation">transplantation</a>.
</p>
<h3><span class="mw-headline" id="Nephron_Progenitors">Nephron Progenitors</span></h3><p>Adult proximal tubule cells were directly transcriptionally reprogrammed to <a href="https://en.wikipedia.org/wiki/Nephron" title="Nephron">nephron</a> progenitors of the embryonic <a href="https://en.wikipedia.org/wiki/Kidney" title="Kidney">kidney</a>,
using a pool of six genes of instructive transcription factors (SIX1,
SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail
homolog 2 (SNAI2)) that activated genes consistent with a cap <a href="https://en.wikipedia.org/wiki/Mesenchyme" title="Mesenchyme">mesenchyme</a>/nephron progenitor phenotype in the adult proximal tubule cell line.
The generation of such cells may lead to cellular therapies for adult <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Renal_disease" title="Renal disease">renal disease</a>. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development.
</p>
<h3><span class="mw-headline" id="Blood_vessel_cells">Blood vessel cells</span></h3><p>As
blood vessels age, they often become abnormal in structure and
function, thereby contributing to numerous age-associated diseases
including myocardial infarction, ischemic stroke and atherosclerosis of
arteries supplying the heart, brain and lower extremities. So, an
important goal is to stimulate vascular growth for the <a href="https://en.wikipedia.org/wiki/Collateral_circulation" title="Collateral circulation">collateral circulation</a>
to prevent the exacerbation of these diseases. Induced Vascular
Progenitor Cells (iVPCs) are useful for cell-based therapy designed to
stimulate coronary collateral growth. They were generated by partially
reprogramming endothelial cells.
The vascular commitment of iVPCs is related to the epigenetic memory of
endothelial cells, which engenders them as cellular components of
growing blood vessels. That is why, when iVPCs were implanted into <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myocardium" title="Myocardium">myocardium</a>,
they engrafted in blood vessels and increased coronary collateral flow
better than iPSCs, mesenchymal stem cells, or native endothelial cells.
</p><p>Ex vivo genetic modification can be an effective strategy to
enhance stem cell function. For example, cellular therapy employing
genetic modification with <a href="https://en.wikipedia.org/wiki/PIM1" title="PIM1">Pim-1</a> kinase (a downstream effector of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Akt" title="Akt">Akt</a>, which positively regulates neovasculogenesis) of <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">bone marrow</a>–derived cells or human cardiac progenitor cells, isolated from failing myocardium results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.
</p><p>Stem cells extracted from fat tissue after <a href="https://en.wikipedia.org/wiki/Liposuction" title="Liposuction">liposuction</a> may be coaxed into becoming progenitor <a href="https://en.wikipedia.org/wiki/Vascular_smooth_muscle" title="Vascular smooth muscle">smooth muscle</a> cells (iPVSMCs) found in arteries and veins.
</p><p>The 2D culture system of human iPS cells in conjunction with triple marker selection (<a href="https://en.wikipedia.org/wiki/CD34" title="CD34">CD34</a> (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblasts), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/NP1" title="NP1">NP1</a> (receptor – neuropilin 1) and <a href="https://en.wikipedia.org/wiki/Kinase_insert_domain_receptor" title="Kinase insert domain receptor">KDR</a>
(kinase insert domain-containing receptor)) for the isolation of
vasculogenic precursor cells from human iPSC, generated endothelial
cells that, after transplantation, formed stable, functional mouse blood
vessels in vivo, lasting for 280 days.
</p><p>To treat infarction, it is important to prevent the formation of
fibrotic scar tissue. This can be achieved in vivo by transient
application of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Paracrine" title="Paracrine">paracrine</a>
factors that redirect native heart progenitor stem cell contributions
from scar tissue to cardiovascular tissue. For example, in a mouse
myocardial infarction model, a single intramyocardial injection of human
<a href="https://en.wikipedia.org/wiki/Vascular_endothelial_growth_factor_A" title="Vascular endothelial growth factor A">vascular endothelial growth factor A</a>
mRNA (VEGF-A modRNA), modified to escape the body's normal defense
system, results in long-term improvement of heart function due to
mobilization and redirection of epicardial progenitor cells toward
cardiovascular cell types.
</p>
<h3><span class="mw-headline" id="Blood_stem_cells">Blood stem cells</span></h3><h4><span class="mw-headline" id="Red_blood_cells">Red blood cells</span></h4><p>RBC <a href="https://en.wikipedia.org/wiki/Blood_transfusion" title="Blood transfusion">transfusion</a>
is necessary for many patients. However, to date the supply of RBCs
remains labile. In addition, transfusion risks infectious disease
transmission. A large supply of safe RBCs generated in vitro would help
to address this issue. Ex vivo erythroid cell generation may provide
alternative transfusion products to meet present and future clinical
requirements. Red blood cells (RBC)s generated in vitro from mobilized <a href="https://en.wikipedia.org/wiki/CD34" title="CD34">CD34</a> positive cells have normal survival when transfused into an autologous recipient. RBC produced in vitro contained exclusively <a href="https://en.wikipedia.org/wiki/Fetal_hemoglobin" title="Fetal hemoglobin">fetal hemoglobin</a>
(HbF), which rescues the functionality of these RBCs. In vivo the
switch of fetal to adult hemoglobin was observed after infusion of
nucleated <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Erythroid" title="Erythroid">erythroid</a> precursors derived from iPSCs.
Although RBCs do not have nuclei and therefore can not form a tumor,
their immediate erythroblasts precursors have nuclei. The terminal
maturation of erythroblasts into functional RBCs requires a complex
remodeling process that ends with extrusion of the nucleus and the
formation of an enucleated RBC.
Cell reprogramming often disrupts enucleation. Transfusion of in
vitro-generated RBCs or erythroblasts does not sufficiently protect
against tumor formation.
</p><p>The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aryl" title="Aryl">aryl</a>
hydrocarbon receptor (AhR) pathway (which has been shown to be involved
in the promotion of cancer cell development) plays an important role in
normal blood cell development. AhR activation in human hematopoietic
progenitor cells (HPs) drives an unprecedented expansion of HPs,
megakaryocyte- and erythroid-lineage cells.
See also Concise Review:
The <a href="https://en.wikipedia.org/wiki/SH2B3" title="SH2B3">SH2B3</a>
gene encodes a negative regulator of cytokine signaling and naturally
occurring loss-of-function variants in this gene increase RBC counts in
vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem
and progenitor cells enhanced the maturation and overall yield of
in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by <a href="https://en.wikipedia.org/wiki/CRISPR" title="CRISPR">CRISPR</a>/<a href="https://en.wikipedia.org/wiki/Cas9" title="Cas9">Cas9</a> genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation.</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:1908_Platelet_Development.jpg"><img class="mw-file-element" data-file-height="1225" data-file-width="846" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/84/1908_Platelet_Development.jpg/220px-1908_Platelet_Development.jpg" width="276" /></a><figcaption>Platelets extruded from megakaryocytes</figcaption></figure>
<h4><span class="mw-headline" id="Platelets">Platelets</span></h4><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Platelets" title="Platelets">Platelets</a> help prevent hemorrhage in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thrombocytopenic" title="Thrombocytopenic">thrombocytopenic</a> patients and patients with <a href="https://en.wikipedia.org/wiki/Thrombocythemia" title="Thrombocythemia">thrombocythemia</a>.
A significant problem for multitransfused patients is refractoriness to
platelet transfusions. Thus, the ability to generate platelet products
ex vivo and platelet products lacking <a href="https://en.wikipedia.org/wiki/Human_leukocyte_antigen" title="Human leukocyte antigen">HLA antigens</a> in serum-free media would have clinical value.
An <a href="https://en.wikipedia.org/wiki/RNA_interference" title="RNA interference">RNA interference</a>-based mechanism used a <a href="https://en.wikipedia.org/wiki/Viral_vector" title="Viral vector">lentiviral vector</a>
to express short-hairpin RNAi targeting β2-microglobulin transcripts in
CD34-positive cells. Generated platelets demonstrated an 85% reduction
in class I HLA antigens. These platelets appeared to have normal
function in vitro
</p><p>One clinically applicable strategy for the derivation of
functional platelets from human iPSC involves the establishment of
stable immortalized megakaryocyte progenitor cell lines (imMKCLs)
through <a href="https://en.wikipedia.org/wiki/Doxycycline" title="Doxycycline">doxycycline</a>-dependent overexpression of <a href="https://en.wikipedia.org/wiki/BMI1" title="BMI1">BMI1</a> and <a href="https://en.wikipedia.org/wiki/Bcl-xL" title="Bcl-xL">BCL-XL</a>. The resulting imMKCLs can be expanded in culture over extended periods (4–5 months), even after <a href="https://en.wikipedia.org/wiki/Cryopreservation" title="Cryopreservation">cryopreservation</a>. Halting the overexpression (by the removal of doxycycline from the medium) of c-MYC, <a href="https://en.wikipedia.org/wiki/BMI1" title="BMI1">BMI1</a> and <a href="https://en.wikipedia.org/wiki/Bcl-xL" title="Bcl-xL">BCL-XL</a> in growing imMKCLs led to the production of <a href="https://en.wikipedia.org/wiki/GP1BA" title="GP1BA">CD42b</a>+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo.
Thomas et al., describe a forward programming strategy relying on the
concurrent exogenous expression of 3 transcription factors: <a href="https://en.wikipedia.org/wiki/GATA1" title="GATA1">GATA1</a>, <a href="https://en.wikipedia.org/wiki/FLI1" title="FLI1">FLI1</a> and <a href="https://en.wikipedia.org/wiki/TAL1" title="TAL1">TAL1</a>. The forward programmed <a href="https://en.wikipedia.org/wiki/Megakaryocyte#Platelet_release" title="Megakaryocyte">megakaryocytes</a> proliferate and differentiate in culture for several months with megakaryocyte purity over 90% reaching up to 2x10<sup>5</sup>
mature megakaryocytes per input hPSC. Functional platelets are
generated throughout the culture allowing the prospective collection of
several transfusion units from as few as one million starting hPSCs.
</p>
<h4><span class="mw-headline" id="Immune_cells">Immune cells</span></h4><p>A specialised type of <a href="https://en.wikipedia.org/wiki/White_blood_cell" title="White blood cell">white blood cell</a>, known as <a href="https://en.wikipedia.org/wiki/Cytotoxic_T_cell" title="Cytotoxic T cell">cytotoxic T</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lymphocytes" title="Lymphocytes">lymphocytes</a> (CTLs), are produced by the <a href="https://en.wikipedia.org/wiki/Immune_system" title="Immune system">immune system</a>
and are able to recognise specific markers on the surface of various
infectious or tumour cells, causing them to launch an attack to kill the
harmful cells. Thence, immunotherapy with functional antigen-specific T
cells has potential as a therapeutic strategy for combating many
cancers and viral infections. However, cell sources are limited, because they are produced in small numbers naturally and have a short lifespan.
</p><p>A potentially efficient approach for generating antigen-specific
CTLs is to revert mature immune T cells into iPSCs, which possess
indefinite proliferative capacity in vitro and after their
multiplication to coax them to redifferentiate back into T cells.
</p><p>Another method combines iPSC and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chimeric_antigen_receptor" title="Chimeric antigen receptor">chimeric antigen receptor</a> (CAR) technologies to generate human T cells targeted to <a href="https://en.wikipedia.org/wiki/CD19" title="CD19">CD19</a>, an antigen expressed by malignant <a href="https://en.wikipedia.org/wiki/B_cell" title="B cell">B cells</a>, in tissue culture. This approach of generating therapeutic human T cells may be useful for cancer immunotherapy and other medical applications.
</p><p>Invariant <a href="https://en.wikipedia.org/wiki/Natural_killer_T_cell" title="Natural killer T cell">natural killer T</a> (iNKT) cells have great clinical potential as <a href="https://en.wikipedia.org/wiki/Adjuvant" title="Adjuvant">adjuvants</a> for cancer immunotherapy. iNKT cells act as innate T lymphocytes and serve as a bridge between the <a href="https://en.wikipedia.org/wiki/Innate_immune_system" title="Innate immune system">innate</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acquired_immune_system" title="Acquired immune system">acquired immune systems</a>. They augment anti-tumor responses by producing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interferon-gamma" title="Interferon-gamma">interferon-gamma</a> (IFN-γ).
The approach of collection, reprogramming/dedifferentiation,
re-differentiation and injection has been proposed for related tumor
treatment.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dendritic_cells" title="Dendritic cells">Dendritic cells</a>
(DC) are specialized to control T-cell responses. DC with appropriate
genetic modifications may survive long enough to stimulate
antigen-specific CTL and after that be eliminated. DC-like
antigen-presenting cells obtained from human induced pluripotent stem
cells can serve as a source for <a href="https://en.wikipedia.org/wiki/Vaccination" title="Vaccination">vaccination</a> therapy.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ccaat-enhancer-binding_proteins" title="Ccaat-enhancer-binding proteins">CCAAT/enhancer binding protein-α (C/EBPα)</a> induces transdifferentiation of <a href="https://en.wikipedia.org/wiki/B_cell" title="B cell">B cells</a> into <a href="https://en.wikipedia.org/wiki/Macrophage" title="Macrophage">macrophages</a> at high efficiencies and enhances reprogramming into iPS cells when co-expressed with transcription factors Oct4, Sox2, Klf4 and Myc. with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population.
Furthermore, C/EBPa can convert selected human B cell lymphoma and
leukemia cell lines into macrophage-like cells at high efficiencies,
impairing the cells' tumor-forming capacity.
</p>
<h3><span class="mw-headline" id="Thymic_epithelial_cells_rejuvenation">Thymic epithelial cells rejuvenation</span></h3><p>The <a href="https://en.wikipedia.org/wiki/Thymus" title="Thymus">thymus</a>
is the first organ to deteriorate as people age. This shrinking is one
of the main reasons the immune system becomes less effective with age.
Diminished expression of the <a href="https://en.wikipedia.org/wiki/Thymic_epithelial_cell" title="Thymic epithelial cell">thymic epithelial cell</a> transcription factor <a href="https://en.wikipedia.org/wiki/FOXN1" title="FOXN1">FOXN1</a> has been implicated as a component of the mechanism regulating age-related involution.
</p><p><a href="https://en.wikipedia.org/wiki/Clare_Blackburn" title="Clare Blackburn">Clare Blackburn</a>
and colleagues show that established age-related thymic involution can
be reversed by forced upregulation of just one transcription factor –
FOXN1 in the thymic epithelial cells in order to promote <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rejuvenation_(aging)" title="Rejuvenation (aging)">rejuvenation</a>, proliferation and differentiation of these cells into fully functional thymic epithelium.
This rejuvenation and increased proliferation was accompanied by upregulation of genes that promote <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a> progression (<a href="https://en.wikipedia.org/wiki/Cyclin_D1" title="Cyclin D1">cyclin D1</a>, ΔN<a href="https://en.wikipedia.org/wiki/TP63" title="TP63">p63</a>, <a href="https://en.wikipedia.org/wiki/Fibroblast_growth_factor_receptor_2#Isoforms" title="Fibroblast growth factor receptor 2">FgfR2IIIb</a>) and that are required in the thymic epithelial cells to promote specific aspects of <a href="https://en.wikipedia.org/wiki/T_cell" title="T cell">T cell</a> development (<a href="https://en.wikipedia.org/wiki/DLL4" title="DLL4">Dll4</a>, <a href="https://en.wikipedia.org/wiki/Stem_cell_factor" title="Stem cell factor">Kitl</a>, <a href="https://en.wikipedia.org/wiki/CCL25" title="CCL25">Ccl25</a>, <a href="https://en.wikipedia.org/wiki/Stromal_cell-derived_factor_1" title="Stromal cell-derived factor 1">Cxcl12</a>, <a href="https://en.wikipedia.org/wiki/CD40_(protein)" title="CD40 (protein)">Cd40</a>, <a href="https://en.wikipedia.org/wiki/CD80" title="CD80">Cd80</a>, <a href="https://en.wikipedia.org/wiki/Cathepsin_L1" title="Cathepsin L1">Ctsl</a>, <a href="https://en.wikipedia.org/wiki/PAX1" title="PAX1">Pax1</a>). In the future, this method may be widely used to enhance immune function and combat <a href="https://en.wikipedia.org/wiki/Inflammaging" title="Inflammaging">Inflammaging</a> in patients by rejuvenating the thymus <i> <a href="https://en.wikipedia.org/wiki/In_situ" title="In situ">in situ</a> </i>.
</p>
<h3><span class="mw-headline" id="Mesenchymal_stem_cells">Mesenchymal stem cells</span></h3><h4><span class="mw-headline" id="Induction">Induction</span></h4><p><a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">Mesenchymal stem/stromal cells</a>
(MSCs) are under investigation for applications in cardiac, renal,
neural, joint and bone repair, as well as in inflammatory conditions and
hemopoietic cotransplantation.<sup class="reference" id="cite_ref-Fu_X_274-0"><a href="https://en.wikipedia.org/wiki/Induced_stem_cells#cite_note-Fu_X-274">[274]</a></sup>
This is because of their immunosuppressive properties and ability to
differentiate into a wide range of mesenchymal-lineage tissues. MSCs are
typically harvested from adult bone marrow or fat, but these require
painful invasive procedures and are low-frequency sources, making up
only 0.001–0.01% of bone marrow cells and 0.05% in liposuction
aspirates.
Of concern for autologous use, in particular in the elderly most in
need of tissue repair, MSCs decline in quantity and quality with age.
</p><p>IPSCs could be obtained by the cells rejuvenation of even centenarians.
Because iPSCs can be harvested free of ethical constraints and culture
can be expanded indefinitely, they are an advantageous source of MSCs. IPSC treatment with <a href="https://en.wikipedia.org/wiki/SB-431542" title="SB-431542">SB-431542</a> leads to rapid and uniform MSC generation from human iPSCs. (SB-431542 is an inhibitor of activin/TGF- pathways by blocking <a href="https://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation">phosphorylation</a> of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ALK4" title="ALK4">ALK4</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ALK5" title="ALK5">ALK5</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ALK7" title="ALK7">ALK7</a>
receptors.) These iPS-MSCs may lack teratoma-forming ability, display a
normal stable karyotype in culture and exhibit growth and
differentiation characteristics that closely resemble those of primary
MSCs. It has potential for in vitro scale-up, enabling MSC-based
therapies.
MSC derived from iPSC have the capacity to aid periodontal regeneration
and are a promising source of readily accessible stem cells for use in
the clinical treatment of periodontitis.
</p><p>Lai et al., & Lu report the chemical method to generate
MSC-like cells (iMSCs), from human primary dermal fibroblasts using six
chemical inhibitors (SP600125, SB202190, Go6983, Y-27632, PD0325901, and
CHIR99021) with or without 3 growth factors (transforming growth
factor-β (TGF-β), basic fibroblast growth factor (bFGF), and leukemia
inhibitory factor (LIF)). The chemical cocktail directly converts human
fibroblasts to iMSCs with a monolayer culture in 6 days, and the
conversion rate was approximately 38%.
</p><p>Besides cell therapy in vivo, the culture of human mesenchymal stem cells can be used in vitro for mass-production of <a href="https://en.wikipedia.org/wiki/Exosome_(vesicle)" title="Exosome (vesicle)">exosomes</a>, which are ideal vehicles for drug delivery.
</p>
<h4><span class="mw-headline" id="Dedifferentiated_adipocytes">Dedifferentiated adipocytes</span></h4><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Adipose" title="Adipose">Adipose</a>
tissue, because of its abundance and relatively less invasive harvest
methods, represents a source of mesenchymal stem cells (MSCs).
Unfortunately, liposuction aspirates are only 0.05% MSCs.
However, a large amount of mature adipocytes, which in general have
lost their proliferative abilities and therefore are typically
discarded, can be easily isolated from the adipose cell suspension and
dedifferentiated into <a href="https://en.wikipedia.org/wiki/Lipid" title="Lipid">lipid</a>-free
fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT
cells re-establish active proliferation ability and express multipotent
capacities.
Compared with adult stem cells, DFAT cells show unique advantages in
abundance, isolation and homogeneity. Under proper induction culture in
vitro or proper environment in vivo, DFAT cells could demonstrate
adipogenic, osteogenic, chondrogenic and myogenic potentials. They could
also exhibit perivascular characteristics and elicit
neovascularization.
</p>
<h3><span class="mw-headline" id="Chondrogenic_cells">Chondrogenic cells</span></h3><p><a href="https://en.wikipedia.org/wiki/Cartilage" title="Cartilage">Cartilage</a>
is the connective tissue responsible for frictionless joint movement.
Its degeneration ultimately results in complete loss of joint function
in the late stages of <a href="https://en.wikipedia.org/wiki/Osteoarthritis" title="Osteoarthritis">osteoarthritis</a>. As an avascular and hypocellular tissue, cartilage has a limited capacity for self-repair. <a href="https://en.wikipedia.org/wiki/Chondrocyte" title="Chondrocyte">Chondrocytes</a> are the only cell type in cartilage, in which they are surrounded by the extracellular matrix that they secrete and assemble.
</p><p>One method of producing cartilage is to induce it from iPS cells.
Alternatively, it is possible to convert fibroblasts directly into
induced chondrogenic cells (iChon) without an intermediate iPS cell
stage, by inserting three reprogramming factors (c-MYC, KLF4 and SOX9). Human iChon cells expressed marker genes for chondrocytes (type II collagen) but not fibroblasts.
</p><p>Implanted into defects created in the articular cartilage of
rats, human iChon cells survived to form cartilaginous tissue for at
least four weeks, with no tumors. The method makes use of c-MYC, which
is thought to have a major role in tumorigenesis and employs a <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retrovirus</a> to introduce the reprogramming factors, excluding it from unmodified use in human therapy.
</p>
<h2><span class="mw-headline" id="Sources_of_cells_for_reprogramming">Sources of cells for reprogramming</span></h2><p>The most frequently used sources for reprogramming are blood cells and fibroblasts, obtained by biopsy of the skin, but taking cells from <a href="https://en.wikipedia.org/wiki/Urine" title="Urine">urine</a> is less invasive.
The latter method does not require a biopsy or blood sampling. As of
2013, urine-derived stem cells had been differentiated into endothelial,
osteogenic, chondrogenic, adipogenic, skeletal myogenic and neurogenic
lineages, without forming teratomas.
Therefore, their epigenetic memory is suited to reprogramming into iPS
cells. However, few cells appear in urine, only low conversion
efficiencies had been achieved and the risk of bacterial contamination
is relatively high.
</p><p>Another promising source of cells for reprogramming are mesenchymal stem cells derived from human hair follicles.
</p><p>The origin of somatic cells used for reprogramming may influence the efficiency of reprogramming, the functional properties of the resulting induced stem cells and the ability to form tumors.
</p><p>IPSCs retain an epigenetic memory of their tissue of origin, which impacts their differentiation potential.
This epigenetic memory does not necessarily manifest itself at the
pluripotency stage – iPSCs derived from different tissues exhibit proper
morphology, express pluripotency markers and are able to differentiate
into the three embryonic layers in vitro and in vivo. However, this
epigenetic memory may manifest during re-differentiation into specific
cell types that require the specific loci bearing residual epigenetic
marks.
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-18179201844602560772024-03-28T16:53:00.002-04:002024-03-28T16:53:48.486-04:00Natural science<p></p><div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Natural_science">https://en.wikipedia.org/wiki/Natural_science</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><div class="thumb tmulti tright"><div class="thumbinner multiimageinner"><div class="trow"><div class="tsingle"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:DNA-fragment-3D-vdW.png"><img alt="" class="mw-file-element" data-file-height="1000" data-file-width="907" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/2c/DNA-fragment-3D-vdW.png/108px-DNA-fragment-3D-vdW.png" width="363" /></a></span></div></div><div class="tsingle"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Carina_Nebula.jpg"><img alt="" class="mw-file-element" data-file-height="8926" data-file-width="13092" height="273" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/ea/Carina_Nebula.jpg/186px-Carina_Nebula.jpg" width="400" /></a></span></div></div></div><div class="trow"><div class="tsingle"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Volcano_q.jpg"><img alt="" class="mw-file-element" data-file-height="449" data-file-width="678" height="266" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Volcano_q.jpg/176px-Volcano_q.jpg" width="400" /></a></span></div></div><div class="tsingle"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Topspun.jpg"><img alt="" class="mw-file-element" data-file-height="1654" data-file-width="1686" height="393" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/94/Topspun.jpg/118px-Topspun.jpg" width="400" /></a></span></div></div></div><div class="trow"><div class="tsingle"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Herd_of_Elephants.jpg"><img alt="" class="mw-file-element" data-file-height="3456" data-file-width="5184" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/93/Herd_of_Elephants.jpg/298px-Herd_of_Elephants.jpg" width="400" /></a></span></div></div></div><div class="trow" style="display: flex;"><div class="thumbcaption">The natural sciences seek to understand how the world and <a href="https://en.wikipedia.org/wiki/Universe" title="Universe">universe</a> around us works. There are five major branches: <a href="https://en.wikipedia.org/wiki/Astronomy" title="Astronomy">astronomy</a>, <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">physics</a>, <a href="https://en.wikipedia.org/wiki/Chemistry" title="Chemistry">chemistry</a>, <a href="https://en.wikipedia.org/wiki/Earth_science" title="Earth science">Earth science</a>, and <a href="https://en.wikipedia.org/wiki/Biology" title="Biology">biology</a>.<b><br /><br />Natural science</b> is one of the <a href="https://en.wikipedia.org/wiki/Branches_of_science" title="Branches of science">branches of science</a> concerned with the description, understanding and prediction of <a href="https://en.wikipedia.org/wiki/Nature" title="Nature">natural</a> <a href="https://en.wikipedia.org/wiki/Phenomenon" title="Phenomenon">phenomena</a>, based on <a href="https://en.wikipedia.org/wiki/Empirical_evidence" title="Empirical evidence">empirical evidence</a> from <a href="https://en.wikipedia.org/wiki/Observation" title="Observation">observation</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Experimentation" title="Experimentation">experimentation</a>. Mechanisms such as <a href="https://en.wikipedia.org/wiki/Peer_review" title="Peer review">peer review</a> and repeatability of findings are used to try to ensure the validity of scientific advances.
</div></div></div></div></div></div></div><p>Natural science can be divided into two main branches: <a href="https://en.wikipedia.org/wiki/List_of_life_sciences" title="List of life sciences">life science</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_physical_science" title="Outline of physical science">physical science</a>. Life science is alternatively known as <a href="https://en.wikipedia.org/wiki/Biology" title="Biology">biology</a>, and physical science is subdivided into branches: <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">physics</a>, <a href="https://en.wikipedia.org/wiki/Chemistry" title="Chemistry">chemistry</a>, <a href="https://en.wikipedia.org/wiki/Earth_science" title="Earth science">earth science</a>, and <a href="https://en.wikipedia.org/wiki/Astronomy" title="Astronomy">astronomy</a>.
These branches of natural science may be further divided into more
specialized branches (also known as fields). As empirical sciences,
natural sciences use tools from the <a href="https://en.wikipedia.org/wiki/Formal_science" title="Formal science">formal sciences</a>, such as <a href="https://en.wikipedia.org/wiki/Mathematics" title="Mathematics">mathematics</a> and <a href="https://en.wikipedia.org/wiki/Logic" title="Logic">logic</a>, converting information about nature into measurements which can be explained as clear statements of the "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Laws_of_science" title="Laws of science">laws of nature</a>".
</p><p>Modern natural science succeeded more classical approaches to <a href="https://en.wikipedia.org/wiki/Natural_philosophy" title="Natural philosophy">natural philosophy</a>. <a href="https://en.wikipedia.org/wiki/Galileo_Galilei" title="Galileo Galilei">Galileo</a>, <a href="https://en.wikipedia.org/wiki/Johannes_Kepler" title="Johannes Kepler">Kepler</a>, <a href="https://en.wikipedia.org/wiki/Ren%C3%A9_Descartes" title="René Descartes">Descartes</a>, <a href="https://en.wikipedia.org/wiki/Francis_Bacon" title="Francis Bacon">Bacon</a>, and <a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Newton</a> debated the benefits of using approaches which were more <a href="https://en.wikipedia.org/wiki/Mathematical_physics" title="Mathematical physics">mathematical</a> and more experimental in a methodical way. Still, philosophical perspectives, <a href="https://en.wikipedia.org/wiki/Conjecture" title="Conjecture">conjectures</a>, and <a href="https://en.wikipedia.org/wiki/Presupposition" title="Presupposition">presuppositions</a>, often overlooked, remain necessary in natural science. Systematic data collection, including <a href="https://en.wikipedia.org/wiki/Discovery_science" title="Discovery science">discovery science</a>, succeeded <a href="https://en.wikipedia.org/wiki/Natural_history" title="Natural history">natural history</a>, which emerged in the 16th century by describing and classifying plants, animals, minerals, and so on. Today, "natural history" suggests observational descriptions aimed at popular audiences.
</p>
<h2><span class="mw-headline" id="Criteria">Criteria</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Philosophy_of_science" title="Philosophy of science">Philosophy of science</a></div>
<p>Philosophers of science have suggested several criteria, including <a href="https://en.wikipedia.org/wiki/Karl_Popper" title="Karl Popper">Karl Popper</a>'s controversial <a href="https://en.wikipedia.org/wiki/Falsifiability" title="Falsifiability">falsifiability</a> criterion, to help them differentiate scientific endeavors from non-scientific ones. <a href="https://en.wikipedia.org/wiki/Validity_(statistics)" title="Validity (statistics)">Validity</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Accuracy" title="Accuracy">accuracy</a>, and <a href="https://en.wikipedia.org/wiki/Quality_control" title="Quality control">quality control</a>, such as <a href="https://en.wikipedia.org/wiki/Peer_review" title="Peer review">peer review</a> and repeatability of findings, are amongst the most respected criteria in today's global scientific community.
</p><p>In natural science, <a href="https://en.wikipedia.org/wiki/Proof_of_impossibility" title="Proof of impossibility">impossibility assertions</a>
come to be widely accepted as overwhelmingly probable rather than
considered proved to the point of being unchallengeable. The basis for
this strong acceptance is a combination of extensive evidence of
something not occurring, combined with an underlying theory, very
successful in making predictions, whose assumptions lead logically to
the conclusion that something is impossible. While an impossibility
assertion in natural science can never be absolutely proved, it could be
refuted by the observation of a single counterexample. Such a
counterexample would require that the assumptions underlying the theory
that implied the impossibility be re-examined.
</p>
<h2><span class="mw-headline" id="Branches_of_natural_science">Branches of natural science</span></h2><div class="hatnote navigation-not-searchable" role="note">For a topical guide, see <a href="https://en.wikipedia.org/wiki/Outline_of_natural_science" title="Outline of natural science">Outline of natural science</a>.</div>
<h3><span class="mw-headline" id="Biology">Biology</span></h3><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Biology" title="Biology">Biology</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_biology#Branches_of_biology" title="Outline of biology">Outline of biology § Branches of biology</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Wilson1900Fig2.jpg"><img class="mw-file-element" data-file-height="1545" data-file-width="2211" height="280" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/37/Wilson1900Fig2.jpg/220px-Wilson1900Fig2.jpg" width="400" /></a><figcaption>Onion (<i><a href="https://en.wikipedia.org/wiki/Allium" title="Allium">Allium</a></i>) cells in different phases of the cell cycle. Growth in an '<a href="https://en.wikipedia.org/wiki/Organism" title="Organism">organism</a>' is carefully controlled by regulating the cell cycle.</figcaption></figure>
<p>This field encompasses a diverse set of disciplines that examines
phenomena related to living organisms. The scale of study can range from
sub-component <a href="https://en.wikipedia.org/wiki/Biophysics" title="Biophysics">biophysics</a> up to complex <a href="https://en.wikipedia.org/wiki/Ecology" title="Ecology">ecologies</a>. Biology is concerned with the characteristics, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Scientific_classification" title="Scientific classification">classification</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Behaviors" title="Behaviors">behaviors</a> of <a href="https://en.wikipedia.org/wiki/Organism" title="Organism">organisms</a>, as well as how <a href="https://en.wikipedia.org/wiki/Species" title="Species">species</a> were formed and their interactions with each other and the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Environment_(biophysical)" title="Environment (biophysical)">environment</a>.
</p><p>The biological fields of <a href="https://en.wikipedia.org/wiki/Botany" title="Botany">botany</a>, <a href="https://en.wikipedia.org/wiki/Zoology" title="Zoology">zoology</a>, and <a href="https://en.wikipedia.org/wiki/Medicine" title="Medicine">medicine</a> date back to early periods of civilization, while <a href="https://en.wikipedia.org/wiki/Microbiology" title="Microbiology">microbiology</a>
was introduced in the 17th century with the invention of the
microscope. However, it was not until the 19th century that biology
became a unified science. Once scientists discovered commonalities
between all living things, it was decided they were best studied as a
whole.
</p><p>Some key developments in biology were the discovery of <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetics</a>, <a href="https://en.wikipedia.org/wiki/Evolution" title="Evolution">evolution</a> through <a href="https://en.wikipedia.org/wiki/Natural_selection" title="Natural selection">natural selection</a>, the <a href="https://en.wikipedia.org/wiki/Germ_theory_of_disease" title="Germ theory of disease">germ theory of disease</a>, and the application of the techniques of <a href="https://en.wikipedia.org/wiki/Biochemistry" title="Biochemistry">chemistry</a> and <a href="https://en.wikipedia.org/wiki/Biophysics" title="Biophysics">physics</a> at the level of the <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cell</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Organic_molecule" title="Organic molecule">organic molecule</a>.
</p><p>Modern biology is divided into subdisciplines by the type of organism and by the scale being studied. <a href="https://en.wikipedia.org/wiki/Molecular_biology" title="Molecular biology">Molecular biology</a> is the study of the fundamental chemistry of life, while <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cellular_biology" title="Cellular biology">cellular biology</a> is the examination of the cell; the basic building block of all life. At a higher level, <a href="https://en.wikipedia.org/wiki/Anatomy" title="Anatomy">anatomy</a> and <a href="https://en.wikipedia.org/wiki/Physiology" title="Physiology">physiology</a> look at the internal structures, and their functions, of an organism, while <a href="https://en.wikipedia.org/wiki/Ecology" title="Ecology">ecology</a> looks at how various organisms interrelate.
</p>
<h3><span class="mw-headline" id="Earth_science">Earth science</span></h3><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Earth_science" title="Earth science">Earth science</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_Earth_sciences#Branches_of_Earth_science" title="Outline of Earth sciences">Outline of Earth sciences § Branches of Earth science</a></div>
<p>Earth science (also known as geoscience), is an all-embracing term for the sciences related to the planet <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Earth_(planet)" title="Earth (planet)">Earth</a>, including <a href="https://en.wikipedia.org/wiki/Geology" title="Geology">geology</a>, <a href="https://en.wikipedia.org/wiki/Geography" title="Geography">geography</a>, <a href="https://en.wikipedia.org/wiki/Geophysics" title="Geophysics">geophysics</a>, <a href="https://en.wikipedia.org/wiki/Geochemistry" title="Geochemistry">geochemistry</a>, <a href="https://en.wikipedia.org/wiki/Climatology" title="Climatology">climatology</a>, <a href="https://en.wikipedia.org/wiki/Glaciology" title="Glaciology">glaciology</a>, <a href="https://en.wikipedia.org/wiki/Hydrology" title="Hydrology">hydrology</a>, <a href="https://en.wikipedia.org/wiki/Meteorology" title="Meteorology">meteorology</a>, and <a href="https://en.wikipedia.org/wiki/Oceanography" title="Oceanography">oceanography</a>.
</p><p>Although <a href="https://en.wikipedia.org/wiki/Mining" title="Mining">mining</a> and <a href="https://en.wikipedia.org/wiki/Gemology" title="Gemology">precious stones</a> have been human interests throughout the history of civilization, the development of the related sciences of <a href="https://en.wikipedia.org/wiki/Economic_geology" title="Economic geology">economic geology</a> and <a href="https://en.wikipedia.org/wiki/Mineralogy" title="Mineralogy">mineralogy</a> did not occur until the 18th century. The study of the earth, particularly <a href="https://en.wikipedia.org/wiki/Paleontology" title="Paleontology">paleontology</a>, blossomed in the 19th century. The growth of other disciplines, such as <a href="https://en.wikipedia.org/wiki/Geophysics" title="Geophysics">geophysics</a>, in the 20th century, led to the development of the theory of <a href="https://en.wikipedia.org/wiki/Plate_tectonics" title="Plate tectonics">plate tectonics</a>
in the 1960s, which has had a similar effect on the Earth sciences as
the theory of evolution had on biology. Earth sciences today are closely
linked to <a href="https://en.wikipedia.org/wiki/Petroleum" title="Petroleum">petroleum</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mineral_resource" title="Mineral resource">mineral resources</a>, <a href="https://en.wikipedia.org/wiki/Climate" title="Climate">climate</a> research and to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Environmental_assessment" title="Environmental assessment">environmental assessment</a> and <a href="https://en.wikipedia.org/wiki/Environmental_remediation" title="Environmental remediation">remediation</a>.
</p>
<h4><span class="mw-headline" id="Atmospheric_sciences">Atmospheric sciences</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Atmospheric_sciences" title="Atmospheric sciences">Atmospheric sciences</a></div>
<p>Although sometimes considered in conjunction with the earth sciences,
due to the independent development of its concepts, techniques, and
practices and also the fact of it having a wide range of sub-disciplines
under its wing, <a href="https://en.wikipedia.org/wiki/Atmospheric_science" title="Atmospheric science">atmospheric science</a>
is also considered a separate branch of natural science. This field
studies the characteristics of different layers of the atmosphere from
ground level to the edge of the space. The timescale of the study also
varies from day to century. Sometimes the field also includes the study
of climatic patterns on planets other than earth.
</p>
<h4><span class="mw-headline" id="Oceanography">Oceanography</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Oceanography" title="Oceanography">Oceanography</a></div>
<p>The serious study of oceans began in the early- to the mid-20th
century. As a field of natural science, it is relatively young but
stand-alone programs offer specializations in the subject. Though some
controversies remain as to the categorization of the field under earth
sciences, interdisciplinary sciences, or as a separate field in its own
right, most modern workers in the field agree that it has matured to a
state that it has its own paradigms and practices.
</p>
<h4><span class="mw-headline" id="Planetary_science">Planetary science</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Planetary_science" title="Planetary science">Planetary science</a></div>
<p><a href="https://en.wikipedia.org/wiki/Planetary_science" title="Planetary science">Planetary science</a> or planetology, is the scientific study of planets, which include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Terrestrial_planets" title="Terrestrial planets">terrestrial planets</a> like the Earth, and other types of planets, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gas_giants" title="Gas giants">gas giants</a> other celestial bodies, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Moons" title="Moons">moons</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Asteroids" title="Asteroids">asteroids</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Comets" title="Comets">comets</a>. This largely includes the <a href="https://en.wikipedia.org/wiki/Solar_System" title="Solar System">Solar System</a>, but recently has started to expand to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Exoplanets" title="Exoplanets">exoplanets</a>, particularly terrestrial <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Exoplanets" title="Exoplanets">exoplanets</a>.
It explores various objects, spanning from micrometeoroids to gas
giants, with the objective of establishing their composition, movements,
genesis, interrelation, and past. Planetary science is an
interdisciplinary domain, having originated from <a href="https://en.wikipedia.org/wiki/Astronomy" title="Astronomy">astronomy</a> and <a href="https://en.wikipedia.org/wiki/Earth_science" title="Earth science">Earth science</a>, and currently encompassing a multitude of areas, such as <a href="https://en.wikipedia.org/wiki/Planetary_geology" title="Planetary geology">planetary geology</a>, <a href="https://en.wikipedia.org/wiki/Cosmochemistry" title="Cosmochemistry">cosmochemistry</a>, <a href="https://en.wikipedia.org/wiki/Atmospheric_science" title="Atmospheric science">atmospheric science</a>, <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">physics</a>, <a href="https://en.wikipedia.org/wiki/Oceanography" title="Oceanography">oceanography</a>, <a href="https://en.wikipedia.org/wiki/Hydrology" title="Hydrology">hydrology</a>, <a href="https://en.wikipedia.org/wiki/Theoretical_planetology" title="Theoretical planetology">theoretical planetology</a>, <a href="https://en.wikipedia.org/wiki/Glaciology" title="Glaciology">glaciology</a>, and exoplanetology. Related fields encompass <a href="https://en.wikipedia.org/wiki/Space_physics" title="Space physics">space physics</a>, which delves into the impact of the Sun on the bodies in the Solar System, and <a href="https://en.wikipedia.org/wiki/Astrobiology" title="Astrobiology">astrobiology</a>.
</p><p>Planetary science comprises interconnected observational and
theoretical branches. Observational research entails a combination of <a href="https://en.wikipedia.org/wiki/Space_exploration" title="Space exploration">space exploration</a>,
primarily through robotic spacecraft missions utilizing remote sensing,
and comparative experimental work conducted in Earth-based
laboratories. The theoretical aspect involves extensive <a href="https://en.wikipedia.org/wiki/Mathematical_model" title="Mathematical model">mathematical modelling</a> and <a href="https://en.wikipedia.org/wiki/Computer_simulation" title="Computer simulation">computer simulation</a>.
</p><p>Typically, planetary scientists are situated within astronomy and
physics or Earth sciences departments in universities or research
centers. However, there are also dedicated planetary science institutes
worldwide. Generally, individuals pursuing a career in planetary science
undergo graduate-level studies in one of the Earth sciences, astronomy,
astrophysics, geophysics, or physics. They then focus their research
within the discipline of planetary science. Major conferences are held
annually, and numerous <a href="https://en.wikipedia.org/wiki/Academic_journal" title="Academic journal">peer reviewed journals</a>
cater to the diverse research interests in planetary science. Some
planetary scientists are employed by private research centers and
frequently engage in collaborative research initiatives.
</p>
<h3><span class="mw-headline" id="Chemistry">Chemistry</span></h3><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Chemistry" title="Chemistry">Chemistry</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_chemistry#Branches_of_chemistry" title="Outline of chemistry">Outline of chemistry § Branches of chemistry</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Caffeine.svg"><img class="mw-file-element" data-file-height="1164" data-file-width="1484" height="315" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d8/Caffeine.svg/220px-Caffeine.svg.png" width="400" /></a><figcaption>This <a href="https://en.wikipedia.org/wiki/Structural_formula" title="Structural formula">structural formula</a> for molecule <a href="https://en.wikipedia.org/wiki/Caffeine" title="Caffeine">caffeine</a> shows a graphical representation of how the atoms are arranged.</figcaption></figure>
<p>Constituting the scientific study of matter at the <a href="https://en.wikipedia.org/wiki/Atom" title="Atom">atomic</a> and <a href="https://en.wikipedia.org/wiki/Molecule" title="Molecule">molecular</a> scale, chemistry deals primarily with collections of atoms, such as <a href="https://en.wikipedia.org/wiki/Gas" title="Gas">gases</a>, molecules, <a href="https://en.wikipedia.org/wiki/Crystal" title="Crystal">crystals</a>, and <a href="https://en.wikipedia.org/wiki/Metal" title="Metal">metals</a>.
The composition, statistical properties, transformations, and reactions
of these materials are studied. Chemistry also involves understanding
the properties and interactions of individual atoms and molecules for
use in larger-scale applications.
</p><p>Most chemical processes can be studied directly in a laboratory,
using a series of (often well-tested) techniques for manipulating
materials, as well as an understanding of the underlying processes.
Chemistry is often called "<a href="https://en.wikipedia.org/wiki/The_central_science" title="The central science">the central science</a>" because of its role in connecting the other natural sciences.
</p><p>Early experiments in chemistry had their roots in the system of <a href="https://en.wikipedia.org/wiki/Alchemy" title="Alchemy">alchemy</a>, a set of beliefs combining mysticism with physical experiments. The science of chemistry began to develop with the work of <a href="https://en.wikipedia.org/wiki/Robert_Boyle" title="Robert Boyle">Robert Boyle</a>, the discoverer of <a href="https://en.wikipedia.org/wiki/Gas" title="Gas">gases</a>, and <a href="https://en.wikipedia.org/wiki/Antoine_Lavoisier" title="Antoine Lavoisier">Antoine Lavoisier</a>, who developed the theory of the <a href="https://en.wikipedia.org/wiki/Conservation_of_mass" title="Conservation of mass">conservation of mass</a>.
</p><p>The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Discoveries_of_the_chemical_elements" title="Discoveries of the chemical elements">discovery of the chemical elements</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Atomic_theory" title="Atomic theory">atomic theory</a> began to systematize this science, and researchers developed a fundamental understanding of <a href="https://en.wikipedia.org/wiki/State_of_matter" title="State of matter">states of matter</a>, <a href="https://en.wikipedia.org/wiki/Ion" title="Ion">ions</a>, <a href="https://en.wikipedia.org/wiki/Chemical_bond" title="Chemical bond">chemical bonds</a> and <a href="https://en.wikipedia.org/wiki/Chemical_reaction" title="Chemical reaction">chemical reactions</a>. The success of this science led to a complementary <a href="https://en.wikipedia.org/wiki/Chemical_industry" title="Chemical industry">chemical industry</a> that now plays a significant role in the world economy.
</p>
<h3><span class="mw-headline" id="Physics">Physics</span></h3><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">Physics</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_physics#Branches_of_physics" title="Outline of physics">Outline of physics § Branches of physics</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:HAtomOrbitals.png"><img class="mw-file-element" data-file-height="316" data-file-width="316" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/cf/HAtomOrbitals.png/220px-HAtomOrbitals.png" width="400" /></a><figcaption>The <a href="https://en.wikipedia.org/wiki/Atomic_orbital" title="Atomic orbital">orbitals</a> of the <a href="https://en.wikipedia.org/wiki/Hydrogen_atom" title="Hydrogen atom">hydrogen atom</a> are descriptions of the <a href="https://en.wikipedia.org/wiki/Probability_distribution" title="Probability distribution">probability distributions</a> of an <a href="https://en.wikipedia.org/wiki/Electron" title="Electron">electron</a> <a href="https://en.wikipedia.org/wiki/Bound_state" title="Bound state">bound</a> to a <a href="https://en.wikipedia.org/wiki/Proton" title="Proton">proton</a>. Their mathematical descriptions are standard problems in <a href="https://en.wikipedia.org/wiki/Quantum_mechanics" title="Quantum mechanics">quantum mechanics</a>, an important branch of physics.</figcaption></figure>
<p>Physics embodies the study of the fundamental constituents of the <a href="https://en.wikipedia.org/wiki/Universe" title="Universe">universe</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Forces" title="Forces">forces</a>
and interactions they exert on one another, and the results produced by
these interactions. In general, physics is regarded as the fundamental
science, because all other natural sciences use and obey the field's
principles and laws. Physics relies heavily on <a href="https://en.wikipedia.org/wiki/Mathematics" title="Mathematics">mathematics</a> as the logical framework for formulating and quantifying principles.
</p><p>The study of the principles of the universe has a long history
and largely derives from direct observation and experimentation. The
formulation of theories about the governing laws of the universe has
been central to the study of physics from very early on, with <a href="https://en.wikipedia.org/wiki/Philosophy" title="Philosophy">philosophy</a>
gradually yielding to systematic, quantitative experimental testing and
observation as the source of verification. Key historical developments
in physics include <a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Isaac Newton</a>'s <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Law_of_universal_gravitation" title="Law of universal gravitation">theory of universal gravitation</a> and <a href="https://en.wikipedia.org/wiki/Classical_mechanics" title="Classical mechanics">classical mechanics</a>, an understanding of <a href="https://en.wikipedia.org/wiki/Electricity" title="Electricity">electricity</a> and its relation to <a href="https://en.wikipedia.org/wiki/Magnetism" title="Magnetism">magnetism</a>, <a href="https://en.wikipedia.org/wiki/Albert_Einstein" title="Albert Einstein">Einstein</a>'s theories of <a href="https://en.wikipedia.org/wiki/Special_relativity" title="Special relativity">special</a> and <a href="https://en.wikipedia.org/wiki/General_relativity" title="General relativity">general relativity</a>, the development of <a href="https://en.wikipedia.org/wiki/Thermodynamics" title="Thermodynamics">thermodynamics</a>, and the <a href="https://en.wikipedia.org/wiki/Quantum_mechanics" title="Quantum mechanics">quantum mechanical</a> model of atomic and subatomic physics.
</p><p>The field of physics is extremely broad, and can include such diverse studies as <a href="https://en.wikipedia.org/wiki/Quantum_mechanics" title="Quantum mechanics">quantum mechanics</a> and <a href="https://en.wikipedia.org/wiki/Theoretical_physics" title="Theoretical physics">theoretical physics</a>, <a href="https://en.wikipedia.org/wiki/Applied_physics" title="Applied physics">applied physics</a> and <a href="https://en.wikipedia.org/wiki/Optics" title="Optics">optics</a>.
Modern physics is becoming increasingly specialized, where researchers
tend to focus on a particular area rather than being "universalists"
like <a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Isaac Newton</a>, <a href="https://en.wikipedia.org/wiki/Albert_Einstein" title="Albert Einstein">Albert Einstein</a> and <a href="https://en.wikipedia.org/wiki/Lev_Landau" title="Lev Landau">Lev Landau</a>, who worked in multiple areas.
</p>
<h3><span class="mw-headline" id="Astronomy">Astronomy</span></h3><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Astronomy" title="Astronomy">Astronomy</a> and <a href="https://en.wikipedia.org/wiki/Outline_of_astronomy#Branches_of_astronomy" title="Outline of astronomy">Outline of astronomy § Branches of astronomy</a></div>
<p>Astronomy is a natural science that studies celestial objects and
phenomena. Objects of interest include planets, moons, stars, nebulae,
galaxies, and comets. Astronomy is the study of everything in the
universe beyond Earth's atmosphere. That includes objects we can see
with our naked eyes. Astronomy is one of the oldest sciences.
</p><p>Astronomers of early civilizations performed methodical
observations of the night sky, and astronomical artifacts have been
found from much earlier periods. There are two types of astronomy:
observational astronomy and theoretical astronomy. Observational
astronomy is focused on acquiring and analyzing data, mainly using basic
principles of physics while Theoretical astronomy is oriented towards
the development of computer or analytical models to describe
astronomical objects and phenomena.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Moon_Dedal_crater.jpg"><img class="mw-file-element" data-file-height="2320" data-file-width="2336" height="396" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a3/Moon_Dedal_crater.jpg/220px-Moon_Dedal_crater.jpg" width="400" /></a><figcaption>Uncrewed and crewed spacecraft missions have been used to image distant locations within the <a href="https://en.wikipedia.org/wiki/Solar_System" title="Solar System">Solar System</a>, such as this <a href="https://en.wikipedia.org/wiki/Apollo_11" title="Apollo 11">Apollo 11</a> view of <a href="https://en.wikipedia.org/wiki/Daedalus_(crater)" title="Daedalus (crater)">Daedalus crater</a> on the <a href="https://en.wikipedia.org/wiki/Far_side_of_the_Moon" title="Far side of the Moon">far side of the Moon</a>.</figcaption></figure>
<p>This discipline is the science of <a href="https://en.wikipedia.org/wiki/Astronomical_object" title="Astronomical object">celestial objects</a> and <a href="https://en.wikipedia.org/wiki/Phenomenon" title="Phenomenon">phenomena</a> that originate outside the <a href="https://en.wikipedia.org/wiki/Atmosphere_of_Earth" title="Atmosphere of Earth">Earth's atmosphere</a>. It is concerned with the evolution, <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">physics</a>, <a href="https://en.wikipedia.org/wiki/Chemistry" title="Chemistry">chemistry</a>, <a href="https://en.wikipedia.org/wiki/Meteorology" title="Meteorology">meteorology</a>, <a href="https://en.wikipedia.org/wiki/Geology" title="Geology">geology</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Motion_(physics)" title="Motion (physics)">motion</a> of celestial objects, as well as the <a href="https://en.wikipedia.org/wiki/Physical_cosmology" title="Physical cosmology">formation and development of the universe</a>.
</p><p>Astronomy includes the examination, study, and modeling of stars,
planets, comets. Most of the information used by astronomers is
gathered by remote observation, although some laboratory reproduction of
celestial phenomena has been performed (such as the molecular chemistry
of the <a href="https://en.wikipedia.org/wiki/Interstellar_medium" title="Interstellar medium">interstellar medium</a>). There is considerable overlap with <a href="https://en.wikipedia.org/wiki/Physics" title="Physics">physics</a> and in some areas of <a href="https://en.wikipedia.org/wiki/Earth_science" title="Earth science">earth science</a>. There are also interdisciplinary fields such as <a href="https://en.wikipedia.org/wiki/Astrophysics" title="Astrophysics">astrophysics</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Planetary_sciences" title="Planetary sciences">planetary sciences</a>, and <a href="https://en.wikipedia.org/wiki/Cosmology" title="Cosmology">cosmology</a>, along with allied disciplines such as <a href="https://en.wikipedia.org/wiki/Space_physics" title="Space physics">space physics</a> and <a href="https://en.wikipedia.org/wiki/Astrochemistry" title="Astrochemistry">astrochemistry</a>.
</p><p>While the origins of the study of celestial features and
phenomena can be traced back to antiquity, the scientific methodology of
this field began to develop in the middle of the 17th century. A key
factor was <a href="https://en.wikipedia.org/wiki/Galileo_Galilei" title="Galileo Galilei">Galileo</a>'s introduction of the telescope to examine the night sky in more detail.
</p><p>The mathematical treatment of astronomy began with <a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Newton</a>'s development of <a href="https://en.wikipedia.org/wiki/Celestial_mechanics" title="Celestial mechanics">celestial mechanics</a> and the laws of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gravitation" title="Gravitation">gravitation</a>, although it was triggered by earlier work of astronomers such as <a href="https://en.wikipedia.org/wiki/Johannes_Kepler" title="Johannes Kepler">Kepler</a>. By the 19th century, astronomy had developed into formal science, with the introduction of instruments such as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spectroscope" title="Spectroscope">spectroscope</a> and <a href="https://en.wikipedia.org/wiki/Photography" title="Photography">photography</a>, along with much-improved telescopes and the creation of professional observatories.
</p>
<h2><span class="mw-headline" id="Interdisciplinary_studies">Interdisciplinary studies</span></h2>
<p>The distinctions between the natural science disciplines are not
always sharp, and they share many cross-discipline fields. Physics plays
a significant role in the other natural sciences, as represented by <a href="https://en.wikipedia.org/wiki/Astrophysics" title="Astrophysics">astrophysics</a>, <a href="https://en.wikipedia.org/wiki/Geophysics" title="Geophysics">geophysics</a>, <a href="https://en.wikipedia.org/wiki/Chemical_physics" title="Chemical physics">chemical physics</a> and <a href="https://en.wikipedia.org/wiki/Biophysics" title="Biophysics">biophysics</a>. Likewise chemistry is represented by such fields as <a href="https://en.wikipedia.org/wiki/Biochemistry" title="Biochemistry">biochemistry</a>, <a href="https://en.wikipedia.org/wiki/Physical_chemistry" title="Physical chemistry">physical chemistry</a>, <a href="https://en.wikipedia.org/wiki/Geochemistry" title="Geochemistry">geochemistry</a> and <a href="https://en.wikipedia.org/wiki/Astrochemistry" title="Astrochemistry">astrochemistry</a>.
</p><p>A particular example of a scientific discipline that draws upon multiple natural sciences is <a href="https://en.wikipedia.org/wiki/Environmental_science" title="Environmental science">environmental science</a>. This field studies the interactions of physical, chemical, geological, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological_components" title="Biological components">biological components</a> of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Environment_(biophysical)" title="Environment (biophysical)">environment</a>, with particular regard to the effect of human activities and the impact on <a href="https://en.wikipedia.org/wiki/Biodiversity" title="Biodiversity">biodiversity</a> and <a href="https://en.wikipedia.org/wiki/Sustainability" title="Sustainability">sustainability</a>. This science also draws upon expertise from other fields such as economics, law, and social sciences.
</p><p>A comparable discipline is <a href="https://en.wikipedia.org/wiki/Oceanography" title="Oceanography">oceanography</a>,
as it draws upon a similar breadth of scientific disciplines.
Oceanography is sub-categorized into more specialized cross-disciplines,
such as <a href="https://en.wikipedia.org/wiki/Physical_oceanography" title="Physical oceanography">physical oceanography</a> and <a href="https://en.wikipedia.org/wiki/Marine_biology" title="Marine biology">marine biology</a>. As the <a href="https://en.wikipedia.org/wiki/Marine_ecosystem" title="Marine ecosystem">marine ecosystem</a> is very large and diverse, marine biology is further divided into many subfields, including specializations in particular <a href="https://en.wikipedia.org/wiki/Species" title="Species">species</a>.
</p><p>There is also a subset of cross-disciplinary fields that have
strong currents that run counter to specialization by the nature of the
problems that they address. Put another way: In some fields of
integrative application, specialists in more than one field are a key
part of the most dialog. Such integrative fields, for example, include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanoscience" title="Nanoscience">nanoscience</a>, <a href="https://en.wikipedia.org/wiki/Astrobiology" title="Astrobiology">astrobiology</a>, and <a href="https://en.wikipedia.org/wiki/Complex_system" title="Complex system">complex system</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Informatics_(academic_field)" title="Informatics (academic field)">informatics</a>.
</p>
<h3><span class="mw-headline" id="Materials_science">Materials science</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Materials_science" title="Materials science">Materials science</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Materials_science_tetrahedron;structure,_processing,_performance,_and_proprerties.svg"><img class="mw-file-element" data-file-height="280" data-file-width="460" height="244" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/59/Materials_science_tetrahedron%3Bstructure%2C_processing%2C_performance%2C_and_proprerties.svg/220px-Materials_science_tetrahedron%3Bstructure%2C_processing%2C_performance%2C_and_proprerties.svg.png" width="400" /></a><figcaption>The materials paradigm represented as a tetrahedron</figcaption></figure>
<p>Materials science is a relatively new, interdisciplinary field that deals with the study of <a href="https://en.wikipedia.org/wiki/Matter" title="Matter">matter</a> and its properties; as well as the discovery and design of new materials. Originally developed through the field of <a href="https://en.wikipedia.org/wiki/Metallurgy" title="Metallurgy">metallurgy</a>,
the study of the properties of materials and solids has now expanded
into all materials. The field covers the chemistry, physics, and
engineering applications of materials including metals, ceramics,
artificial polymers, and many others. The core of the field deals with
relating the structure of materials with their properties.
</p><p>It is at the forefront of research in science and engineering. It is an important part of <a href="https://en.wikipedia.org/wiki/Forensic_engineering" title="Forensic engineering">forensic engineering</a>
(the investigation of materials, products, structures or components
that fail or do not operate or function as intended, causing personal
injury or damage to property) and <a href="https://en.wikipedia.org/wiki/Failure_analysis" title="Failure analysis">failure analysis</a>,
the latter being the key to understanding, for example, the cause of
various aviation accidents. Many of the most pressing scientific
problems that are faced today are due to the limitations of the
materials that are available and, as a result, breakthroughs in this
field are likely to have a significant impact on the future of
technology.
</p><p>The basis of materials science involves studying the structure of materials, and relating them to their <a href="https://en.wikipedia.org/wiki/Property" title="Property">properties</a>.
Once a materials scientist knows about this structure-property
correlation, they can then go on to study the relative performance of a
material in a certain application. The major determinants of the
structure of a material and thus of its properties are its constituent
chemical elements and how it has been processed into its final form.
These characteristics, taken together and related through the laws of <a href="https://en.wikipedia.org/wiki/Thermodynamics" title="Thermodynamics">thermodynamics</a> and <a href="https://en.wikipedia.org/wiki/Kinetics_(physics)" title="Kinetics (physics)">kinetics</a>, govern a material's <a href="https://en.wikipedia.org/wiki/Microstructure" title="Microstructure">microstructure</a>, and thus its properties.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Natural_philosophy" title="Natural philosophy">Natural philosophy</a> and <a href="https://en.wikipedia.org/wiki/History_of_science" title="History of science">History of science</a></div>
<p>Some scholars trace the origins of natural science as far back as
pre-literate human societies, where understanding the natural world was
necessary for survival.
People observed and built up knowledge about the behavior of animals
and the usefulness of plants as food and medicine, which was passed down
from generation to generation. These primitive understandings gave way to more formalized inquiry around 3500 to 3000 BC in the <a href="https://en.wikipedia.org/wiki/Mesopotamia" title="Mesopotamia">Mesopotamian</a> and <a href="https://en.wikipedia.org/wiki/Ancient_Egypt" title="Ancient Egypt">Ancient Egyptian</a> cultures, which produced the first known written evidence of <a href="https://en.wikipedia.org/wiki/Natural_philosophy" title="Natural philosophy">natural philosophy</a>, the precursor of natural science.
While the writings show an interest in astronomy, mathematics, and
other aspects of the physical world, the ultimate aim of inquiry about
nature's workings was in all cases religious or mythological, not
scientific.
</p><p>A tradition of scientific inquiry also emerged in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ancient_China" title="Ancient China">Ancient China</a>, where <a href="https://en.wikipedia.org/wiki/Taoism" title="Taoism">Taoist</a> <a href="https://en.wikipedia.org/wiki/Alchemy" title="Alchemy">alchemists</a> and philosophers experimented with elixirs to <a href="https://en.wikipedia.org/wiki/Life_extension" title="Life extension">extend life</a> and cure ailments. They focused on the <a href="https://en.wikipedia.org/wiki/Yin_and_yang" title="Yin and yang">yin and yang</a>,
or contrasting elements in nature; the yin was associated with
femininity and coldness, while yang was associated with masculinity and
warmth.
The five phases – fire, earth, metal, wood, and water – described a
cycle of transformations in nature. The water turned into wood, which
turned into the fire when it burned. The ashes left by fire were earth.
Using these principles, Chinese philosophers and doctors explored human
anatomy, characterizing organs as predominantly yin or yang, and
understood the relationship between the pulse, the heart, and the flow
of blood in the body centuries before it became accepted in the West.
</p><p>Little evidence survives of how <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ancient_India" title="Ancient India">Ancient Indian</a> cultures around the <a href="https://en.wikipedia.org/wiki/Indus_River" title="Indus River">Indus River</a> understood nature, but some of their perspectives may be reflected in the <a href="https://en.wikipedia.org/wiki/Vedas" title="Vedas">Vedas</a>, a set of sacred <a href="https://en.wikipedia.org/wiki/Hinduism" title="Hinduism">Hindu</a> texts. They reveal a conception of the universe as ever-expanding and constantly being recycled and reformed. Surgeons in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ayurvedic" title="Ayurvedic">Ayurvedic</a> tradition saw health and illness as a combination of three humors: <a href="https://en.wikipedia.org/wiki/Wind" title="Wind">wind</a>, <a href="https://en.wikipedia.org/wiki/Bile" title="Bile">bile</a> and <a href="https://en.wikipedia.org/wiki/Phlegm" title="Phlegm">phlegm</a>. A healthy life was the result of a balance among these humors. In Ayurvedic thought, the body consisted of five elements: earth, water, fire, wind, and space. Ayurvedic surgeons performed complex surgeries and developed a detailed understanding of human anatomy.
</p><p><a href="https://en.wikipedia.org/wiki/Pre-Socratic_philosophy" title="Pre-Socratic philosophy">Pre-Socratic</a> philosophers in <a href="https://en.wikipedia.org/wiki/Ancient_Greece" title="Ancient Greece">Ancient Greek</a>
culture brought natural philosophy a step closer to direct inquiry
about cause and effect in nature between 600 and 400 BC, although an
element of magic and mythology remained.
Natural phenomena such as earthquakes and eclipses were explained
increasingly in the context of nature itself instead of being attributed
to angry gods. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thales" title="Thales">Thales of Miletus</a>,
an early philosopher who lived from 625 to 546 BC, explained
earthquakes by theorizing that the world floated on water and that water
was the fundamental element in nature. In the 5th century BC, <a href="https://en.wikipedia.org/wiki/Leucippus" title="Leucippus">Leucippus</a> was an early exponent of <a href="https://en.wikipedia.org/wiki/Atomism" title="Atomism">atomism</a>, the idea that the world is made up of fundamental indivisible particles. <a href="https://en.wikipedia.org/wiki/Pythagoras" title="Pythagoras">Pythagoras</a> applied Greek innovations in mathematics to astronomy, and suggested that the earth was <a href="https://en.wikipedia.org/wiki/Sphere" title="Sphere">spherical</a>.
</p>
<h3><span id="Aristotelian_natural_philosophy_.28400_BC.E2.80.931100_AD.29"></span><span class="mw-headline" id="Aristotelian_natural_philosophy_(400_BC–1100_AD)">Aristotelian natural philosophy (400 BC–1100 AD)</span></h3><figure class="mw-default-size mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Aristotle%27s_model_of_Inheritance.png"><img class="mw-file-element" data-file-height="720" data-file-width="960" height="301" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/52/Aristotle%27s_model_of_Inheritance.png/290px-Aristotle%27s_model_of_Inheritance.png" width="400" /></a><figcaption>Aristotle's
view of inheritance, as a model of the transmission of patterns of
movement of the body fluids from parents to child, and of <a href="https://en.wikipedia.org/wiki/Hylomorphism" title="Hylomorphism">Aristotelian form</a> from the father</figcaption></figure>
<div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Aristotle%27s_biology" title="Aristotle's biology">Aristotle's biology</a></div>
<p>Later <a href="https://en.wikipedia.org/wiki/Socrates" title="Socrates">Socratic</a> and <a href="https://en.wikipedia.org/wiki/Plato" title="Plato">Platonic</a>
thought focused on ethics, morals and art and did not attempt an
investigation of the physical world; Plato criticized pre-Socratic
thinkers as materialists and anti-religionists. <a href="https://en.wikipedia.org/wiki/Aristotle" title="Aristotle">Aristotle</a>, however, a student of Plato who lived from 384 to 322 BC, paid closer attention to the natural world in his philosophy. In his <i><a href="https://en.wikipedia.org/wiki/History_of_Animals" title="History of Animals">History of Animals</a></i>, he described the inner workings of 110 species, including the <a href="https://en.wikipedia.org/wiki/Stingray" title="Stingray">stingray</a>, <a href="https://en.wikipedia.org/wiki/Catfish" title="Catfish">catfish</a> and <a href="https://en.wikipedia.org/wiki/Bee" title="Bee">bee</a>. He investigated chick embryos by breaking open eggs and observing them at various stages of development. Aristotle's works were influential through the 16th century, and he is considered to be the <a href="https://en.wikipedia.org/wiki/Aristotle%27s_biology" title="Aristotle's biology">father of biology for his pioneering work in that science</a>. He also presented philosophies about physics, nature, and astronomy using <a href="https://en.wikipedia.org/wiki/Inductive_reasoning" title="Inductive reasoning">inductive reasoning</a> in his works <i><a href="https://en.wikipedia.org/wiki/Physics_(Aristotle)" title="Physics (Aristotle)">Physics</a></i> and <i><a href="https://en.wikipedia.org/wiki/Meteorology_(Aristotle)" title="Meteorology (Aristotle)">Meteorology</a></i>.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Sanzio_01_Plato_Aristotle.jpg"><img class="mw-file-element" data-file-height="1052" data-file-width="804" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/98/Sanzio_01_Plato_Aristotle.jpg/170px-Sanzio_01_Plato_Aristotle.jpg" width="306" /></a><figcaption>Plato (left) and Aristotle in <a href="https://en.wikipedia.org/wiki/The_School_of_Athens" title="The School of Athens">a 1509 painting</a> by <a href="https://en.wikipedia.org/wiki/Raphael" title="Raphael">Raphael</a>.
Plato rejected inquiry into natural philosophy as against religion,
while his student, Aristotle, created a body of work on the natural
world that influenced generations of scholars.</figcaption></figure>
<p>While Aristotle considered natural philosophy more seriously than his
predecessors, he approached it as a theoretical branch of science. Still, inspired by his work, <a href="https://en.wikipedia.org/wiki/Ancient_Rome" title="Ancient Rome">Ancient Roman</a> philosophers of the early 1st century AD, including <a href="https://en.wikipedia.org/wiki/Lucretius" title="Lucretius">Lucretius</a>, <a href="https://en.wikipedia.org/wiki/Seneca_the_Younger" title="Seneca the Younger">Seneca</a> and <a href="https://en.wikipedia.org/wiki/Pliny_the_Elder" title="Pliny the Elder">Pliny the Elder</a>, wrote treatises that dealt with the rules of the natural world in varying degrees of depth. Many <a href="https://en.wikipedia.org/wiki/Ancient_Rome" title="Ancient Rome">Ancient Roman</a> <a href="https://en.wikipedia.org/wiki/Neoplatonism" title="Neoplatonism">Neoplatonists</a>
of the 3rd to the 6th centuries also adapted Aristotle's teachings on
the physical world to a philosophy that emphasized spiritualism. Early <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medieval" title="Medieval">medieval</a> philosophers including <a href="https://en.wikipedia.org/wiki/Macrobius" title="Macrobius">Macrobius</a>, <a href="https://en.wikipedia.org/wiki/Calcidius" title="Calcidius">Calcidius</a> and <a href="https://en.wikipedia.org/wiki/Martianus_Capella" title="Martianus Capella">Martianus Capella</a> also examined the physical world, largely from a cosmological and <a href="https://en.wikipedia.org/wiki/Cosmography" title="Cosmography">cosmographical</a>
perspective, putting forth theories on the arrangement of celestial
bodies and the heavens, which were posited as being composed of <a href="https://en.wikipedia.org/wiki/Aether_(classical_element)" title="Aether (classical element)">aether</a>.
</p><p>Aristotle's works on natural philosophy continued to be translated and studied amid the rise of the <a href="https://en.wikipedia.org/wiki/Byzantine_Empire" title="Byzantine Empire">Byzantine Empire</a> and <a href="https://en.wikipedia.org/wiki/Abbasid_Caliphate" title="Abbasid Caliphate">Abbasid Caliphate</a>.
</p><p>In the Byzantine Empire, <a href="https://en.wikipedia.org/wiki/John_Philoponus" title="John Philoponus">John Philoponus</a>,
an Alexandrian Aristotelian commentator and Christian theologian was
the first who questioned Aristotle's teaching of physics. Unlike
Aristotle who based his physics on verbal argument, Philoponus instead
relied on observation and argued for observation rather than resorting
to a verbal argument. He introduced the <a href="https://en.wikipedia.org/wiki/Theory_of_impetus" title="Theory of impetus">theory of impetus</a>. John Philoponus' criticism of Aristotelian principles of physics served as inspiration for Galileo Galilei during the <a href="https://en.wikipedia.org/wiki/Scientific_Revolution" title="Scientific Revolution">Scientific Revolution</a>.
</p><p>A revival in mathematics and science took place during the time of the <a href="https://en.wikipedia.org/wiki/Abbasid_Caliphate" title="Abbasid Caliphate">Abbasid Caliphate</a> from the 9th century onward, when Muslim scholars expanded upon Greek and <a href="https://en.wikipedia.org/wiki/India" title="India">Indian</a> natural philosophy. The words <i><a class="mw-redirect mw-disambig" href="https://en.wikipedia.org/wiki/Alcohol_(disambiguation)" title="Alcohol (disambiguation)">alcohol</a></i>, <i><a href="https://en.wikipedia.org/wiki/Algebra" title="Algebra">algebra</a></i> and <i><a href="https://en.wikipedia.org/wiki/Zenith" title="Zenith">zenith</a></i> all have <a href="https://en.wikipedia.org/wiki/Arabic" title="Arabic">Arabic</a> roots.
</p>
<h3><span id="Medieval_natural_philosophy_.281100.E2.80.931600.29"></span><span class="mw-headline" id="Medieval_natural_philosophy_(1100–1600)">Medieval natural philosophy (1100–1600)</span></h3><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Renaissance_of_the_12th_century" title="Renaissance of the 12th century">Renaissance of the 12th century</a></div>
<p>Aristotle's works and other Greek natural philosophy did not reach
the West until about the middle of the 12th century, when works were
translated from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Greek_people" title="Greek people">Greek</a> and Arabic into <a href="https://en.wikipedia.org/wiki/Latin" title="Latin">Latin</a>. The development of European civilization later in the Middle Ages brought with it further advances in natural philosophy. European inventions such as the <a href="https://en.wikipedia.org/wiki/Horseshoe" title="Horseshoe">horseshoe</a>, <a href="https://en.wikipedia.org/wiki/Horse_collar" title="Horse collar">horse collar</a> and <a href="https://en.wikipedia.org/wiki/Crop_rotation" title="Crop rotation">crop rotation</a>
allowed for rapid population growth, eventually giving way to
urbanization and the foundation of schools connected to monasteries and
cathedrals in modern-day <a href="https://en.wikipedia.org/wiki/France" title="France">France</a> and <a href="https://en.wikipedia.org/wiki/England" title="England">England</a>. Aided by the schools, an approach to Christian <a href="https://en.wikipedia.org/wiki/Theology" title="Theology">theology</a> developed that sought to answer questions about nature and other subjects using logic. This approach, however, was seen by some detractors as <a href="https://en.wikipedia.org/wiki/Heresy" title="Heresy">heresy</a>.
By the 12th century, Western European scholars and philosophers came
into contact with a body of knowledge of which they had previously been
ignorant: a large corpus of works in Greek and Arabic that were
preserved by Islamic scholars. Through translation into Latin, Western Europe was introduced to Aristotle and his natural philosophy. These works were taught at new universities in <a href="https://en.wikipedia.org/wiki/Paris" title="Paris">Paris</a> and <a href="https://en.wikipedia.org/wiki/Oxford" title="Oxford">Oxford</a> by the early 13th century, although the practice was frowned upon by the Catholic church. A 1210 decree from the <a href="https://en.wikipedia.org/wiki/Synod" title="Synod">Synod</a>
of Paris ordered that "no lectures are to be held in Paris either
publicly or privately using Aristotle's books on natural philosophy or
the commentaries, and we forbid all this under pain of
ex-communication."
</p><p>In the late Middle Ages, <a href="https://en.wikipedia.org/wiki/Spain" title="Spain">Spanish</a> philosopher <a href="https://en.wikipedia.org/wiki/Dominicus_Gundissalinus" title="Dominicus Gundissalinus">Dominicus Gundissalinus</a> translated a treatise by the earlier Persian scholar <a href="https://en.wikipedia.org/wiki/Al-Farabi" title="Al-Farabi">Al-Farabi</a> called <i>On the Sciences</i> into Latin, calling the study of the mechanics of nature <i>Scientia naturalis</i>, or natural science. Gundissalinus also proposed his own classification of the natural sciences in his 1150 work <i>On the Division of Philosophy</i>. This was the first detailed classification of the sciences based on Greek and Arab philosophy to reach Western Europe.
Gundissalinus defined natural science as "the science considering only
things unabstracted and with motion," as opposed to mathematics and
sciences that rely on mathematics.
Following Al-Farabi, he then separated the sciences into eight parts,
including physics, cosmology, meteorology, minerals science, and plant
and animal science.
</p><p>Later philosophers made their own classifications of the natural sciences. <a href="https://en.wikipedia.org/wiki/Robert_Kilwardby" title="Robert Kilwardby">Robert Kilwardby</a> wrote <i>On the Order of the Sciences</i>
in the 13th century that classed medicine as a mechanical science,
along with agriculture, hunting and theater while defining natural
science as the science that deals with bodies in motion. <a href="https://en.wikipedia.org/wiki/Roger_Bacon" title="Roger Bacon">Roger Bacon</a>,
an English friar and philosopher, wrote that natural science dealt with
"a principle of motion and rest, as in the parts of the elements of
fire, air, earth and water, and in all inanimate things made from them." These sciences also covered plants, animals and celestial bodies. Later in the 13th century, a Catholic priest and theologian <a href="https://en.wikipedia.org/wiki/Thomas_Aquinas" title="Thomas Aquinas">Thomas Aquinas</a>
defined natural science as dealing with "mobile beings" and "things
which depend on a matter not only for their existence but also for their
definition."
There was wide agreement among scholars in medieval times that natural
science was about bodies in motion, although there was division about
the inclusion of fields including medicine, music, and perspective.
Philosophers pondered questions including the existence of a vacuum,
whether motion could produce heat, the colors of rainbows, the motion of
the earth, whether elemental chemicals exist, and were in the
atmosphere rain is formed.
</p><p>In the centuries up through the end of the Middle Ages, natural
science was often mingled with philosophies about magic and the occult. Natural philosophy appeared in a wide range of forms, from treatises to encyclopedias to commentaries on Aristotle. The interaction between natural philosophy and <a href="https://en.wikipedia.org/wiki/Christianity" title="Christianity">Christianity</a> was complex during this period; some early theologians, including <a href="https://en.wikipedia.org/wiki/Tatian" title="Tatian">Tatian</a> and <a href="https://en.wikipedia.org/wiki/Eusebius" title="Eusebius">Eusebius</a>, considered natural philosophy an outcropping of pagan Greek science and were suspicious of it.
Although some later Christian philosophers, including Aquinas, came to
see natural science as a means of interpreting scripture, this suspicion
persisted until the 12th and 13th centuries. The <a href="https://en.wikipedia.org/wiki/Condemnations_of_1210%E2%80%931277" title="Condemnations of 1210–1277">Condemnation of 1277</a>,
which forbade setting philosophy on a level equal with theology and the
debate of religious constructs in a scientific context, showed the
persistence with which Catholic leaders resisted the development of
natural philosophy even from a theological perspective. Aquinas and <a href="https://en.wikipedia.org/wiki/Albertus_Magnus" title="Albertus Magnus">Albertus Magnus</a>, another Catholic theologian of the era, sought to distance theology from science in their works. "I don't see what one's interpretation of Aristotle has to do with the teaching of the faith," he wrote in 1271.
</p>
<h3><span id="Newton_and_the_scientific_revolution_.281600.E2.80.931800.29"></span><span class="mw-headline" id="Newton_and_the_scientific_revolution_(1600–1800)">Newton and the scientific revolution (1600–1800)</span></h3><p>By
the 16th and 17th centuries, natural philosophy underwent an evolution
beyond commentary on Aristotle as more early Greek philosophy was
uncovered and translated. The invention of the printing press in the 15th century, the invention of the microscope and telescope, and the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protestant_Reformation" title="Protestant Reformation">Protestant Reformation</a> fundamentally altered the social context in which scientific inquiry evolved in the West. <a href="https://en.wikipedia.org/wiki/Christopher_Columbus" title="Christopher Columbus">Christopher Columbus</a>'s discovery of a new world changed perceptions about the physical makeup of the world, while observations by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Copernicus" title="Copernicus">Copernicus</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tyco_Brahe" title="Tyco Brahe">Tyco Brahe</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Galileo" title="Galileo">Galileo</a> brought a more accurate picture of the solar system as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heliocentric" title="Heliocentric">heliocentric</a> and proved many of Aristotle's theories about the heavenly bodies false. Several 17th-century philosophers, including <a href="https://en.wikipedia.org/wiki/Thomas_Hobbes" title="Thomas Hobbes">Thomas Hobbes</a>, <a href="https://en.wikipedia.org/wiki/John_Locke" title="John Locke">John Locke</a> and <a href="https://en.wikipedia.org/wiki/Francis_Bacon" title="Francis Bacon">Francis Bacon</a>
made a break from the past by rejecting Aristotle and his medieval
followers outright, calling their approach to natural philosophy
superficial.
</p>
<figure class="mw-default-size mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:JKepler.jpg"><img class="mw-file-element" data-file-height="1200" data-file-width="836" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/74/JKepler.jpg/220px-JKepler.jpg" width="278" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Johannes_Kepler" title="Johannes Kepler">Johannes Kepler</a> (1571–1630). Kepler's <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Astronomia_Nova" title="Astronomia Nova">Astronomia Nova</a>
is "the first published account wherein a scientist documents how he
has coped with the multitude of imperfect data to forge a theory of
surpassing accuracy", therefore laying the groundwork for the scientific
method.</figcaption></figure>
<p>The titles of Galileo's work <i>Two New Sciences</i> and <a href="https://en.wikipedia.org/wiki/Johannes_Kepler" title="Johannes Kepler">Johannes Kepler</a>'s <i>New Astronomy</i>
underscored the atmosphere of change that took hold in the 17th century
as Aristotle was dismissed in favor of novel methods of inquiry into
the natural world. Bacon was instrumental in popularizing this change; he argued that people should use the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Arts" title="Arts">arts</a> and sciences to gain dominion over nature. To achieve this, he wrote that "human life [must] be endowed with discoveries and powers."
He defined natural philosophy as "the knowledge of Causes and secret
motions of things; and enlarging the bounds of Human Empire, to the
effecting of all things possible."
Bacon proposed that scientific inquiry be supported by the state and
fed by the collaborative research of scientists, a vision that was
unprecedented in its scope, ambition, and forms at the time.
Natural philosophers came to view nature increasingly as a mechanism
that could be taken apart and understood, much like a complex clock. Natural philosophers including <a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Isaac Newton</a>, <a href="https://en.wikipedia.org/wiki/Evangelista_Torricelli" title="Evangelista Torricelli">Evangelista Torricelli</a> and <a href="https://en.wikipedia.org/wiki/Francesco_Redi" title="Francesco Redi">Francesco Redi</a> conducted experiments focusing on the flow of water, measuring <a href="https://en.wikipedia.org/wiki/Atmospheric_pressure" title="Atmospheric pressure">atmospheric pressure</a> using a <a href="https://en.wikipedia.org/wiki/Barometer" title="Barometer">barometer</a> and disproving <a href="https://en.wikipedia.org/wiki/Spontaneous_generation" title="Spontaneous generation">spontaneous generation</a>. Scientific societies and scientific journals emerged and were spread widely through the printing press, touching off the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Scientific_revolution" title="Scientific revolution">scientific revolution</a>. Newton in 1687 published his <i>The Mathematical Principles of Natural Philosophy</i>, or <i>Principia Mathematica</i>, which set the groundwork for physical laws that remained current until the 19th century.
</p><p>Some modern scholars, including Andrew Cunningham, Perry Williams, and <a href="https://en.wikipedia.org/wiki/Floris_Cohen" title="Floris Cohen">Floris Cohen</a>,
argue that natural philosophy is not properly called a science, and
that genuine scientific inquiry began only with the scientific
revolution.
According to Cohen, "the emancipation of science from an overarching
entity called 'natural philosophy is one defining characteristic of the
Scientific Revolution." Other historians of science, including <a href="https://en.wikipedia.org/wiki/Edward_Grant" title="Edward Grant">Edward Grant</a>,
contend that the scientific revolution that blossomed in the 17th,
18th, and 19th centuries occurred when principles learned in the exact
sciences of optics, mechanics, and astronomy began to be applied to
questions raised by natural philosophy.
Grant argues that Newton attempted to expose the mathematical basis of
nature – the immutable rules it obeyed – and in doing so joined natural
philosophy and mathematics for the first time, producing an early work
of modern physics.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Portrait_of_Sir_Isaac_Newton,_1689.jpg"><img class="mw-file-element" data-file-height="2671" data-file-width="2218" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/3b/Portrait_of_Sir_Isaac_Newton%2C_1689.jpg/170px-Portrait_of_Sir_Isaac_Newton%2C_1689.jpg" width="332" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Isaac_Newton" title="Isaac Newton">Isaac Newton</a> is widely regarded as one of the most influential scientists of all time.</figcaption></figure>
<p>The scientific revolution, which began to take hold in the 17th
century, represented a sharp break from Aristotelian modes of inquiry. One of its principal advances was the use of the <a href="https://en.wikipedia.org/wiki/Scientific_method" title="Scientific method">scientific method</a> to investigate nature. Data was collected and <a href="https://en.wikipedia.org/wiki/Repeatability" title="Repeatability">repeatable</a> measurements were made in <a href="https://en.wikipedia.org/wiki/Experiment" title="Experiment">experiments</a>. Scientists then formed <a href="https://en.wikipedia.org/wiki/Hypothesis" title="Hypothesis">hypotheses</a> to explain the results of these experiments. The hypothesis was then tested using the principle of <a href="https://en.wikipedia.org/wiki/Falsifiability" title="Falsifiability">falsifiability</a> to prove or disprove its accuracy.
The natural sciences continued to be called natural philosophy, but the
adoption of the scientific method took science beyond the realm of
philosophical conjecture and introduced a more structured way of
examining nature.
</p><p>Newton, an English mathematician, and physicist was the seminal figure in the scientific revolution. Drawing on advances made in astronomy by Copernicus, Brahe, and Kepler, Newton derived the <a href="https://en.wikipedia.org/wiki/Newton%27s_law_of_universal_gravitation" title="Newton's law of universal gravitation">universal law of gravitation</a> and <a href="https://en.wikipedia.org/wiki/Newton%27s_laws_of_motion" title="Newton's laws of motion">laws of motion</a>.
These laws applied both on earth and in outer space, uniting two
spheres of the physical world previously thought to function
independently of each other, according to separate physical rules. Newton, for example, showed that the <a href="https://en.wikipedia.org/wiki/Tide" title="Tide">tides</a> were caused by the gravitational pull of the <a href="https://en.wikipedia.org/wiki/Moon" title="Moon">moon</a>. Another of Newton's advances was to make mathematics a powerful explanatory tool for natural phenomena.
While natural philosophers had long used mathematics as a means of
measurement and analysis, its principles were not used as a means of
understanding cause and effect in nature until Newton.
</p><p>In the 18th century and 19th century, scientists including <a href="https://en.wikipedia.org/wiki/Charles-Augustin_de_Coulomb" title="Charles-Augustin de Coulomb">Charles-Augustin de Coulomb</a>, <a href="https://en.wikipedia.org/wiki/Alessandro_Volta" title="Alessandro Volta">Alessandro Volta</a>, and <a href="https://en.wikipedia.org/wiki/Michael_Faraday" title="Michael Faraday">Michael Faraday</a> built upon Newtonian mechanics by exploring <a href="https://en.wikipedia.org/wiki/Electromagnetism" title="Electromagnetism">electromagnetism</a>, or the interplay of forces with positive and negative charges on <a href="https://en.wikipedia.org/wiki/Electric_charge" title="Electric charge">electrically charged</a> particles. Faraday proposed that forces in nature operated in "<a href="https://en.wikipedia.org/wiki/Field_(physics)" title="Field (physics)">fields</a>" that filled space.
The idea of fields contrasted with the Newtonian construct of
gravitation as simply "action at a distance", or the attraction of
objects with nothing in the space between them to intervene. <a href="https://en.wikipedia.org/wiki/James_Clerk_Maxwell" title="James Clerk Maxwell">James Clerk Maxwell</a> in the 19th century unified these discoveries in a coherent <a href="https://en.wikipedia.org/wiki/Maxwell%27s_equations" title="Maxwell's equations">theory of electrodynamics</a>.
Using mathematical equations and experimentation, Maxwell discovered
that space was filled with charged particles that could act upon
themselves and each other and that they were a medium for the
transmission of charged waves.
</p><p>Significant advances in chemistry also took place during the scientific revolution. <a href="https://en.wikipedia.org/wiki/Antoine_Lavoisier" title="Antoine Lavoisier">Antoine Lavoisier</a>, a French chemist, refuted the <a href="https://en.wikipedia.org/wiki/Phlogiston_theory" title="Phlogiston theory">phlogiston theory</a>, which posited that things burned by releasing "phlogiston" into the air. <a href="https://en.wikipedia.org/wiki/Joseph_Priestley" title="Joseph Priestley">Joseph Priestley</a> had discovered <a href="https://en.wikipedia.org/wiki/Oxygen" title="Oxygen">oxygen</a> in the 18th century, but Lavoisier discovered that <a href="https://en.wikipedia.org/wiki/Combustion" title="Combustion">combustion</a> was the result of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oxidation" title="Oxidation">oxidation</a>. He also constructed a table of 33 elements and invented modern chemical nomenclature. Formal biological science remained in its infancy in the 18th century, when the focus lay upon the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Scientific_classification" title="Scientific classification">classification and categorization</a> of natural life. This growth in <a href="https://en.wikipedia.org/wiki/Natural_history" title="Natural history">natural history</a> was led by <a href="https://en.wikipedia.org/wiki/Carl_Linnaeus" title="Carl Linnaeus">Carl Linnaeus</a>, whose 1735 <a href="https://en.wikipedia.org/wiki/Taxonomy_(biology)" title="Taxonomy (biology)">taxonomy</a> of the natural world is still in use. Linnaeus in the 1750s introduced <a href="https://en.wikipedia.org/wiki/Binomial_nomenclature" title="Binomial nomenclature">scientific names</a> for all his species.
</p>
<h3><span id="19th-century_developments_.281800.E2.80.931900.29"></span><span class="mw-headline" id="19th-century_developments_(1800–1900)">19th-century developments (1800–1900)</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Michelson-Morley_experiment_(en).svg"><img class="mw-file-element" data-file-height="320" data-file-width="425" height="302" src="https://upload.wikimedia.org/wikipedia/commons/thumb/0/06/Michelson-Morley_experiment_%28en%29.svg/220px-Michelson-Morley_experiment_%28en%29.svg.png" width="400" /></a><figcaption>The <a href="https://en.wikipedia.org/wiki/Michelson%E2%80%93Morley_experiment" title="Michelson–Morley experiment">Michelson–Morley experiment</a> was used to disprove that light propagated through a <a href="https://en.wikipedia.org/wiki/Luminiferous_aether" title="Luminiferous aether">luminiferous aether</a>. This 19th-century concept was then superseded by <a href="https://en.wikipedia.org/wiki/Albert_Einstein" title="Albert Einstein">Albert Einstein</a>'s <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Special_theory_of_relativity" title="Special theory of relativity">special theory of relativity</a>.</figcaption></figure>
<p>By the 19th century, the study of science had come into the purview
of professionals and institutions. In so doing, it gradually acquired
the more modern name of <i>natural science.</i> The term <i>scientist</i> was coined by <a href="https://en.wikipedia.org/wiki/William_Whewell" title="William Whewell">William Whewell</a> in an 1834 review of <a href="https://en.wikipedia.org/wiki/Mary_Somerville" title="Mary Somerville">Mary Somerville</a>'s <i>On the Connexion of the Sciences</i>. But the word did not enter general use until nearly the end of the same century.
</p>
<h3><span id="Modern_natural_science_.281900.E2.80.93present.29"></span><span class="mw-headline" id="Modern_natural_science_(1900–present)">Modern natural science (1900–present)</span></h3><p>According to a famous 1923 textbook, <i>Thermodynamics and the Free Energy of Chemical Substances</i>, by the American chemist <a href="https://en.wikipedia.org/wiki/Gilbert_N._Lewis" title="Gilbert N. Lewis">Gilbert N. Lewis</a> and the American physical chemist <a href="https://en.wikipedia.org/wiki/Merle_Randall" title="Merle Randall">Merle Randall</a>, the natural sciences contain three great branches:
</p>
<blockquote><p>Aside from the logical and mathematical sciences, there are three great branches of <i>natural science</i>
which stand apart by reason of the variety of far reaching deductions
drawn from a small number of primary postulates — they are <a href="https://en.wikipedia.org/wiki/Mechanics" title="Mechanics">mechanics</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electrodynamics" title="Electrodynamics">electrodynamics</a>, and <a href="https://en.wikipedia.org/wiki/Thermodynamics" title="Thermodynamics">thermodynamics</a>.</p></blockquote>
<p>Today, natural sciences are more commonly divided into life sciences,
such as botany and zoology; and physical sciences, which include
physics, chemistry, astronomy, and Earth sciences.
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-68087946386583655232024-03-28T16:27:00.007-04:002024-03-28T16:27:41.776-04:00Cell potency<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia<br /><a href="https://en.wikipedia.org/wiki/Cell_potency">https://en.wikipedia.org/wiki/Cell_potency</a><br /></div>
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<p><b>Cell potency</b> is a <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cell</a>'s ability to <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">differentiate</a> into other cell types.
The more cell types a cell can differentiate into, the greater its
potency. Potency is also described as the gene activation potential
within a cell, which like a continuum, begins with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Totipotency" title="Totipotency">totipotency</a> to designate a cell with the most differentiation potential, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotency</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multipotency" title="Multipotency">multipotency</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oligopotency" title="Oligopotency">oligopotency</a>, and finally <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Unipotency" title="Unipotency">unipotency</a>.
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<figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Stem_cells_diagram.png"><img class="mw-file-element" data-file-height="927" data-file-width="1015" height="365" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/3c/Stem_cells_diagram.png/300px-Stem_cells_diagram.png" width="400" /></a><figcaption><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotent" title="Pluripotent">Pluripotent</a>, embryonic <a href="https://en.wikipedia.org/wiki/Stem_cell" title="Stem cell">stem cells</a> originate as inner mass cells within a <a href="https://en.wikipedia.org/wiki/Blastocyst" title="Blastocyst">blastocyst</a>. These stem cells can become any tissue in the body, excluding a <a href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">placenta</a>. Only the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Morula" title="Morula">morula</a>'s cells are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Totipotent" title="Totipotent">totipotent</a>, able to become all tissues and a placenta.</figcaption></figure>
<h2><span class="mw-headline" id="Totipotency">Totipotency</span></h2></div></div></div><p>Totipotency (Latin: <i lang="la">totipotentia</i>, <small><abbr title="literal translation">lit.</abbr> </small>'ability for all [things]') is the ability of a single <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cell</a> to divide and produce all of the differentiated cells in an <a href="https://en.wikipedia.org/wiki/Organism" title="Organism">organism</a>. <a href="https://en.wikipedia.org/wiki/Spore" title="Spore">Spores</a> and <a href="https://en.wikipedia.org/wiki/Zygote" title="Zygote">zygotes</a> are examples of totipotent cells.
In the spectrum of cell potency, totipotency represents the cell with the greatest <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">differentiation</a> potential, being able to differentiate into any <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryonic</a> cell, as well as any <a href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">extraembryonic tissue</a> cell. In contrast, pluripotent cells can only differentiate into embryonic cells.
</p><p>A fully differentiated cell can return to a state of totipotency.
The conversion to totipotency is complex and not fully understood. In
2011, research revealed that cells may differentiate not into a fully
totipotent cell, but instead into a "complex cellular variation" of
totipotency. Stem cells resembling totipotent <a href="https://en.wikipedia.org/wiki/Blastomere" title="Blastomere">blastomeres</a> from 2-cell stage embryos can arise spontaneously in mouse embryonic stem cell cultures and also can be induced to arise more frequently <i><a href="https://en.wikipedia.org/wiki/In_vitro" title="In vitro">in vitro</a></i> through down-regulation of the <a href="https://en.wikipedia.org/wiki/Chromatin" title="Chromatin">chromatin</a> assembly activity of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/CAF-1" title="CAF-1">CAF-1</a>.
</p><p>The human development model can be used to describe how totipotent cells arise. Human development begins when a <a href="https://en.wikipedia.org/wiki/Spermatozoon" title="Spermatozoon">sperm</a> fertilizes an egg and the resulting fertilized egg creates a single totipotent cell, a <a href="https://en.wikipedia.org/wiki/Zygote" title="Zygote">zygote</a>.
In the first hours after fertilization, this zygote divides into
identical totipotent cells, which can later develop into any of the
three germ layers of a human (<a href="https://en.wikipedia.org/wiki/Endoderm" title="Endoderm">endoderm</a>, <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesoderm</a>, or <a href="https://en.wikipedia.org/wiki/Ectoderm" title="Ectoderm">ectoderm</a>), or into cells of the placenta (<a href="https://en.wikipedia.org/wiki/Cytotrophoblast" title="Cytotrophoblast">cytotrophoblast</a> or <a href="https://en.wikipedia.org/wiki/Syncytiotrophoblast" title="Syncytiotrophoblast">syncytiotrophoblast</a>). After reaching a 16-cell stage, the totipotent cells of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Morula" title="Morula">morula</a> differentiate into cells that will eventually become either the <a href="https://en.wikipedia.org/wiki/Blastocyst" title="Blastocyst">blastocyst</a>'s <a href="https://en.wikipedia.org/wiki/Inner_cell_mass" title="Inner cell mass">Inner cell mass</a> or the outer <a href="https://en.wikipedia.org/wiki/Trophoblast" title="Trophoblast">trophoblasts</a>.
Approximately four days after fertilization and after several cycles of
cell division, these totipotent cells begin to specialize. The inner
cell mass, the source of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryonic_stem_cells" title="Embryonic stem cells">embryonic stem cells</a>, becomes pluripotent.
</p><p>Research on <i><a href="https://en.wikipedia.org/wiki/Caenorhabditis_elegans" title="Caenorhabditis elegans">Caenorhabditis elegans</a></i> suggests that multiple mechanisms including <a href="https://en.wikipedia.org/wiki/Post-transcriptional_regulation" title="Post-transcriptional regulation">RNA regulation</a> may play a role in maintaining totipotency at different stages of development in some species. Work with <a href="https://en.wikipedia.org/wiki/Zebrafish" title="Zebrafish">zebrafish</a> and mammals suggest a further interplay between <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MiRNA" title="MiRNA">miRNA</a> and <a href="https://en.wikipedia.org/wiki/RNA-binding_protein" title="RNA-binding protein">RNA-binding proteins</a> (RBPs) in determining development differences.
</p>
<h3><span class="mw-headline" id="Primordial_germ_cells">Primordial germ cells</span></h3><p>In mouse primordial <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Germ_cells" title="Germ cells">germ cells</a>, <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a>-wide reprogramming leading to totipotency involves erasure of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epigenetic" title="Epigenetic">epigenetic</a> imprints. Reprogramming is facilitated by active <a href="https://en.wikipedia.org/wiki/DNA_demethylation" title="DNA demethylation">DNA demethylation</a> involving the DNA <a href="https://en.wikipedia.org/wiki/Base_excision_repair" title="Base excision repair">base excision repair</a> enzymatic pathway. This pathway entails erasure of <a href="https://en.wikipedia.org/wiki/CpG_site" title="CpG site">CpG</a> methylation (5mC) in primordial germ cells via the initial conversion of 5mC to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/5-hydroxymethylcytosine" title="5-hydroxymethylcytosine">5-hydroxymethylcytosine</a> (5hmC), a reaction driven by high levels of the ten-eleven dioxygenase enzymes <a href="https://en.wikipedia.org/wiki/Tet_methylcytosine_dioxygenase_1" title="Tet methylcytosine dioxygenase 1">
TET-1</a> and <a href="https://en.wikipedia.org/wiki/Tet_methylcytosine_dioxygenase_2" title="Tet methylcytosine dioxygenase 2">
TET-2</a>.
</p>
<h2><span class="mw-headline" id="Pluripotency">Pluripotency</span></h2><div class="hatnote navigation-not-searchable" role="note">For substances having the capacity to produce several distinct biological responses, see <a href="https://en.wikipedia.org/wiki/Pluripotency_(biological_compounds)" title="Pluripotency (biological compounds)">Pluripotency (biological compounds)</a>.</div>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Stem_cell" title="Stem cell">Stem cell</a></div>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_embryonic_stem_cells.png"><img class="mw-file-element" data-file-height="1899" data-file-width="1010" height="470" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Human_embryonic_stem_cells.png/250px-Human_embryonic_stem_cells.png" width="250" /></a><figcaption>A: Human <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryonic</a> stem cells (cell colonies that are not yet differentiated).<br />B: <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">Nerve</a> cells</figcaption></figure>
<p>In cell biology, pluripotency (Latin: <i lang="la">pluripotentia</i>, <small><abbr title="literal translation">lit.</abbr> </small>'ability for many [things]') refers to a stem cell that has the potential to <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">differentiate</a> into any of the three <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Germ_layers" title="Germ layers">germ layers</a>: <a href="https://en.wikipedia.org/wiki/Endoderm" title="Endoderm">endoderm</a> (gut, lungs and liver), <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesoderm</a> (muscle, skeleton, blood vascular, urogenital, dermis), or <a href="https://en.wikipedia.org/wiki/Ectoderm" title="Ectoderm">ectoderm</a> (nervous, sensory, epidermis), but not into extra-embryonic tissues like the placenta or yolk sac.
However, cell pluripotency is a continuum, ranging from the completely
pluripotent cell that can form every cell of the embryo proper, e.g.,
embryonic stem cells and iPSCs, to the incompletely or partially
pluripotent cell that can form cells of all three germ layers but that
may not exhibit all the characteristics of completely pluripotent cells.
</p>
<h3><span class="mw-headline" id="Induced_pluripotency">Induced pluripotency</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells" title="Induced pluripotent stem cells">Induced pluripotent stem cells</a></div>
<p>Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs, are a type of pluripotent <a href="https://en.wikipedia.org/wiki/Stem_cell" title="Stem cell">stem cell</a> artificially derived from a non-pluripotent cell, typically an adult <a href="https://en.wikipedia.org/wiki/Somatic_cell" title="Somatic cell">somatic cell</a>, by inducing a "forced" expression of certain <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">genes</a> and <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factors</a>.
These transcription factors play a key role in determining the state of
these cells and also highlights the fact that these somatic cells do
preserve the same genetic information as early embryonic cells. The ability to induce cells into a pluripotent state was initially pioneered in 2006 using mouse <a href="https://en.wikipedia.org/wiki/Fibroblast" title="Fibroblast">fibroblasts</a> and four transcription factors, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oct4" title="Oct4">Oct4</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sox2" title="Sox2">Sox2</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Klf4" title="Klf4">Klf4</a> and c-<a href="https://en.wikipedia.org/wiki/Myc" title="Myc">Myc</a>; this technique, called <a href="https://en.wikipedia.org/wiki/Reprogramming" title="Reprogramming">reprogramming</a>, later earned <a href="https://en.wikipedia.org/wiki/Shinya_Yamanaka" title="Shinya Yamanaka">Shinya Yamanaka</a> and <a href="https://en.wikipedia.org/wiki/John_Gurdon" title="John Gurdon">John Gurdon</a> the Nobel Prize in Physiology or Medicine.
This was then followed in 2007 by the successful induction of human
iPSCs derived from human dermal fibroblasts using methods similar to
those used for the induction of mouse cells.
These induced cells exhibit similar traits to those of embryonic stem
cells (ESCs) but do not require the use of embryos. Some of the
similarities between ESCs and iPSCs include pluripotency, <a href="https://en.wikipedia.org/wiki/Morphology_(biology)" title="Morphology (biology)">morphology</a>, self-renewal ability, a trait that implies that they can divide and replicate indefinitely, and <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a>.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epigenetic" title="Epigenetic">Epigenetic</a>
factors are also thought to be involved in the actual reprogramming of
somatic cells in order to induce pluripotency. It has been theorized
that certain epigenetic factors might actually work to clear the
original somatic epigenetic marks in order to acquire the new epigenetic
marks that are part of achieving a pluripotent state. Chromatin is also
reorganized in iPSCs and becomes like that found in ESCs in that it is
less condensed and therefore more accessible. <a href="https://en.wikipedia.org/wiki/Euchromatin" title="Euchromatin">Euchromatin</a> modifications are also common which is also consistent with the state of <a href="https://en.wikipedia.org/wiki/Euchromatin" title="Euchromatin">euchromatin</a> found in ESCs.
</p><p>Due to their great similarity to ESCs, the medical and research
communities are interested iPSCs. iPSCs could potentially have the same
therapeutic implications and applications as ESCs but without the
controversial use of embryos in the process, a topic of great bioethical
debate. The induced pluripotency of somatic cells into <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">undifferentiated</a> <a href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell" title="Induced pluripotent stem cell">iPS cells</a> was originally hailed as the end of the <a href="https://en.wikipedia.org/wiki/Stem_cell_controversy" title="Stem cell controversy">controversial use</a> of <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">embryonic stem cells</a>. However, iPSCs were found to be potentially <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumorigenic" title="Tumorigenic">tumorigenic</a>, and, despite advances,
were never approved for clinical stage research in the United States
until recently. Currently, autologous iPSC-derived dopaminergic
progenitor cells are used in trials for treating Parkinson's disease. Setbacks such as low replication rates and early senescence have also been encountered when making iPSCs, hindering their use as ESCs replacements.
</p><p>Somatic expression of combined <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factors</a> can directly induce other defined somatic cell fates (<a href="https://en.wikipedia.org/wiki/Transdifferentiation" title="Transdifferentiation">transdifferentiation</a>);
researchers identified three neural-lineage-specific transcription
factors that could directly convert mouse fibroblasts (connective tissue
cells) into fully functional <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neurons</a>. This result challenges the terminal nature of <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">cellular differentiation</a> and the integrity of lineage commitment; and implies that with the proper tools, <i>all</i> cells are totipotent and may form all kinds of tissue.
</p><p>Some of the possible medical and therapeutic uses for iPSCs
derived from patients include their use in cell and tissue transplants
without the risk of rejection that is commonly encountered. iPSCs can
potentially replace animal models unsuitable as well as <i>in vitro</i> models used for disease research.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Naive-hPSC.tif"><img class="mw-file-element" data-file-height="1038" data-file-width="1376" height="302" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/ff/Naive-hPSC.tif/lossy-page1-220px-Naive-hPSC.tif.jpg" width="400" /></a><figcaption>Naive human pluripotent stem cell colony here seen growing on feeder cells (mouse).</figcaption></figure>
<h3><span class="mw-headline" id="Naive_vs._primed_pluripotency_states">Naive vs. primed pluripotency states</span></h3><p>Findings with respect to <a href="https://en.wikipedia.org/wiki/Epiblast" title="Epiblast">epiblasts</a>
before and after implantation have produced proposals for classifying
pluripotency into two states: "naive" and "primed", representing pre-
and post-implnatation epiblast, respectively.
Naive-to-primed continuum is controlled by reduction of Sox2/Oct4
dimerization on SoxOct DNA elements controlling naive pluripotency.
Primed pluripotent stem cells from different species could be reset to
naive state using a cocktail containing Klf4 and Sox2 or "super-Sox" − a
chimeric transcription factor with enhanced capacity to dimerize with
Oct4.
</p><p>The baseline stem cells commonly used in science that are
referred as embryonic stem cells (ESCs) are derived from a
pre-implantation epiblast; such epiblast is able to generate the entire
fetus, and one epiblast cell is able to contribute to all cell lineages
if injected into another blastocyst. On the other hand, several marked
differences can be observed between the pre- and post-implantation
epiblasts, such as their difference in morphology, in which the epiblast
after implantation changes its morphology into a cup-like shape called
the "egg cylinder" as well as chromosomal alteration in which one of the
X-chromosomes under random inactivation in the early stage of the egg
cylinder, known as <a href="https://en.wikipedia.org/wiki/X-inactivation" title="X-inactivation">X-inactivation</a>. During this development, the egg cylinder epiblast cells are systematically targeted by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fibroblast_growth_factors" title="Fibroblast growth factors">Fibroblast growth factors</a>, <a href="https://en.wikipedia.org/wiki/Wnt_signaling_pathway" title="Wnt signaling pathway">Wnt</a> signaling, and other inductive factors via the surrounding yolk sac and the trophoblast tissue, such that they become instructively specific according to the spatial organization.
</p><p>Another major difference is that post-implantation epiblast stem cells are unable to contribute to blastocyst <a href="https://en.wikipedia.org/wiki/Chimera_(genetics)" title="Chimera (genetics)">chimeras</a>,
which distinguishes them from other known pluripotent stem cells. Cell
lines derived from such post-implantation epiblasts are referred to as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epiblast-derived_stem_cells" title="Epiblast-derived stem cells">epiblast-derived stem cells</a>,
which were first derived in laboratory in 2007. Both ESCs and EpiSCs
are derived from epiblasts but at difference phases of development.
Pluripotency is still intact in the post-implantation epiblast, as
demonstrated by the conserved expression of <a href="https://en.wikipedia.org/wiki/Homeobox_protein_NANOG" title="Homeobox protein NANOG">Nanog</a>, <a class="new" href="https://en.wikipedia.org/w/index.php?title=Fut4&action=edit&redlink=1" title="Fut4 (page does not exist)">Fut4</a>, and <a href="https://en.wikipedia.org/wiki/Oct-4" title="Oct-4">Oct-4</a> in EpiSCs, until <a href="https://en.wikipedia.org/wiki/Somitogenesis" title="Somitogenesis">somitogenesis</a> and can be reversed midway through induced expression of <a href="https://en.wikipedia.org/wiki/Oct-4" title="Oct-4">Oct-4</a>.
</p>
<h3><span class="mw-headline" id="Native_pluripotency_in_plants">Native pluripotency in plants</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:(MHNT)_Ranunculus_asiaticus_-_example_of_Totipotency.jpg"><img class="mw-file-element" data-file-height="4697" data-file-width="7348" height="141" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c5/%28MHNT%29_Ranunculus_asiaticus_-_example_of_Totipotency.jpg/220px-%28MHNT%29_Ranunculus_asiaticus_-_example_of_Totipotency.jpg" width="220" /></a><figcaption><i>Ranunculus asiaticus</i> example of totipotency of two individuals <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MHNT" title="MHNT">MHNT</a></figcaption></figure>
<p>Un-induced pluripotency has been observed in <a class="new" href="https://en.wikipedia.org/w/index.php?title=Root_meristem&action=edit&redlink=1" title="Root meristem (page does not exist)">root meristem</a>
tissue culture, especially by Kareem et al 2015, Kim et al 2018, and
Rosspopoff et al 2017. This pluripotency is regulated by various
regulators, including <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLETHORA_1" title="PLETHORA 1">PLETHORA 1</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLETHORA_2" title="PLETHORA 2">PLETHORA 2</a>; and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLETHORA_3" title="PLETHORA 3">PLETHORA 3</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLETHORA_5" title="PLETHORA 5">PLETHORA 5</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLETHORA_7" title="PLETHORA 7">PLETHORA 7</a>, whose expression were found by Kareem to be <a href="https://en.wikipedia.org/wiki/Auxin" title="Auxin">auxin</a>-provoked. (These are also known as PLT1, PLT2, PLT3, PLT5, PLT7, and expressed by genes of the same names.) As of 2019, this is expected to open up future research into pluripotency in root tissues.
</p>
<h2><span class="mw-headline" id="Multipotency">Multipotency</span></h2><div class="hatnote navigation-not-searchable" role="note">Further information: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Progenitor_cells" title="Progenitor cells">Progenitor cells</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Hematopoiesis_(human)_diagram_en.svg"><img class="mw-file-element" data-file-height="1092" data-file-width="1405" height="311" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Hematopoiesis_%28human%29_diagram_en.svg/220px-Hematopoiesis_%28human%29_diagram_en.svg.png" width="400" /></a><figcaption>Hematopoietic
stem cells are an example of multipotency. When they differentiate into
myeloid or lymphoid progenitor cells, they lose potency and become
oligopotent cells with the ability to give rise to all cells of its
lineage.</figcaption></figure>
<p>Multipotency is when <a href="https://en.wikipedia.org/wiki/Progenitor_cell" title="Progenitor cell">progenitor cells</a>
have the gene activation potential to differentiate into discrete cell
types. For example, a hematopoietic stem cell – and this cell type can
differentiate itself into several types of blood cell like <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lymphocytes" title="Lymphocytes">lymphocytes</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Monocytes" title="Monocytes">monocytes</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neutrophils" title="Neutrophils">neutrophils</a>, etc., but it is still ambiguous whether <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell" title="Hematopoietic stem cell">HSC</a> possess the ability to differentiate into <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Brain_cells" title="Brain cells">brain cells</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bone_cells" title="Bone cells">bone cells</a> or other non-blood cell types.
</p><p>Research related to multipotent cells suggests that multipotent
cells may be capable of conversion into unrelated cell types. In another
case, human umbilical cord blood stem cells were converted into human
neurons. There is also research on converting multipotent cells into pluripotent cells.
</p><p>Multipotent cells are found in many, but not all human cell types. Multipotent cells have been found in <a href="https://en.wikipedia.org/wiki/Cord_blood" title="Cord blood">cord blood</a>, adipose tissue, cardiac cells, <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">bone marrow</a>, and <a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">mesenchymal stem cells</a> (MSCs) which are found in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Third_molar" title="Third molar">third molar</a>.
</p><p>MSCs may prove to be a valuable source for stem cells from molars
at 8–10 years of age, before adult dental calcification. MSCs can
differentiate into osteoblasts, chondrocytes, and adipocytes.
</p>
<h2><span class="mw-headline" id="Oligopotency">Oligopotency</span></h2><p>In biology, oligopotency is the ability of progenitor cells to differentiate into a few <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cell_types" title="Cell types">cell types</a>. It is a degree of <a href="https://en.wikipedia.org/wiki/Stem_cell#Potency_meaning" title="Stem cell">potency</a>. Examples of oligopotent stem cells are the lymphoid or myeloid stem cells.
A lymphoid cell specifically, can give rise to various blood cells such
as B and T cells, however, not to a different blood cell type like a red
blood cell. Examples of progenitor cells are vascular stem cells that have the capacity to become both <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Endothelial" title="Endothelial">endothelial</a> or smooth muscle cells.
</p>
<h2><span class="mw-headline" id="Unipotency">Unipotency</span></h2><div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Precursor_cell" title="Precursor cell">Precursor cell</a></div>
<p>In <a href="https://en.wikipedia.org/wiki/Cell_biology" title="Cell biology">cell biology</a>, a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type. It is currently unclear if true unipotent stem cells exist. Hepatoblasts, which differentiate into <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hepatocytes" title="Hepatocytes">hepatocytes</a> (which constitute most of the <a href="https://en.wikipedia.org/wiki/Liver" title="Liver">liver</a>) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cholangiocytes" title="Cholangiocytes">cholangiocytes</a> (epithelial cells of the bile duct), are bipotent. A close synonym for <i>unipotent cell</i> is <i><a href="https://en.wikipedia.org/wiki/Precursor_cell" title="Precursor cell">precursor cell</a>.</i>
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-19765646108440445762024-03-28T16:07:00.002-04:002024-03-28T16:07:24.153-04:00Stem cell<p></p><div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Stem_cell">https://en.wikipedia.org/wiki/Stem_cell</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background-color: thistle;">Stem cell</th></tr><tr><td class="infobox-image" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:MSC_high_magnification.jpg"><img class="mw-file-element" data-file-height="2400" data-file-width="1803" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/52/MSC_high_magnification.jpg/250px-MSC_high_magnification.jpg" width="300" /></a></span><div class="infobox-caption"><a href="https://en.wikipedia.org/wiki/Transmission_electron_microscopy" title="Transmission electron microscopy">Transmission</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electron_micrograph" title="Electron micrograph">electron micrograph</a> of a <a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">mesenchymal stem cell</a> displaying typical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ultrastructural" title="Ultrastructural">ultrastructural</a> characteristics</div><div class="infobox-caption"> </div></td></tr><tr><th class="infobox-header" colspan="2" style="background-color: #efefef;">Details</th></tr><tr><th class="infobox-header" colspan="2" style="background-color: #efefef;">Identifiers</th></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Latin" title="Latin">Latin</a></th><td class="infobox-data"><i>cellula praecursoria</i></td></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Medical_Subject_Headings" title="Medical Subject Headings">MeSH</a></th><td class="infobox-data"><a class="external text" href="https://meshb.nlm.nih.gov/record/ui?ui=D013234" rel="nofollow">D013234</a></td></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Terminologia_Histologica" title="Terminologia Histologica">TH</a></th><td class="infobox-data"><a class="external text" href="https://ifaa.unifr.ch/Public/EntryPage/PDF/TH%20Chapter%20H1.00.pdf" rel="nofollow">H1.00.01.0.00028, H2.00.01.0.00001 </a></td></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Foundational_Model_of_Anatomy" title="Foundational Model of Anatomy">FMA</a></th><td class="infobox-data"><a class="external text" href="https://bioportal.bioontology.org/ontologies/FMA/?p=classes&conceptid=http%3A%2F%2Fpurl.org%2Fsig%2Font%2Ffma%2Ffma63368" rel="nofollow">63368</a></td></tr><tr><td class="infobox-below" colspan="2"></td></tr></tbody></table><p>In <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multicellular_organisms" title="Multicellular organisms">multicellular organisms</a>, <b>stem cells</b> are <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">undifferentiated</a> or partially differentiated <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a> that can change into various <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Types_of_cells" title="Types of cells">types of cells</a> and <a href="https://en.wikipedia.org/wiki/Cell_proliferation" title="Cell proliferation">proliferate</a> indefinitely to produce more of the same stem cell. They are the earliest type of cell in a <a href="https://en.wikipedia.org/wiki/Cell_lineage" title="Cell lineage">cell lineage</a>. They are found in both <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryonic</a> and adult organisms, but they have slightly different properties in each. They are usually distinguished from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Progenitor_cells" title="Progenitor cells">progenitor cells</a>, which cannot divide indefinitely, and <a href="https://en.wikipedia.org/wiki/Precursor_cell" title="Precursor cell">precursor</a> or blast cells, which are usually committed to differentiating into one cell type.
</p><p>In <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mammals" title="Mammals">mammals</a>, roughly 50 to 150 cells make up the <a href="https://en.wikipedia.org/wiki/Inner_cell_mass" title="Inner cell mass">inner cell mass</a> during the <a href="https://en.wikipedia.org/wiki/Blastocyst" title="Blastocyst">blastocyst</a> stage of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryonic_development" title="Embryonic development">embryonic development</a>, around days 5–14. These have stem-cell capability. <i><a href="https://en.wikipedia.org/wiki/In_vivo" title="In vivo">In vivo</a></i>, they eventually differentiate into all of the body's cell types (making them <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotent" title="Pluripotent">pluripotent</a>). This process starts with the differentiation into the three <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Germ_layers" title="Germ layers">germ layers</a> – the <a href="https://en.wikipedia.org/wiki/Ectoderm" title="Ectoderm">ectoderm</a>, <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesoderm</a> and <a href="https://en.wikipedia.org/wiki/Endoderm" title="Endoderm">endoderm</a> – at the <a href="https://en.wikipedia.org/wiki/Gastrulation" title="Gastrulation">gastrulation</a> stage. However, when they are isolated and <a href="https://en.wikipedia.org/wiki/Cell_culture" title="Cell culture">cultured</a> <i><a href="https://en.wikipedia.org/wiki/In_vitro" title="In vitro">in vitro</a></i>, they can be kept in the stem-cell stage and are known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryonic_stem_cells" title="Embryonic stem cells">embryonic stem cells</a> (ESCs).
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Adult_stem_cells" title="Adult stem cells">Adult stem cells</a> are found in a few select locations in the body, known as <a href="https://en.wikipedia.org/wiki/Stem-cell_niche" title="Stem-cell niche">niches</a>, such as those in the <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">bone marrow</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gonads" title="Gonads">gonads</a>. They exist to replenish rapidly lost cell types and are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multipotent" title="Multipotent">multipotent</a>
or unipotent, meaning they only differentiate into a few cell types or
one type of cell. In mammals, they include, among others, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cells" title="Hematopoietic stem cells">hematopoietic stem cells</a>, which replenish blood and immune cells, <a href="https://en.wikipedia.org/wiki/Stratum_basale" title="Stratum basale">basal cells</a>, which maintain the skin <a href="https://en.wikipedia.org/wiki/Epithelium" title="Epithelium">epithelium</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cells" title="Mesenchymal stem cells">mesenchymal stem cells</a>, which maintain bone, <a href="https://en.wikipedia.org/wiki/Cartilage" title="Cartilage">cartilage</a>,
muscle and fat cells. Adult stem cells are a small minority of cells;
they are vastly outnumbered by the progenitor cells and terminally
differentiated cells that they differentiate into.
</p><p>Research into stem cells grew out of findings by Canadian biologists <a href="https://en.wikipedia.org/wiki/Ernest_McCulloch" title="Ernest McCulloch">Ernest McCulloch</a>, <a href="https://en.wikipedia.org/wiki/James_Till" title="James Till">James Till</a> and Andrew J. Becker at the <a href="https://en.wikipedia.org/wiki/University_of_Toronto" title="University of Toronto">University of Toronto</a> and the Ontario Cancer Institute in the 1960s. As of 2016, the only established <a href="https://en.wikipedia.org/wiki/Stem-cell_therapy" title="Stem-cell therapy">medical therapy using stem cells</a> is <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplantation" title="Hematopoietic stem cell transplantation">hematopoietic stem cell transplantation</a>, first performed in 1958 by French oncologist <a href="https://en.wikipedia.org/wiki/Georges_Math%C3%A9" title="Georges Mathé">Georges Mathé</a>. Since 1998 however, it has been possible to culture and differentiate human embryonic stem cells (in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem-cell_lines" title="Stem-cell lines">stem-cell lines</a>). The process of isolating these cells has been <a href="https://en.wikipedia.org/wiki/Stem_cell_controversy" title="Stem cell controversy">controversial</a>, because it typically results in the destruction of the embryo. Sources for isolating ESCs have been <a href="https://en.wikipedia.org/wiki/Stem_cell_laws" title="Stem cell laws">restricted</a> in some European countries and Canada, but others such as the UK and China have promoted the research. <a href="https://en.wikipedia.org/wiki/Somatic_cell_nuclear_transfer" title="Somatic cell nuclear transfer">Somatic cell nuclear transfer</a> is a <a href="https://en.wikipedia.org/wiki/Cloning" title="Cloning">cloning</a> method that can be used to create a cloned embryo for the use of its embryonic stem cells in stem cell therapy. In 2006, a Japanese team led by <a href="https://en.wikipedia.org/wiki/Shinya_Yamanaka" title="Shinya Yamanaka">Shinya Yamanaka</a> discovered a method to convert mature body cells back into stem cells. These were termed <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells" title="Induced pluripotent stem cells">induced pluripotent stem cells</a> (iPSCs).
</p>
<h2><span class="mw-headline" id="History">History</span></h2></div></div></div><p>The term <i>stem cell</i> was coined by <a href="https://en.wikipedia.org/wiki/Theodor_Boveri" title="Theodor Boveri">Theodor Boveri</a> and <a href="https://en.wikipedia.org/wiki/Valentin_Haecker" title="Valentin Haecker">Valentin Haecker</a> in late 19th century. Pioneering works in theory of blood stem cell were conducted in the beginning of 20th century by <a href="https://en.wikipedia.org/wiki/Artur_Pappenheim" title="Artur Pappenheim">Artur Pappenheim</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alexander_Maximow" title="Alexander Maximow">Alexander Maximow</a>, <a href="https://en.wikipedia.org/wiki/Franz_Ernst_Christian_Neumann" title="Franz Ernst Christian Neumann">Franz Ernst Christian Neumann</a>.
</p><p>The key properties of a stem cell were first defined by <a href="https://en.wikipedia.org/wiki/Ernest_McCulloch" title="Ernest McCulloch">Ernest McCulloch</a> and <a href="https://en.wikipedia.org/wiki/James_Till" title="James Till">James Till</a>
at the University of Toronto and the Ontario Cancer Institute in the
early 1960s. They discovered the blood-forming stem cell, the
hematopoietic stem cell (HSC), through their pioneering work in mice.
McCulloch and Till began a series of experiments in which bone marrow
cells were injected into irradiated mice. They observed lumps in the
spleens of the mice that were linearly proportional to the number of
bone marrow cells injected. They hypothesized that each lump (colony)
was a clone arising from a single marrow cell (stem cell). In subsequent
work, McCulloch and Till, joined by graduate student <a class="new" href="https://en.wikipedia.org/w/index.php?title=Andrew_John_Becker&action=edit&redlink=1" title="Andrew John Becker (page does not exist)">Andrew John Becker</a> and senior scientist <a href="https://en.wikipedia.org/wiki/Louis_Siminovitch" title="Louis Siminovitch">Louis Siminovitch</a>, confirmed that each lump did in fact arise from a single cell. Their results were published in <i>Nature</i>
in 1963. In that same year, Siminovitch was a lead investigator for
studies that found colony-forming cells were capable of self-renewal,
which is a key defining property of stem cells that Till and McCulloch
had theorized.
</p><p>The first therapy using stem cells was a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bone_marrow_transplant" title="Bone marrow transplant">bone marrow transplant</a> performed by French oncologist <a href="https://en.wikipedia.org/wiki/Georges_Math%C3%A9" title="Georges Mathé">Georges Mathé</a> in 1958 on five workers at the <a href="https://en.wikipedia.org/wiki/Vin%C4%8Da_Nuclear_Institute" title="Vinča Nuclear Institute">Vinča Nuclear Institute</a> in <a href="https://en.wikipedia.org/wiki/Socialist_Federal_Republic_of_Yugoslavia" title="Socialist Federal Republic of Yugoslavia">Yugoslavia</a> who had been affected by a <a href="https://en.wikipedia.org/wiki/Criticality_accident" title="Criticality accident">criticality accident</a>. The workers all survived.
</p><p>In 1981, embryonic stem (ES) cells were first isolated and successfully cultured using mouse blastocysts by British biologists <a href="https://en.wikipedia.org/wiki/Martin_Evans" title="Martin Evans">Martin Evans</a> and <a href="https://en.wikipedia.org/wiki/Matthew_Kaufman" title="Matthew Kaufman">Matthew Kaufman</a>.
This allowed the formation of murine genetic models, a system in which
the genes of mice are deleted or altered in order to study their
function in pathology. By 1998, human embryonic stem cells were first
isolated by American biologist <a href="https://en.wikipedia.org/wiki/James_Thomson_(cell_biologist)" title="James Thomson (cell biologist)">James Thomson</a>, which made it possible to have new transplantation methods or various cell types for testing new treatments. In 2006, <a href="https://en.wikipedia.org/wiki/Shinya_Yamanaka" title="Shinya Yamanaka">Shinya Yamanaka</a>'s
team in Kyoto, Japan converted fibroblasts into pluripotent stem cells
by modifying the expression of only four genes. The feat represents the
origin of induced pluripotent stem cells, known as iPS cells.
</p><p>In 2011, a female <a href="https://en.wikipedia.org/wiki/Maned_wolf" title="Maned wolf">maned wolf</a>, run over by a truck, underwent stem cell treatment at the <a class="new" href="https://en.wikipedia.org/w/index.php?title=Zoo_Bras%C3%ADlia&action=edit&redlink=1" title="Zoo Brasília (page does not exist)">Zoo Brasília</a>, this being the first recorded case of the use of stem cells to heal injuries in a wild animal.
</p>
<h2><span class="mw-headline" id="Properties">Properties</span></h2><p>The classical definition of a stem cell requires that it possesses two properties:
</p>
<ul><li>Self-renewal: the ability to go through numerous <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cycles</a> of <a href="https://en.wikipedia.org/wiki/Cell_growth" title="Cell growth">cell growth</a> and <a href="https://en.wikipedia.org/wiki/Cell_division" title="Cell division">cell division</a>, known as <a href="https://en.wikipedia.org/wiki/Cell_proliferation" title="Cell proliferation">cell proliferation</a>, while maintaining the undifferentiated state.</li><li><a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">Potency</a>: the capacity to <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">differentiate</a> into specialized cell types. In the strictest sense, this requires stem cells to be either <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Totipotency" title="Totipotency">totipotent</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotent</a>—to be able to give rise to any mature cell type, although <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multipotent" title="Multipotent">multipotent</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Unipotent_cell" title="Unipotent cell">unipotent</a> <a href="https://en.wikipedia.org/wiki/Progenitor_cell" title="Progenitor cell">progenitor cells</a>
are sometimes referred to as stem cells. Apart from this, it is said
that stem cell function is regulated in a feedback mechanism.</li></ul>
<h3><span class="mw-headline" id="Self-renewal">Self-renewal</span></h3><p>Two mechanisms ensure that a stem cell population is maintained (doesn't shrink in size):
</p><p>1. <a href="https://en.wikipedia.org/wiki/Asymmetric_cell_division" title="Asymmetric cell division">Asymmetric cell division</a>:
a stem cell divides into one mother cell, which is identical to the
original stem cell, and another daughter cell, which is differentiated.
</p><p>When a stem cell self-renews, it divides and does not disrupt the
undifferentiated state. This self-renewal demands control of cell cycle
as well as upkeep of multipotency or pluripotency, which all depends on
the stem cell.
</p><p>2. Stochastic differentiation: when one stem cell grows and
divides into two differentiated daughter cells, another stem cell
undergoes <a href="https://en.wikipedia.org/wiki/Mitosis" title="Mitosis">mitosis</a> and produces two stem cells identical to the original.
</p><p>Stem cells use <a href="https://en.wikipedia.org/wiki/Telomerase" title="Telomerase">telomerase</a>, a protein that restores <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Telomeres" title="Telomeres">telomeres</a>, to protect their DNA and extend their cell division limit (the <a href="https://en.wikipedia.org/wiki/Hayflick_limit" title="Hayflick limit">Hayflick limit</a>).
</p>
<h3><span class="mw-headline" id="Potency_meaning">Potency meaning</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">Cell potency</a></div>
<figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Stem_cells_diagram.png"><img class="mw-file-element" data-file-height="927" data-file-width="1015" height="365" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/3c/Stem_cells_diagram.png/330px-Stem_cells_diagram.png" width="400" /></a><figcaption>Pluripotent,
embryonic stem cells originate as inner cell mass (ICM) cells within a
blastocyst. These stem cells can become any tissue in the body,
excluding a placenta. Only cells from an earlier stage of the embryo,
known as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Morula" title="Morula">morula</a>, are totipotent, able to become all tissues in the body and the extraembryonic placenta.</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_embryonic_stem_cells.png"><img class="mw-file-element" data-file-height="1899" data-file-width="1010" height="414" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Human_embryonic_stem_cells.png/220px-Human_embryonic_stem_cells.png" width="220" /></a><figcaption>Human <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryonic</a> stem cells <br /> A: Stem cell colonies that are not yet differentiated. <br /> B: <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">Nerve</a> cells, an example of a <a href="https://en.wikipedia.org/wiki/Cell_type" title="Cell type">cell type</a> after differentiation.</figcaption></figure>
<p><a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">Potency</a> specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
</p>
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Totipotency" title="Totipotency">Totipotent</a>
(also known as omnipotent) stem cells can differentiate into embryonic
and extraembryonic cell types. Such cells can construct a complete,
viable organism. These cells are produced from the <a href="https://en.wikipedia.org/wiki/Cell_fusion" title="Cell fusion">fusion</a> of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">Pluripotent</a> stem cells are the descendants of totipotent cells and can differentiate into nearly all cells, i.e. cells derived from any of the three <a href="https://en.wikipedia.org/wiki/Germ_layer" title="Germ layer">germ layers</a>.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multipotency" title="Multipotency">Multipotent</a> stem cells can differentiate into a number of cell types, but only those of a closely related family of cells.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oligopotency" title="Oligopotency">Oligopotent</a> stem cells can differentiate into only a few cell types, such as lymphoid or myeloid stem cells.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Unipotency" title="Unipotency">Unipotent</a> cells can produce only one cell type, their own, but have the property of self-renewal, which distinguishes them from non-stem cells</li></ul>
<h3><span class="mw-headline" id="Identification">Identification</span></h3><p>In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell" title="Hematopoietic stem cell">hematopoietic stem cells</a>
(HSCs) is the ability to transplant the cells and save an individual
without HSCs. This demonstrates that the cells can produce new blood
cells over a long term. It should also be possible to isolate stem cells
from the transplanted individual, which can themselves be transplanted
into another individual without HSCs, demonstrating that the stem cell
was able to self-renew.
</p><p>Properties of stem cells can be illustrated <i><a href="https://en.wikipedia.org/wiki/In_vitro" title="In vitro">in vitro</a></i>, using methods such as <a href="https://en.wikipedia.org/wiki/Clonogenic_assay" title="Clonogenic assay">clonogenic assays</a>, in which single cells are assessed for their ability to differentiate and self-renew. Stem cells can also be isolated by their possession of a distinctive set of cell surface markers. However, <i>in vitro</i> culture conditions can alter the behavior of cells, making it unclear whether the cells shall behave in a similar manner <i><a href="https://en.wikipedia.org/wiki/In_vivo" title="In vivo">in vivo</a></i>. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.
</p>
<h2><span class="mw-headline" id="Embryonic">Embryonic</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">Embryonic stem cell</a></div>
<p><a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">Embryonic stem cells</a> (ESCs) are the cells of the <a href="https://en.wikipedia.org/wiki/Inner_cell_mass" title="Inner cell mass">inner cell mass</a> of a <a href="https://en.wikipedia.org/wiki/Blastocyst" title="Blastocyst">blastocyst</a>, formed prior to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Implantation_(human_embryo)" title="Implantation (human embryo)">implantation</a> in the uterus. In <a href="https://en.wikipedia.org/wiki/Human_embryonic_development" title="Human embryonic development">human embryonic development</a> the <a href="https://en.wikipedia.org/wiki/Blastocyst" title="Blastocyst">blastocyst</a> stage is reached 4–5 days after <a href="https://en.wikipedia.org/wiki/Human_fertilization" title="Human fertilization">fertilization</a>, at which time it consists of 50–150 cells. ESCs are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotent" title="Pluripotent">pluripotent</a> and give rise during development to all derivatives of the three <a href="https://en.wikipedia.org/wiki/Germ_layer" title="Germ layer">germ layers</a>: <a href="https://en.wikipedia.org/wiki/Ectoderm" title="Ectoderm">ectoderm</a>, <a href="https://en.wikipedia.org/wiki/Endoderm" title="Endoderm">endoderm</a> and <a href="https://en.wikipedia.org/wiki/Mesoderm" title="Mesoderm">mesoderm</a>. In other words, they can develop into each of the more than 200 cell types of the adult <a href="https://en.wikipedia.org/wiki/Human_body" title="Human body">body</a> when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the <a href="https://en.wikipedia.org/wiki/Extraembryonic_membrane" title="Extraembryonic membrane">extraembryonic membranes</a> or to the <a href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">placenta</a>.
</p><p>During embryonic development the cells of the inner cell mass
continuously divide and become more specialized. For example, a portion
of the ectoderm in the dorsal part of the embryo specializes as '<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurectoderm" title="Neurectoderm">neurectoderm</a>', which will become the future <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>. Later in development, <a href="https://en.wikipedia.org/wiki/Neurulation" title="Neurulation">neurulation</a> causes the neurectoderm to form the <a href="https://en.wikipedia.org/wiki/Neural_tube" title="Neural tube">neural tube</a>. At the neural tube stage, the anterior portion undergoes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Encephalization" title="Encephalization">encephalization</a>
to generate or 'pattern' the basic form of the brain. At this stage of
development, the principal cell type of the CNS is considered a <a href="https://en.wikipedia.org/wiki/Neural_stem_cell" title="Neural stem cell">neural stem cell</a>.
</p><p>The neural stem cells self-renew and at some point transition into <a href="https://en.wikipedia.org/wiki/Radial_glial_cell" title="Radial glial cell">radial glial progenitor cells</a> (RGPs). Early-formed RGPs self-renew by symmetrical division to form a reservoir group of <a href="https://en.wikipedia.org/wiki/Progenitor_cell" title="Progenitor cell">progenitor cells</a>. These cells transition to a <a href="https://en.wikipedia.org/wiki/Neurogenesis" title="Neurogenesis">neurogenic</a> state and start to divide <a href="https://en.wikipedia.org/wiki/Asymmetric_cell_division" title="Asymmetric cell division">asymmetrically</a>
to produce a large diversity of many different neuron types, each with
unique gene expression, morphological, and functional characteristics.
The process of generating neurons from radial glial cells is called <a href="https://en.wikipedia.org/wiki/Neurogenesis" title="Neurogenesis">neurogenesis</a>.
The radial glial cell, has a distinctive bipolar morphology with highly
elongated processes spanning the thickness of the neural tube wall. It
shares some <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glial" title="Glial">glial</a> characteristics, most notably the expression of <a href="https://en.wikipedia.org/wiki/Glial_fibrillary_acidic_protein" title="Glial fibrillary acidic protein">glial fibrillary acidic protein</a> (GFAP). The radial glial cell is the primary neural stem cell of the developing <a href="https://en.wikipedia.org/wiki/Vertebrate" title="Vertebrate">vertebrate</a> CNS, and its cell body resides in the <a href="https://en.wikipedia.org/wiki/Ventricular_zone" title="Ventricular zone">ventricular zone</a>, adjacent to the developing <a href="https://en.wikipedia.org/wiki/Ventricular_system" title="Ventricular system">ventricular system</a>. Neural stem cells are committed to the neuronal lineages (<a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neurons</a>, <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a>, and <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocytes</a>), and thus their potency is restricted.
</p><p>Nearly all research to date has made use of mouse embryonic stem cells (mES) or <b>human embryonic stem cells </b> <b>(hES)</b>
derived from the early inner cell mass. Both have the essential stem
cell characteristics, yet they require very different environments in
order to maintain an undifferentiated state. Mouse ES cells are grown on
a layer of <a href="https://en.wikipedia.org/wiki/Gelatin" title="Gelatin">gelatin</a> as an <a href="https://en.wikipedia.org/wiki/Extracellular_matrix" title="Extracellular matrix">extracellular matrix</a> (for support) and require the presence of <a href="https://en.wikipedia.org/wiki/Leukemia_inhibitory_factor" title="Leukemia inhibitory factor">leukemia inhibitory factor</a> (LIF) in serum media. A drug cocktail containing inhibitors to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/GSK3B" title="GSK3B">GSK3B</a> and the <a href="https://en.wikipedia.org/wiki/MAPK/ERK_pathway" title="MAPK/ERK pathway">MAPK/ERK pathway</a>, called 2i, has also been shown to maintain pluripotency in stem cell culture. Human ESCs are grown on a feeder layer of mouse embryonic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fibroblasts" title="Fibroblasts">fibroblasts</a> and require the presence of basic fibroblast growth factor (bFGF or FGF-2). Without optimal culture conditions or genetic manipulation, embryonic stem cells will rapidly differentiate.
</p><p>A human embryonic stem cell is also defined by the expression of
several transcription factors and cell surface proteins. The
transcription factors <a href="https://en.wikipedia.org/wiki/Oct-4" title="Oct-4">Oct-4</a>, <a href="https://en.wikipedia.org/wiki/Homeobox_protein_NANOG" title="Homeobox protein NANOG">Nanog</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sox2" title="Sox2">Sox2</a>
form the core regulatory network that ensures the suppression of genes
that lead to differentiation and the maintenance of pluripotency. The cell surface antigens most commonly used to identify hES cells are the glycolipids <a href="https://en.wikipedia.org/wiki/Stage_specific_embryonic_antigen_3" title="Stage specific embryonic antigen 3">stage specific embryonic antigen 3</a>
and 4, and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The
molecular definition of a stem cell includes many more proteins and
continues to be a topic of research.
</p><p>By using human embryonic stem cells to produce specialized cells
like nerve cells or heart cells in the lab, scientists can gain access
to adult human cells without taking tissue from patients. They can then
study these specialized adult cells in detail to try to discern
complications of diseases, or to study cell reactions to proposed new
drugs.
</p><p>Because of their combined abilities of unlimited expansion and
pluripotency, embryonic stem cells remain a theoretically potential
source for <a href="https://en.wikipedia.org/wiki/Regenerative_medicine" title="Regenerative medicine">regenerative medicine</a> and tissue replacement after injury or disease.,
however, there are currently no approved treatments using ES cells. The
first human trial was approved by the US Food and Drug Administration
in January 2009. However, the human trial was not initiated until October 13, 2010 in Atlanta for <a href="https://en.wikipedia.org/wiki/Spinal_cord_injury_research" title="Spinal cord injury research">spinal cord injury research</a>. On November 14, 2011 the company conducting the trial (<a href="https://en.wikipedia.org/wiki/Geron_Corporation" title="Geron Corporation">Geron Corporation</a>) announced that it will discontinue further development of its stem cell programs.
Differentiating ES cells into usable cells while avoiding transplant
rejection are just a few of the hurdles that embryonic stem cell
researchers still face.
Embryonic stem cells, being pluripotent, require specific signals for
correct differentiation – if injected directly into another body, ES
cells will differentiate into many different types of cells, causing a <a href="https://en.wikipedia.org/wiki/Teratoma" title="Teratoma">teratoma</a>.
Ethical considerations regarding the use of unborn human tissue are
another reason for the lack of approved treatments using embryonic stem
cells. Many nations currently have <a href="https://en.wikipedia.org/wiki/Moratorium_(law)" title="Moratorium (law)">moratoria</a> or limitations on either human ES cell research or the production of new human ES cell lines.
</p>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Mouse_embryonic_stem_cells.jpg" title="Mouse embryonic stem cells with fluorescent marker"><img alt="Mouse embryonic stem cells with fluorescent marker" class="mw-file-element" data-file-height="507" data-file-width="600" height="337" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f0/Mouse_embryonic_stem_cells.jpg/120px-Mouse_embryonic_stem_cells.jpg" width="400" /></a></span></div>
<div class="gallerytext"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mus_musculus" title="Mus musculus">Mouse</a> <a href="https://en.wikipedia.org/wiki/Mammalian_embryogenesis" title="Mammalian embryogenesis">embryonic</a> stem cells with fluorescent marker</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_embryonic_stem_cell_colony_phase.jpg" title="Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer"><img alt="Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer" class="mw-file-element" data-file-height="894" data-file-width="1024" height="350" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Human_embryonic_stem_cell_colony_phase.jpg/120px-Human_embryonic_stem_cell_colony_phase.jpg" width="400" /></a></span></div>
<div class="gallerytext">Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer</div>
</li></ul>
<h3><span class="mw-headline" id="Mesenchymal_stem_cells">Mesenchymal stem cells</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_mesenchymal_stem_cells.gif"><img class="mw-file-element" data-file-height="598" data-file-width="600" height="398" src="https://upload.wikimedia.org/wikipedia/commons/thumb/0/04/Human_mesenchymal_stem_cells.gif/220px-Human_mesenchymal_stem_cells.gif" width="400" /></a><figcaption>Human mesenchymal stem cells</figcaption></figure>
<p>Mesenchymal stem cells (MSC) or mesenchymal stromal cells, also known
as medicinal signaling cells are known to be multipotent, which can be
found in adult tissues, for example, in the muscle, liver, bone marrow
and adipose tissue. Mesenchymal stem cells usually function as
structural support in various organs as mentioned above, and control the
movement of substances. MSC can differentiate into numerous cell
categories as an illustration of adipocytes, osteocytes, and
chondrocytes, derived by the mesodermal layer.
Where the mesoderm layer provides an increase to the body's skeletal
elements, such as relating to the cartilage or bone. The term "meso"
means middle, infusion originated from the Greek, signifying that
mesenchymal cells are able to range and travel in early embryonic growth
among the ectodermal and endodermal layers. This mechanism helps with
space-filling thus, key for repairing wounds in adult organisms that
have to do with mesenchymal cells in the dermis (skin), bone, or muscle.
</p><p>Mesenchymal stem cells are known to be essential for regenerative medicine. They are broadly studied in <a href="https://en.wikipedia.org/wiki/List_of_countries_by_stem_cell_research_trials" title="List of countries by stem cell research trials">clinical trials</a>.
Since they are easily isolated and obtain high yield, high plasticity,
which makes able to facilitate inflammation and encourage cell growth,
cell differentiation, and restoring tissue derived from immunomodulation
and immunosuppression. MSC comes from the bone marrow, which requires
an aggressive procedure when it comes to isolating the quantity and
quality of the isolated cell, and it varies by how old the donor. When
comparing the rates of MSC in the bone marrow aspirates and bone marrow
stroma, the aspirates tend to have lower rates of MSC than the stroma.
MSC are known to be heterogeneous, and they express a high level of
pluripotent markers when compared to other types of stem cells, such as
embryonic stem cells. MSCs injection leads to wound healing primarily through stimulation of angiogenesis.
</p>
<h3><span class="mw-headline" id="Cell_cycle_control">Cell cycle control</span></h3><div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">Cell cycle</a></div>
<p>Embryonic stem cells (ESCs) have the ability to divide indefinitely while keeping their <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotency</a>, which is made possible through specialized mechanisms of <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a> control. Compared to proliferating <a href="https://en.wikipedia.org/wiki/Somatic_cell" title="Somatic cell">somatic cells</a>, ESCs have unique cell cycle characteristics—such as rapid cell division caused by shortened <a href="https://en.wikipedia.org/wiki/G1_phase" title="G1 phase">G1 phase</a>, absent <a href="https://en.wikipedia.org/wiki/G2_phase" title="G2 phase">G0 phase</a>, and modifications in <a href="https://en.wikipedia.org/wiki/Cell_cycle_checkpoint" title="Cell cycle checkpoint">cell cycle checkpoints</a>—which leaves the cells mostly in <a href="https://en.wikipedia.org/wiki/S_phase" title="S phase">S phase</a> at any given time.
ESCs' rapid division is demonstrated by their short doubling time,
which ranges from 8 to 10 hours, whereas somatic cells have doubling
time of approximately 20 hours or longer.
As cells differentiate, these properties change: G1 and G2 phases
lengthen, leading to longer cell division cycles. This suggests that a
specific cell cycle structure may contribute to the establishment of
pluripotency.
</p><p>Particularly because G1 phase is the phase in which cells have
increased sensitivity to differentiation, shortened G1 is one of the key
characteristics of ESCs and plays an important role in maintaining
undifferentiated <a href="https://en.wikipedia.org/wiki/Phenotype" title="Phenotype">phenotype</a>.
Although the exact molecular mechanism remains only partially
understood, several studies have shown insight on how ESCs progress
through G1—and potentially other phases—so rapidly.
</p><p>The cell cycle is regulated by complex network of <a href="https://en.wikipedia.org/wiki/Cyclin" title="Cyclin">cyclins</a>, <a href="https://en.wikipedia.org/wiki/Cyclin-dependent_kinase" title="Cyclin-dependent kinase">cyclin-dependent kinases</a> (Cdk), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_inhibitor" title="Cyclin-dependent kinase inhibitor">cyclin-dependent kinase inhibitors</a> (Cdkn), pocket proteins of the retinoblastoma (Rb) family, and other accessory factors. Foundational insight into the distinctive regulation of ESC cell cycle was gained by studies on mouse ESCs (mESCs).
mESCs showed a cell cycle with highly abbreviated G1 phase, which
enabled cells to rapidly alternate between M phase and S phase. In a
somatic cell cycle, oscillatory activity of Cyclin-Cdk complexes is
observed in sequential action, which controls crucial regulators of the
cell cycle to induce unidirectional transitions between phases: <a href="https://en.wikipedia.org/wiki/Cyclin_D" title="Cyclin D">Cyclin D</a> and Cdk4/6 are active in the G1 phase, while <a href="https://en.wikipedia.org/wiki/Cyclin_E" title="Cyclin E">Cyclin E</a> and <a href="https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_2" title="Cyclin-dependent kinase 2">Cdk2</a> are active during the late G1 phase and S phase; and <a href="https://en.wikipedia.org/wiki/Cyclin_A" title="Cyclin A">Cyclin A</a> and Cdk2 are active in the S phase and G2, while <a href="https://en.wikipedia.org/wiki/Cyclin_B" title="Cyclin B">Cyclin B</a> and <a href="https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_1" title="Cyclin-dependent kinase 1">Cdk1</a> are active in G2 and M phase.
However, in mESCs, this typically ordered and oscillatory activity of
Cyclin-Cdk complexes is absent. Rather, the Cyclin E/Cdk2 complex is
constitutively active throughout the cycle, keeping <a href="https://en.wikipedia.org/wiki/Retinoblastoma_protein" title="Retinoblastoma protein">retinoblastoma protein</a> (pRb) <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hyperphosphorylated" title="Hyperphosphorylated">hyperphosphorylated</a>
and thus inactive. This allows for direct transition from M phase to
the late G1 phase, leading to absence of D-type cyclins and therefore a
shortened G1 phase.
Cdk2 activity is crucial for both cell cycle regulation and cell-fate
decisions in mESCs; downregulation of Cdk2 activity prolongs G1 phase
progression, establishes a somatic cell-like cell cycle, and induces
expression of differentiation markers.
</p><p>In human ESCs (hESCs), the duration of G1 is dramatically
shortened. This has been attributed to high mRNA levels of G1-related
Cyclin D2 and Cdk4 genes and low levels of cell cycle regulatory
proteins that inhibit cell cycle progression at G1, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/P21Cip1" title="P21Cip1">p21<sup>CipP1</sup></a>, p27<sup>Kip1</sup>, and p57<sup>Kip2</sup>.
Furthermore, regulators of Cdk4 and Cdk6 activity, such as members of
the Ink family of inhibitors (p15, p16, p18, and p19), are expressed at
low levels or not at all. Thus, similar to mESCs, hESCs show high Cdk
activity, with Cdk2 exhibiting the highest kinase activity. Also similar
to mESCs, hESCs demonstrate the importance of Cdk2 in G1 phase
regulation by showing that G1 to S transition is delayed when Cdk2
activity is inhibited and G1 is arrest when Cdk2 is knocked down.
However unlike mESCs, hESCs have a functional G1 phase. hESCs show that
the activities of Cyclin E/Cdk2 and Cyclin A/Cdk2 complexes are cell
cycle-dependent and the Rb checkpoint in G1 is functional.
</p><p>ESCs are also characterized by G1 checkpoint non-functionality,
even though the G1 checkpoint is crucial for maintaining genomic
stability. In response to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/DNA_damage" title="DNA damage">DNA damage</a>,
ESCs do not stop in G1 to repair DNA damages but instead, depend on S
and G2/M checkpoints or undergo apoptosis. The absence of G1 checkpoint
in ESCs allows for the removal of cells with damaged DNA, hence avoiding
potential mutations from inaccurate DNA repair. Consistent with this idea, ESCs are hypersensitive to DNA damage to minimize mutations passed onto the next generation.
</p>
<h2><span class="mw-headline" id="Fetal">Fetal</span></h2><p>The primitive stem cells located in the organs of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fetuses" title="Fetuses">fetuses</a> are referred to as fetal stem cells.
</p><p>There are two types of fetal stem cells:
</p>
<ol><li>Fetal proper stem cells come from the tissue of the fetus proper and are generally obtained after an <a href="https://en.wikipedia.org/wiki/Abortion" title="Abortion">abortion</a>. These stem cells are not immortal but have a high level of division and are multipotent.</li><li>Extraembryonic fetal stem cells come from <a href="https://en.wikipedia.org/wiki/Extraembryonic_membrane" title="Extraembryonic membrane">extraembryonic membranes</a>,
and are generally not distinguished from adult stem cells. These stem
cells are acquired after birth, they are not immortal but have a high
level of cell division, and are pluripotent.</li></ol>
<h2><span class="mw-headline" id="Adult">Adult</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Adult_stem_cell" title="Adult stem cell">Adult stem cell</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Stem_cell_division_and_differentiation.svg"><img class="mw-file-element" data-file-height="400" data-file-width="200" height="440" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/18/Stem_cell_division_and_differentiation.svg/220px-Stem_cell_division_and_differentiation.svg.png" width="220" /></a><figcaption>Stem
cell division and differentiation A: stem cell; B: progenitor cell;
C: differentiated cell; 1: symmetric stem cell division; 2: asymmetric
stem cell division; 3: progenitor division; 4: terminal differentiation</figcaption></figure>
<p>Adult stem cells, also called <a href="https://en.wikipedia.org/wiki/Somatic_(biology)" title="Somatic (biology)">somatic</a> (from Greek σωματικóς, "of the body") stem cells, are stem cells which maintain and repair the tissue in which they are found. They can be found in children, as well as adults.
</p><p>There are three known accessible sources of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autologous" title="Autologous">autologous</a> adult stem cells in humans:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">Bone marrow</a>, which requires extraction by <i>harvesting</i>, usually from pelvic bones via surgery.</li><li>Adipose tissue (fat cells), which requires extraction by liposuction.</li><li>Blood, which requires extraction through <a href="https://en.wikipedia.org/wiki/Apheresis" title="Apheresis">apheresis</a>,
wherein blood is drawn from the donor (similar to a blood donation),
and passed through a machine that extracts the stem cells and returns
other portions of the blood to the donor.</li></ol>
<p>Stem cells can also be taken from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Umbilical_cord_blood" title="Umbilical cord blood">umbilical cord blood</a>
just after birth. Of all stem cell types, autologous harvesting
involves the least risk. By definition, autologous cells are obtained
from one's own body, just as one may bank their own blood for elective
surgical procedures.
</p><p>Pluripotent adult stem cells are rare and generally small in
number, but they can be found in umbilical cord blood and other tissues. Bone marrow is a rich source of adult stem cells, which have been used in treating several conditions including liver cirrhosis, chronic limb ischemia and endstage heart failure. The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years. Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.
DNA damage accumulates with age in both stem cells and the cells that
comprise the stem cell environment. This accumulation is considered to
be responsible, at least in part, for increasing stem cell dysfunction
with aging (see <a href="https://en.wikipedia.org/wiki/DNA_damage_theory_of_aging" title="DNA damage theory of aging">DNA damage theory of aging</a>).
</p><p>Most adult stem cells are lineage-restricted (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multipotent" title="Multipotent">multipotent</a>) and are generally referred to by their tissue origin (<a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">mesenchymal stem cell</a>, adipose-derived stem cell, <a href="https://en.wikipedia.org/wiki/Endothelial_stem_cell" title="Endothelial stem cell">endothelial stem cell</a>, <a href="https://en.wikipedia.org/wiki/Dental_pulp_stem_cell" title="Dental pulp stem cell">dental pulp stem cell</a>, etc.). <a href="https://en.wikipedia.org/wiki/Muse_cell" title="Muse cell">Muse cells</a>
(multi-lineage differentiating stress enduring cells) are a recently
discovered pluripotent stem cell type found in multiple adult tissues,
including adipose, dermal fibroblasts, and bone marrow. While rare, muse
cells are identifiable by their expression of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SSEA-3" title="SSEA-3">SSEA-3</a>, a marker for undifferentiated stem cells, and general mesenchymal stem cells markers such as CD90, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/CD105" title="CD105">CD105</a>.
When subjected to single cell suspension culture, the cells will
generate clusters that are similar to embryoid bodies in morphology as
well as gene expression, including canonical pluripotency markers <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oct4" title="Oct4">Oct4</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sox2" title="Sox2">Sox2</a>, and <a href="https://en.wikipedia.org/wiki/Homeobox_protein_NANOG" title="Homeobox protein NANOG">Nanog</a>.
</p><p>Adult stem cell treatments have been successfully used for many
years to treat leukemia and related bone/blood cancers through bone
marrow transplants. Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.
</p><p>The use of adult stem cells in research and therapy is not as <a href="https://en.wikipedia.org/wiki/Stem_cell_controversy" title="Stem cell controversy">controversial</a> as the use of <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">embryonic stem cells</a>, because the production of adult stem cells does not require the destruction of an <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryo</a>. Additionally, in instances where adult stem cells are obtained from the intended recipient (an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autograft" title="Autograft">autograft</a>),
the risk of rejection is essentially non-existent. Consequently, more
US government funding is being provided for adult stem cell research.
</p><p>With the increasing demand of human adult stem cells for both
research and clinical purposes (typically 1–5 million cells per kg of
body weight are required per treatment) it becomes of utmost importance
to bridge the gap between the need to expand the cells in vitro and the
capability of harnessing the factors underlying replicative senescence.
Adult stem cells are known to have a limited lifespan in vitro and to
enter replicative senescence almost undetectably upon starting in vitro
culturing.
</p>
<h3><span class="mw-headline" id="Hematopoietic_stem_cells">Hematopoietic stem cells</span></h3><p><a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell" title="Hematopoietic stem cell">Hematopoietic stem cells</a> (HSCs) are vulnerable to <a href="https://en.wikipedia.org/wiki/DNA_damage_(naturally_occurring)" title="DNA damage (naturally occurring)">DNA damage</a> and <a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">mutations</a> that increase with age. This vulnerability may explain the increased risk of slow growing blood cancers (myeloid malignancies) in the elderly. Several factors appear to influence HSC aging including responses to the production of <a href="https://en.wikipedia.org/wiki/Reactive_oxygen_species" title="Reactive oxygen species">reactive oxygen species</a> that may cause DNA damage and genetic mutations as well as altered <a href="https://en.wikipedia.org/wiki/Epigenetics" title="Epigenetics">epigenetic</a> profiling.
</p>
<h2><span class="mw-headline" id="Amniotic">Amniotic</span></h2><p>Also called perinatal stem cells, these multipotent stem cells are found in <a href="https://en.wikipedia.org/wiki/Amniotic_fluid" title="Amniotic fluid">amniotic fluid</a> and umbilical cord blood. These stem cells are very active, expand extensively without feeders and are not tumorigenic. <a href="https://en.wikipedia.org/wiki/Amniotic_stem_cells" title="Amniotic stem cells">Amniotic stem cells</a>
are multipotent and can differentiate in cells of adipogenic,
osteogenic, myogenic, endothelial, hepatic and also neuronal lines.
Amniotic stem cells are a topic of active research.
</p><p>Use of stem cells from <a href="https://en.wikipedia.org/wiki/Amniotic_fluid" title="Amniotic fluid">amniotic fluid</a> overcomes the ethical objections to using human embryos as a source of cells. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Roman_Catholic" title="Roman Catholic">Roman Catholic</a> teaching forbids the use of embryonic stem cells in experimentation; accordingly, the <a href="https://en.wikipedia.org/wiki/Holy_See" title="Holy See">Vatican</a> newspaper "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Osservatore_Romano" title="Osservatore Romano">Osservatore Romano</a>" called amniotic stem cells "the future of medicine".
</p><p>It is possible to collect amniotic stem cells for donors or for autologous use: the first US amniotic stem cells bank was opened in 2009 in Medford, MA, by <a href="https://en.wikipedia.org/wiki/Biocell_Center" title="Biocell Center">Biocell Center</a> Corporation and collaborates with various hospitals and universities all over the world.
</p>
<h2><span class="mw-headline" id="Induced_pluripotent">Induced pluripotent</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell" title="Induced pluripotent stem cell">Induced pluripotent stem cell</a></div>
<p>Adult stem cells have limitations with their potency; unlike <a href="https://en.wikipedia.org/wiki/Embryonic_stem_cell" title="Embryonic stem cell">embryonic stem cells</a> (ESCs), they are not able to differentiate into cells from all three <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Germ_layers" title="Germ layers">germ layers</a>. As such, they are deemed <a href="https://en.wikipedia.org/wiki/Cell_potency" title="Cell potency">multipotent</a>.
</p><p>However, <a href="https://en.wikipedia.org/wiki/Reprogramming" title="Reprogramming">reprogramming</a> allows for the creation of pluripotent cells, <a href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell" title="Induced pluripotent stem cell">induced pluripotent stem cells</a>
(iPSCs), from adult cells. These are not adult stem cells, but somatic
cells (e.g. epithelial cells) reprogrammed to give rise to cells with
pluripotent capabilities. Using genetic reprogramming with protein <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transcription_factors" title="Transcription factors">transcription factors</a>, pluripotent stem cells with ESC-like capabilities have been derived.<sup> </sup>The first demonstration of induced pluripotent stem cells was conducted by <a href="https://en.wikipedia.org/wiki/Shinya_Yamanaka" title="Shinya Yamanaka">Shinya Yamanaka</a> and his colleagues at <a href="https://en.wikipedia.org/wiki/Kyoto_University" title="Kyoto University">Kyoto University</a>. They used the transcription factors <a href="https://en.wikipedia.org/wiki/Oct-4" title="Oct-4">Oct3/4</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sox2" title="Sox2">Sox2</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/C-Myc" title="C-Myc">c-Myc</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Klf4" title="Klf4">Klf4</a> to reprogram mouse fibroblast cells into pluripotent cells. Subsequent work used these factors to induce pluripotency in human fibroblast cells. <a href="https://en.wikipedia.org/wiki/Junying_Yu" title="Junying Yu">Junying Yu</a>, <a href="https://en.wikipedia.org/wiki/James_Thomson_(cell_biologist)" title="James Thomson (cell biologist)">James Thomson</a>, and their colleagues at the <a href="https://en.wikipedia.org/wiki/University_of_Wisconsin%E2%80%93Madison" title="University of Wisconsin–Madison">University of Wisconsin–Madison</a> used a different set of factors, Oct4, Sox2, Nanog and Lin28, and carried out their experiments using cells from human <a href="https://en.wikipedia.org/wiki/Foreskin" title="Foreskin">foreskin</a>. However, they were able to replicate <a href="https://en.wikipedia.org/wiki/Yamanaka" title="Yamanaka">Yamanaka</a>'s finding that inducing pluripotency in human cells was possible.
</p><p>Induced pluripotent stem cells differ from embryonic stem cells. They share many similar properties, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotency</a> and differentiation potential, the expression of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotency</a> genes, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epigenetic" title="Epigenetic">epigenetic</a> patterns, <a href="https://en.wikipedia.org/wiki/Embryoid_body" title="Embryoid body">embryoid body</a> and <a href="https://en.wikipedia.org/wiki/Teratoma" title="Teratoma">teratoma</a> formation, and viable <a href="https://en.wikipedia.org/wiki/Chimera_(genetics)" title="Chimera (genetics)">chimera</a> formation,
but there are many differences within these properties. The chromatin
of iPSCs appears to be more "closed" or methylated than that of ESCs. Similarly, the gene expression pattern between ESCs and iPSCs, or even iPSCs sourced from different origins. There are thus questions about the "completeness" of <a href="https://en.wikipedia.org/wiki/Reprogramming" title="Reprogramming">reprogramming</a>
and the somatic memory of induced pluripotent stem cells. Despite this,
inducing somatic cells to be pluripotent appears to be viable.
</p><p>As a result of the success of these experiments, <a href="https://en.wikipedia.org/wiki/Ian_Wilmut" title="Ian Wilmut">Ian Wilmut</a>, who helped create the first cloned animal <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dolly_the_Sheep" title="Dolly the Sheep">Dolly the Sheep</a>, has announced that he will abandon <a href="https://en.wikipedia.org/wiki/Somatic_cell_nuclear_transfer" title="Somatic cell nuclear transfer">somatic cell nuclear transfer</a> as an avenue of research.
</p><p>IPSCs has helped the field of medicine significantly by finding
numerous ways to cure diseases. Since human IPSCc has given the
advantage to make <i>in vitro</i> models to study toxins and pathogenesis.
</p><p>Furthermore, induced pluripotent stem cells provide several therapeutic advantages. Like ESCs, they are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotent" title="Pluripotent">pluripotent</a>. They thus have great differentiation potential; theoretically, they could produce any cell within the human body (if <a href="https://en.wikipedia.org/wiki/Reprogramming" title="Reprogramming">reprogramming</a> to pluripotency was "complete"). Moreover, unlike ESCs, they potentially could allow doctors to create a pluripotent stem cell line for each individual patient. Frozen blood samples can be used as a valuable source of induced pluripotent stem cells.
Patient specific stem cells allow for the screening for side effects
before drug treatment, as well as the reduced risk of transplantation
rejection. Despite their current limited use therapeutically, iPSCs hold great potential for future use in medical treatment and research.
</p>
<h3><span class="mw-headline" id="Cell_cycle_control_2">Cell cycle control</span></h3><p>The key factors controlling the cell cycle also regulate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pluripotency" title="Pluripotency">pluripotency</a>. Thus, manipulation of relevant genes can maintain pluripotency and reprogram somatic cells to an induced pluripotent state. However, reprogramming of somatic cells is often low in efficiency and considered <a href="https://en.wikipedia.org/wiki/Stochastic" title="Stochastic">stochastic</a>.
</p><p>With the idea that a more rapid cell cycle is a key component of
pluripotency, reprogramming efficiency can be improved. Methods for
improving pluripotency through manipulation of cell cycle regulators
include: overexpression of Cyclin D/Cdk4, phosphorylation of <a href="https://en.wikipedia.org/wiki/SOX2" title="SOX2">Sox2</a> at S39 and S253, overexpression of Cyclin A and Cyclin E, knockdown of Rb, and knockdown of members of the <a href="https://en.wikipedia.org/wiki/CIP/KIP" title="CIP/KIP">Cip/Kip</a> family or the Ink family.
Furthermore, reprogramming efficiency is correlated with the number of
cell divisions happened during the stochastic phase, which is suggested
by the growing inefficiency of reprogramming of older or slow diving
cells.
</p>
<h2><span class="mw-headline" id="Lineage">Lineage</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cell_line" title="Stem cell line">Stem cell line</a></div>
<p>Lineage is an important procedure to analyze developing embryos.
Since cell lineages shows the relationship between cells at each
division. This helps in analyzing stem cell lineages along the way which
helps recognize stem cell effectiveness, lifespan, and other factors.
With the technique of cell lineage mutant genes can be analyzed in stem
cell clones that can help in genetic pathways. These pathways can
regulate how the stem cell perform.
</p><p>To ensure self-renewal, stem cells undergo two types of cell division (see <i>Stem cell division and differentiation</i>
diagram). Symmetric division gives rise to two identical daughter cells
both endowed with stem cell properties. Asymmetric division, on the
other hand, produces only one stem cell and a <a href="https://en.wikipedia.org/wiki/Progenitor_cell" title="Progenitor cell">progenitor cell</a> with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cell_differentiation" title="Cell differentiation">differentiating</a>
into a mature cell. It is possible that the molecular distinction
between symmetric and asymmetric divisions lies in differential
segregation of cell membrane proteins (such as <a href="https://en.wikipedia.org/wiki/Receptor_(biochemistry)" title="Receptor (biochemistry)">receptors</a>) between the daughter cells.
</p><p>An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular <a href="https://en.wikipedia.org/wiki/Stem-cell_niche" title="Stem-cell niche">niche</a>. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in <i>Drosophila</i> germarium have identified the signals <a href="https://en.wikipedia.org/wiki/Decapentaplegic" title="Decapentaplegic">decapentaplegic</a> and adherens junctions that prevent germarium stem cells from differentiating.
</p><p>In the United States, Executive Order 13505 established that
federal money can be used for research in which approved human embryonic
stem-cell (hESC) lines are used, but it cannot be used to derive new
lines.
The National Institutes of Health (NIH) Guidelines on Human Stem Cell
Research, effective July 7, 2009, implemented the Executive Order 13505
by establishing criteria which hESC lines must meet to be approved for
funding.
The NIH Human Embryonic Stem Cell Registry can be accessed online and
has updated information on cell lines eligible for NIH funding. There are 486 approved lines as of January 2022.
</p>
<h2><span class="mw-headline" id="Therapies">Therapies</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cell_therapy" title="Stem cell therapy">Stem cell therapy</a></div>
<p>Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bone_marrow_transplant" title="Bone marrow transplant">Bone marrow transplant</a> is a form of stem cell therapy that has been used for many years because it has proven to be effective in clinical trials. Stem cell implantation may help in strengthening the left-ventricle of
the heart, as well as retaining the heart tissue to patients who have
suffered from heart attacks in the past.
</p><p>For over 90 years, <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplantation" title="Hematopoietic stem cell transplantation">hematopoietic stem cell transplantation</a> (HSCT) has been used to treat people with conditions such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Leukaemia" title="Leukaemia">leukaemia</a> and <a href="https://en.wikipedia.org/wiki/Lymphoma" title="Lymphoma">lymphoma</a>; this is the only widely practiced form of stem-cell therapy. As of 2016, the only established therapy using stem cells is <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplantation" title="Hematopoietic stem cell transplantation">hematopoietic stem cell transplantation</a>. This usually takes the form of a <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">bone-marrow</a> transplantation, but the cells can also be derived from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Umbilical_cord_blood" title="Umbilical cord blood">umbilical cord blood</a>. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegenerative_diseases" title="Neurodegenerative diseases">neurodegenerative diseases</a> and conditions such as <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_disease" title="Heart disease">heart disease</a>.
</p>
<h3><span class="mw-headline" id="Advantages">Advantages</span></h3><p>Stem
cell treatments may lower symptoms of the disease or condition that is
being treated. The lowering of symptoms may allow patients to reduce the
drug intake of the disease or condition. Stem cell treatment may also
provide knowledge for society to further stem cell understanding and
future treatments.
The physicians' creed would be to do no injury, and stem cells make
that simpler than ever before. Surgical processes by their character are
harmful. Tissue has to be dropped as a way to reach a successful
outcome. One may prevent the dangers of surgical interventions using
stem cells. Additionally, there's a possibility of disease, and whether
the procedure fails, further surgery may be required. Risks associated
with anesthesia can also be eliminated with stem cells.
On top of that, stem cells have been harvested from the patient's body
and redeployed in which they're wanted. Since they come from the
patient's own body, this is referred to as an autologous treatment.
Autologous remedies are thought to be the safest because there's likely
zero probability of donor substance rejection.
</p>
<h3><span class="mw-headline" id="Disadvantages">Disadvantages</span></h3><p>Stem cell treatments may require <a href="https://en.wikipedia.org/wiki/Immunosuppression" title="Immunosuppression">immunosuppression</a>
because of a requirement for radiation before the transplant to remove
the person's previous cells, or because the patient's immune system may
target the stem cells. One approach to avoid the second possibility is
to use stem cells from the same patient who is being treated.
</p><p>Pluripotency in certain stem cells could also make it difficult
to obtain a specific cell type. It is also difficult to obtain the exact
cell type needed, because not all cells in a population differentiate
uniformly. Undifferentiated cells can create tissues other than desired
types.
</p><p>Some stem cells form tumors after transplantation;
pluripotency is linked to tumor formation especially in embryonic stem
cells, fetal proper stem cells, induced pluripotent stem cells. Fetal
proper stem cells form tumors despite multipotency.
</p><p>Ethical concerns are also raised about the practice of using or
researching embryonic stem cells. Harvesting cells from the blastocyst
results in the death of the blastocyst. The concern is whether or not
the blastocyst should be considered as a human life. The debate on this issue is mainly a philosophical one, not a scientific one.
</p>
<h3><span class="mw-headline" id="Stem_cell_tourism">Stem cell tourism</span></h3><p>Stem cell tourism is the part of the <a href="https://en.wikipedia.org/wiki/Medical_tourism" title="Medical tourism">medical tourism</a> industry in which patients travel to obtain stem cell procedures.
</p><p>The United States has had an explosion of "stem cell clinics".
Stem cell procedures are highly profitable for clinics. The
advertising sounds authoritative but the efficacy and safety of the
procedures is unproven. Patients sometimes experience complications,
such as spinal tumors and death. The high expense can also lead to financial problems. According to researchers, there is a need to educate the public, patients, and doctors about this issue.
</p><p>According to the <a href="https://en.wikipedia.org/wiki/International_Society_for_Stem_Cell_Research" title="International Society for Stem Cell Research">International Society for Stem Cell Research</a>,
the largest academic organization that advocates for stem cell
research, stem cell therapies are under development and cannot yet be
said to be proven.
Doctors should inform patients that clinical trials continue to
investigate whether these therapies are safe and effective but that
unethical clinics present them as proven.
</p>
<h2><span class="mw-headline" id="Research">Research</span></h2><div class="hatnote navigation-not-searchable" role="note">Further information: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Consumer_Watchdog_vs._Wisconsin_Alumni_Research_Foundation" title="Consumer Watchdog vs. Wisconsin Alumni Research Foundation">Consumer Watchdog vs. Wisconsin Alumni Research Foundation</a></div>
<p>Some of the fundamental <a href="https://en.wikipedia.org/wiki/Patent" title="Patent">patents</a> covering human embryonic stem cells are owned by the <a href="https://en.wikipedia.org/wiki/Wisconsin_Alumni_Research_Foundation" title="Wisconsin Alumni Research Foundation">Wisconsin Alumni Research Foundation</a> (WARF) – they are patents 5,843,780, 6,200,806, and 7,029,913 invented by <a href="https://en.wikipedia.org/wiki/James_Thomson_(cell_biologist)" title="James Thomson (cell biologist)">James A. Thomson</a>. WARF does not enforce these patents against academic scientists, but does enforce them against companies.
</p><p>In 2006, a request for the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/US_Patent_and_Trademark_Office" title="US Patent and Trademark Office">US Patent and Trademark Office</a> (USPTO) to re-examine the three patents was filed by the <a class="external text" href="https://www.guidestar.org/profile/20-0236613" rel="nofollow">Public Patent Foundation</a> on behalf of its client, the non-profit patent-watchdog group <a href="https://en.wikipedia.org/wiki/Consumer_Watchdog" title="Consumer Watchdog">Consumer Watchdog</a> (formerly the Foundation for Taxpayer and Consumer Rights).
In the re-examination process, which involves several rounds of
discussion between the USPTO and the parties, the USPTO initially agreed
with Consumer Watchdog and rejected all the claims in all three
patents,
however in response, WARF amended the claims of all three patents to
make them more narrow, and in 2008 the USPTO found the amended claims in
all three patents to be patentable. The decision on one of the patents
(7,029,913) was appealable, while the decisions on the other two were
not.
Consumer Watchdog appealed the granting of the '913 patent to the
USPTO's Board of Patent Appeals and Interferences (BPAI) which granted
the appeal, and in 2010 the BPAI decided that the amended claims of the
'913 patent were not patentable.
However, WARF was able to re-open prosecution of the case and did so,
amending the claims of the '913 patent again to make them more narrow,
and in January 2013 the amended claims were allowed.
</p><p>In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Court_of_Appeals_for_the_Federal_Circuit" title="Court of Appeals for the Federal Circuit">Court of Appeals for the Federal Circuit</a> (CAFC), the federal appeals court that hears patent cases. At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Legal_standing" title="Legal standing">legal standing</a> to appeal; the case could not proceed until that issue was resolved.
</p>
<h3><span class="mw-headline" id="Investigations">Investigations</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Stem_cell_treatments.svg"><img class="mw-file-element" data-file-height="1190" data-file-width="1450" height="328" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/bd/Stem_cell_treatments.svg/330px-Stem_cell_treatments.svg.png" width="400" /></a><figcaption>Diseases and conditions where stem cell treatment is being investigated</figcaption></figure>
<p>Diseases and conditions where stem cell treatment is being investigated include:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">Diabetes</a></li><li><a href="https://en.wikipedia.org/wiki/Pattern_hair_loss" title="Pattern hair loss">Androgenic Alopecia and hair loss</a></li><li><a href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis">Rheumatoid arthritis</a></li><li><a href="https://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease">Parkinson's disease</a></li><li><a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a></li><li><a href="https://en.wikipedia.org/wiki/Respiratory_disease" title="Respiratory disease">Respiratory disease</a></li><li><a href="https://en.wikipedia.org/wiki/Osteoarthritis" title="Osteoarthritis">Osteoarthritis</a></li><li><a href="https://en.wikipedia.org/wiki/Stroke" title="Stroke">Stroke</a> and <a href="https://en.wikipedia.org/wiki/Traumatic_brain_injury" title="Traumatic brain injury">traumatic brain injury</a> repair</li><li><a href="https://en.wikipedia.org/wiki/Learning_disability" title="Learning disability">Learning disability</a> due to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Congenital_disorder" title="Congenital disorder">congenital disorder</a></li><li><a href="https://en.wikipedia.org/wiki/Spinal_cord_injury" title="Spinal cord injury">Spinal cord injury</a> repair</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_infarction" title="Heart infarction">Heart infarction</a></li><li>Anti-<a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a> treatments</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Baldness" title="Baldness">Baldness</a> reversal</li><li>Replace missing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Teeth" title="Teeth">teeth</a></li><li>Repair <a href="https://en.wikipedia.org/wiki/Hearing" title="Hearing">hearing</a></li><li>Restore <a href="https://en.wikipedia.org/wiki/Visual_system" title="Visual system">vision</a> and repair damage to the <a href="https://en.wikipedia.org/wiki/Cornea" title="Cornea">cornea</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis" title="Amyotrophic lateral sclerosis">Amyotrophic lateral sclerosis</a></li><li><a href="https://en.wikipedia.org/wiki/Crohn%27s_disease" title="Crohn's disease">Crohn's disease</a></li><li><a href="https://en.wikipedia.org/wiki/Wound_healing" title="Wound healing">Wound healing</a></li><li><a href="https://en.wikipedia.org/wiki/Male_infertility" title="Male infertility">Male infertility</a> due to absence of spermatogonial stem cells.
In recent studies, scientists have found a way to solve this problem by
reprogramming a cell and turning it into a spermatozoon. Other studies
have proven the restoration of spermatogenesis by introducing human iPSC
cells in mice testicles. This could mean the end of <a href="https://en.wikipedia.org/wiki/Azoospermia" title="Azoospermia">azoospermia</a>.</li><li><a href="https://en.wikipedia.org/wiki/Female_infertility" title="Female infertility">Female infertility</a>:
oocytes made from embryonic stem cells. Scientists have found the
ovarian stem cells, a rare type of cells (0.014%) found in the ovary.
They could be used as a treatment not only for infertility, but also for
premature ovarian insufficiency.</li><li>Critical Limb Ischemia</li></ul>
<p>Research is underway to develop various sources for stem cells, and to apply stem cell treatments for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegenerative_diseases" title="Neurodegenerative diseases">neurodegenerative diseases</a> and conditions, <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_disease" title="Heart disease">heart disease</a>, and other conditions. Research is also underway in generating <a href="https://en.wikipedia.org/wiki/Organoid" title="Organoid">organoids</a> using stem cells, which would allow for further understanding of human development, <a href="https://en.wikipedia.org/wiki/Organogenesis" title="Organogenesis">organogenesis</a>, and modeling of human diseases.
</p><p>In more recent years, with the ability of scientists to isolate and culture <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryonic_stem_cells" title="Embryonic stem cells">embryonic stem cells</a>, and with scientists' growing ability to create stem cells using <a href="https://en.wikipedia.org/wiki/Somatic_cell_nuclear_transfer" title="Somatic cell nuclear transfer">somatic cell nuclear transfer</a> and techniques to create <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells" title="Induced pluripotent stem cells">induced pluripotent stem cells</a>, <a href="https://en.wikipedia.org/wiki/Stem_cell_controversy" title="Stem cell controversy">controversy</a> has crept in, both related to <a href="https://en.wikipedia.org/wiki/Abortion_debate" title="Abortion debate">abortion politics</a> and to <a href="https://en.wikipedia.org/wiki/Human_cloning" title="Human cloning">human cloning</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Hepatotoxicity" title="Hepatotoxicity">Hepatotoxicity</a>
and drug-induced liver injury account for a substantial number of
failures of new drugs in development and market withdrawal, highlighting
the need for screening assays such as stem cell-derived hepatocyte-like
cells, that are capable of detecting toxicity early in the <a href="https://en.wikipedia.org/wiki/Drug_development" title="Drug development">drug development</a> process.
</p>
<h2><span class="mw-headline" id="Notable_studies">Notable studies</span></h2>In August 2021, researchers in the <a href="https://en.wikipedia.org/wiki/Princess_Margaret_Cancer_Centre" title="Princess Margaret Cancer Centre">Princess Margaret Cancer Centre</a> at the <a href="https://en.wikipedia.org/wiki/University_Health_Network" title="University Health Network">University Health Network</a> published their discovery of a dormancy mechanism in key stem cells which could help develop cancer treatments in the future.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-89220046069687656082024-03-28T09:57:00.000-04:002024-03-28T09:57:21.346-04:00Rejuvenation<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Rejuvenation">https://en.wikipedia.org/wiki/Rejuvenation</a><br /><p><b>Rejuvenation</b> is a medical discipline focused on the practical reversal of the <a href="https://en.wikipedia.org/wiki/Senescence" title="Senescence">aging process</a>.
</p><p>Rejuvenation is distinct from <a href="https://en.wikipedia.org/wiki/Life_extension" title="Life extension">life extension</a>. Life extension strategies often study the causes of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aging" title="Aging">aging</a> and try to oppose those causes in order to slow aging. Rejuvenation is the <i>reversal</i> of aging and thus requires a different strategy, namely repair of the <a href="https://en.wikipedia.org/wiki/Damage" title="Damage">damage</a>
that is associated with aging or replacement of damaged tissue with new
tissue. Rejuvenation can be a means of life extension, but most life
extension strategies do not involve rejuvenation.
</p>
<h2><span class="mw-headline" id="Historical_and_cultural_background">Historical and cultural background</span></h2></div></div></div><p>Various myths tell the stories about the quest for rejuvenation. It was believed that <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Magic_(paranormal)" title="Magic (paranormal)">magic</a> or intervention of a <a href="https://en.wikipedia.org/wiki/Supernatural" title="Supernatural">supernatural</a>
power can bring back youth and many mythical adventurers set out on a
journey to do that, for themselves, their relatives or some authority
that sent them anonymously.
</p><p>An ancient Chinese emperor actually sent out ships of young men
and women to find a pearl that would rejuvenate him. This led to a myth
among modern Chinese that Japan was founded by these people.
</p><p>In some religions, people were to be rejuvenated after death prior to placing them in <a href="https://en.wikipedia.org/wiki/Heaven" title="Heaven">heaven</a>.
</p><p>The stories continued well into the 16th century. The Spanish explorer <a href="https://en.wikipedia.org/wiki/Juan_Ponce_de_Le%C3%B3n" title="Juan Ponce de León">Juan Ponce de León</a> led an expedition around the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Caribbean_islands" title="Caribbean islands">Caribbean islands</a> and into <a href="https://en.wikipedia.org/wiki/Florida" title="Florida">Florida</a> to find the <a href="https://en.wikipedia.org/wiki/Fountain_of_Youth" title="Fountain of Youth">Fountain of Youth</a>.
Led by the rumors, the expedition continued the search and many
perished. The Fountain was nowhere to be found as locals were unaware of
its exact location.
</p><p>Since the emergence of <a href="https://en.wikipedia.org/wiki/Philosophy" title="Philosophy">philosophy</a>, <a href="https://en.wikipedia.org/wiki/Wise_old_man" title="Wise old man">sages</a> and self-proclaimed <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Wizard_(fantasy)" title="Wizard (fantasy)">wizards</a> always made enormous efforts to find the secret of youth, both for themselves and for their noble <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Patron" title="Patron">patrons</a> and <a href="https://en.wikipedia.org/wiki/Sponsor_(commercial)" title="Sponsor (commercial)">sponsors</a>. It was widely believed that some <a href="https://en.wikipedia.org/wiki/Potion" title="Potion">potions</a> may restore the youth.
</p><p>Another commonly cited approach was attempting to transfer the <a href="https://en.wikipedia.org/wiki/Essence" title="Essence">essence</a> of youth from young people to old. Some examples of this approach were sleeping with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Virgin" title="Virgin">virgins</a> or <a href="https://en.wikipedia.org/wiki/Child" title="Child">children</a> (sometimes literally sleeping, not necessarily having sex), bathing in or drinking their blood.
</p><p>The quest for rejuvenation reached its height with <a href="https://en.wikipedia.org/wiki/Alchemy" title="Alchemy">alchemy</a>. All around Europe, and also beyond, alchemists were looking for the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Philosopher%27s_Stone" title="Philosopher's Stone">Philosopher's Stone</a>,
the mythical substance that, as it was believed, could not only turn
lead into gold, but also prolong life and restore youth. Although the
set goal was not achieved, alchemy paved the way to the <a href="https://en.wikipedia.org/wiki/Scientific_method" title="Scientific method">scientific method</a> and so to the medical advances of today.
</p><p><a href="https://en.wikipedia.org/wiki/Serge_Voronoff" title="Serge Voronoff">Serge Abrahamovitch Voronoff</a>
was a French surgeon born in Russia who gained fame for his technique
of grafting monkey testicle tissue on to the testicles of men while
working in France in the 1920s and 1930s. This was one of the first
medically accepted rejuvenation therapies (before he was proved to be
wrong around 1930–1940). The technique brought him a great deal of
money, although he was already independently wealthy. As his work fell
out of favor, he went from being a highly respected surgeon to a subject
of ridicule. By the early 1930s, over 500 men had been treated in
France by his rejuvenation technique, and thousands more around the
world, such as in a special clinic set up in <a href="https://en.wikipedia.org/wiki/Algiers" title="Algiers">Algiers</a>. Noteworthy people who had the surgery included <a href="https://en.wikipedia.org/wiki/Harold_Fowler_McCormick" title="Harold Fowler McCormick">Harold McCormick</a>, chairman of the board of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/International_Harvester_Company" title="International Harvester Company">International Harvester Company</a>, and the aging premier of <a href="https://en.wikipedia.org/wiki/Turkey" title="Turkey">Turkey</a>.
</p><p>Swiss doctor <a href="https://en.wikipedia.org/wiki/Paul_Niehans" title="Paul Niehans">Paul Niehans</a>,
who was one of the fathers of cellular therapy, developed in 1931–1949
years the so-called Fresh cell therapy. Fresh cell therapy is mainly the
use of live animal embryo organs cells which are injected into the
patient with the purpose of achieving a revitalizing effect. These cells
are generally extracted from <a href="https://en.wikipedia.org/wiki/Sheep" title="Sheep">sheep</a>’s <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fetus_(biology)" title="Fetus (biology)">fetuses</a>
because in comparison to other animals, like pigs, rabbits and cows,
sheep are clean animals and rarely contract diseases. Of course animal
cells are not able to be included in human tissue, but they can secrete
factors for rejuvenating. That's why this rejuvenation technology,
despite the harsh criticism is practiced to this day.
</p><p>Rejuvenation technology and its effects on individuals and society have long been a subject of science fiction. The <a href="https://en.wikipedia.org/wiki/Misspent_Youth" title="Misspent Youth">Misspent Youth</a> and <a href="https://en.wikipedia.org/wiki/Commonwealth_Saga" title="Commonwealth Saga">Commonwealth Saga</a> by <a href="https://en.wikipedia.org/wiki/Peter_F._Hamilton" title="Peter F. Hamilton">Peter F. Hamilton</a>
are among the most well known examples of this, dealing with the short-
and long-term effects of a near perfect 80-year-old to 20-year-old body
change with mind intact. The less perfect rejuvenation featured in the <a href="https://en.wikipedia.org/wiki/Mars_trilogy" title="Mars trilogy">Mars trilogy</a> by <a href="https://en.wikipedia.org/wiki/Kim_Stanley_Robinson" title="Kim Stanley Robinson">Kim Stanley Robinson</a> results in long-term memory loss and sheer boredom that comes with extreme age. The post-mortal characters in the <a href="https://en.wikipedia.org/wiki/Revelation_Space" title="Revelation Space">Revelation Space</a>
series have long-term or essentially infinite lifespans, and sheer
boredom induces them to undertake activities of extreme risk.
</p>
<h2><span class="mw-headline" id="Modern_developments">Modern developments</span></h2><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aging" title="Aging">Aging</a> is the accumulation of <a href="https://en.wikipedia.org/wiki/Damage" title="Damage">damage</a> to <a href="https://en.wikipedia.org/wiki/Macromolecule" title="Macromolecule">macromolecules</a>, <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological_tissue" title="Biological tissue">tissues</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Organ_(anatomy)" title="Organ (anatomy)">organs</a> in and on the body which, when it can no longer be tolerated by an <a href="https://en.wikipedia.org/wiki/Organism" title="Organism">organism</a>, ultimately leads to its <a href="https://en.wikipedia.org/wiki/Death" title="Death">death</a>. If any of that damage can be repaired, the result is rejuvenation.
</p><p>There have been many experiments which have been shown to increase the <a href="https://en.wikipedia.org/wiki/Maximum_life_span" title="Maximum life span">maximum life span</a> of <a href="https://en.wikipedia.org/wiki/Laboratory" title="Laboratory">laboratory</a> animals, thereby achieving <a href="https://en.wikipedia.org/wiki/Life_extension" title="Life extension">life extension</a>. A few experimental methods such as replacing <a href="https://en.wikipedia.org/wiki/Hormone" title="Hormone">hormones</a> to youthful levels have had considerable success in partially rejuvenating <a href="https://en.wikipedia.org/wiki/Laboratory" title="Laboratory">laboratory</a>
animals and humans. A 2011 experiment involved breeding genetically
manipulated mice that lacked an enzyme called telomerase, causing the
mice to age prematurely and suffer ailments. When the mice were given
injections to reactivate the enzyme, it repaired the damaged tissues and
reversed the signs of aging. There are at least eight important hormones that decline with age: 1. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_growth_hormone" title="Human growth hormone">human growth hormone</a> (HGH); 2. the sexual hormones: testosterone or oestrogen/progesterone; 3. <a href="https://en.wikipedia.org/wiki/Erythropoietin" title="Erythropoietin">erythropoietin</a> (EPO); 4. insulin; 5. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/DHEA" title="DHEA">DHEA</a>;
6. melatonin; 7. thyroid; 8. pregnenolone. In theory, if all or some of
these hormones are replaced, the body will respond to them as it did
when it was younger, thus repairing and restoring many body functions.
In line with this, recent experiments show that heterochronic <a href="https://en.wikipedia.org/wiki/Parabiosis" title="Parabiosis">parabiosis</a>,
i.e. connecting the circulatory systems of young and old animal, leads
to the rejuvenation of the old animal, including restoration of proper
stem cell function. Similar experiments show that grafting old muscles
into young hosts leads to their complete restoration, whereas grafting
young muscles into old hosts does not. These experiments show that aging
is mediated by systemic environment, rather than being an intrinsic
cell property. Clinical trials based on transfusion of young blood were scheduled to begin in 2014. Another intervention that is gaining popularity is epigenetic reprogramming. Through the use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Yamanaka_factors" title="Yamanaka factors">Yamanaka factors</a>, aged cells can revert to a younger state.
</p><p>Most attempts at <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetic</a> repair have traditionally involved the use of a <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retrovirus</a> to insert a new <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">gene</a> into a random position on a <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosome</a>. But by attaching <a href="https://en.wikipedia.org/wiki/Zinc_finger" title="Zinc finger">zinc fingers</a> (which determine where <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factors</a> bind) to <a href="https://en.wikipedia.org/wiki/Endonuclease" title="Endonuclease">endonucleases</a> (which break <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> strands), <a href="https://en.wikipedia.org/wiki/Homologous_recombination" title="Homologous recombination">homologous recombination</a>
can be induced to correct and replace defective (or undesired) DNA
sequences. The first applications of this technology are to isolate <a href="https://en.wikipedia.org/wiki/Stem_cell" title="Stem cell">stem cells</a> from the <a href="https://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow">bone marrow</a> of patients having <a href="https://en.wikipedia.org/wiki/Blood" title="Blood">blood</a> disease <a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">mutations</a>, to correct those mutations in <a href="https://en.wikipedia.org/wiki/Petri_dish" title="Petri dish">laboratory dishes</a> using zinc finger endonucleases and to transplant the stem cells back into the patients. More recent efforts leverage CRISPR-Cas systems or adeno-associated viruses (AAVs).
</p><p>Enhanced <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA repair</a> has been proposed as a potential rejuvenation strategy.
</p><p>Stem cell <a href="https://en.wikipedia.org/wiki/Regenerative_medicine" title="Regenerative medicine">regenerative medicine</a> uses three different strategies:
</p>
<ol><li>Implantation of <a href="https://en.wikipedia.org/wiki/Stem_cell" title="Stem cell">stem cells</a> from <a href="https://en.wikipedia.org/wiki/Cell_culture" title="Cell culture">culture</a> into an existing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological_tissue" title="Biological tissue">tissue</a> structure</li><li>Implantation of stem cells into a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tissue_scaffold" title="Tissue scaffold">tissue scaffold</a> that guides restoration</li><li>Induction of residual <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a> of a tissue structure to regenerate the necessary body part</li></ol>
<p>A <a href="https://en.wikipedia.org/wiki/Salamander" title="Salamander">salamander</a> can not only regenerate a <a href="https://en.wikipedia.org/wiki/Limb_(anatomy)" title="Limb (anatomy)">limb</a>, but can regenerate the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lens_(anatomy)" title="Lens (anatomy)">lens</a> or <a href="https://en.wikipedia.org/wiki/Retina" title="Retina">retina</a> of an <a href="https://en.wikipedia.org/wiki/Eye" title="Eye">eye</a> and can regenerate an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intestine" title="Intestine">intestine</a>. For regeneration the salamander tissues form a <a href="https://en.wikipedia.org/wiki/Blastema" title="Blastema">blastema</a> by <a href="https://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation">de-differentiation</a> of <a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">mesenchymal cells</a>, and the <a href="https://en.wikipedia.org/wiki/Blastema" title="Blastema">blastema</a> functions as a self-organizing system to regenerate the limb.
</p><p>Yet another option involves cosmetic changes to the individual to
create the appearance of youth. These are generally superficial and do
little to make the person healthier or live longer, but the real
improvement in a person's appearance may elevate their mood and have
positive side effects normally correlated with <a href="https://en.wikipedia.org/wiki/Happiness" title="Happiness">happiness</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cosmetic_surgery" title="Cosmetic surgery">Cosmetic surgery</a>
is a large industry offering treatments such as removal of wrinkles
("face lift"), removal of extra fat (liposuction) and reshaping or
augmentation of various body parts (<a href="https://en.wikipedia.org/wiki/Abdomen" title="Abdomen">abdomen</a>, <a href="https://en.wikipedia.org/wiki/Breast" title="Breast">breasts</a>, <a href="https://en.wikipedia.org/wiki/Face" title="Face">face</a>).
</p><p>There are also, as commonly found throughout history, many fake
rejuvenation products that have been shown to be ineffective. Chief
among these are powders, sprays, gels, and <a href="https://en.wikipedia.org/wiki/Homeopathy" title="Homeopathy">homeopathic</a>
substances that claim to contain growth hormones. Authentic growth
hormones are only effective when injected, mainly due to the fact that
the <a href="https://en.wikipedia.org/wiki/Growth_hormone" title="Growth hormone">191-amino acid protein</a> is too large to be absorbed through the <a href="https://en.wikipedia.org/wiki/Mucous_membrane" title="Mucous membrane">mucous membranes</a>, and would be broken up in the stomach if swallowed.
</p><p>The <a href="https://en.wikipedia.org/wiki/Methuselah_Foundation" title="Methuselah Foundation">Mprize</a>
scientific competition is under way to deliver on the mission of
extending healthy human life. It directly accelerates the development of
revolutionary new life extension therapies by awarding two cash prizes:
one to the research team that breaks the world record for the
oldest-ever mouse; and one to the team that develops the most successful
late-onset rejuvenation. Current Mprize winner for rejuvenation is
Steven Spindler. Caloric restriction (CR), the consumption of fewer
calories while avoiding malnutrition, was applied as a robust method of
decelerating aging and the development of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Age-related_diseases" title="Age-related diseases">age-related diseases</a>.
</p>
<h2><span class="mw-headline" id="Strategies_for_engineered_negligible_senescence">Strategies for engineered negligible senescence</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Strategies_for_engineered_negligible_senescence" title="Strategies for engineered negligible senescence">Strategies for engineered negligible senescence</a></div>
<p>The biomedical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gerontologist" title="Gerontologist">gerontologist</a> <a href="https://en.wikipedia.org/wiki/Aubrey_de_Grey" title="Aubrey de Grey">Aubrey de Grey</a>
has initiated a project, strategies for engineered negligible
senescence (SENS), to study how to reverse the damage caused by aging.
He has proposed seven strategies for what he calls the seven deadly sins
of aging:
</p>
<ol><li>Cell loss can be repaired (reversed) just by suitable <a href="https://en.wikipedia.org/wiki/Exercise" title="Exercise">exercise</a> in the case of <a href="https://en.wikipedia.org/wiki/Muscle" title="Muscle">muscle</a>. For other tissues it needs various <a href="https://en.wikipedia.org/wiki/Growth_factor" title="Growth factor">growth factors</a> to stimulate <a href="https://en.wikipedia.org/wiki/Cell_division" title="Cell division">cell division</a>, or in some cases it needs <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cells" title="Stem cells">stem cells</a>.</li><li>Senescent <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a> can be removed by activating the <a href="https://en.wikipedia.org/wiki/Immune_system" title="Immune system">immune system</a> against them. Or they can be destroyed by <a href="https://en.wikipedia.org/wiki/Gene_therapy" title="Gene therapy">gene therapy</a> to introduce "suicide <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">genes</a>" that only kill senescent cells.</li><li><a href="https://en.wikipedia.org/wiki/Protein" title="Protein">Protein</a> <a href="https://en.wikipedia.org/wiki/Cross-link" title="Cross-link">cross-linking</a> can largely be reversed by <a href="https://en.wikipedia.org/wiki/Medication" title="Medication">drugs</a> that break the links. But to break some of the cross-links we may need to develop enzymatic methods.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Extracellular" title="Extracellular">Extracellular</a> garbage (like <a href="https://en.wikipedia.org/wiki/Amyloid" title="Amyloid">amyloid</a>) can be eliminated by <a href="https://en.wikipedia.org/wiki/Vaccination" title="Vaccination">vaccination</a> that gets <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Immune" title="Immune">immune</a> cells to "eat" the garbage.</li><li>For intracellular junk we need to introduce new <a href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzymes</a>, possibly enzymes from soil <a href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a>, that can degrade the junk (<a href="https://en.wikipedia.org/wiki/Lipofuscin" title="Lipofuscin">lipofuscin</a>) that our own natural enzymes cannot degrade.</li><li>For <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondrial" title="Mitochondrial">mitochondrial</a>
mutations the plan is not to repair them but to prevent harm from the
mutations by putting suitably modified copies of the mitochondrial genes
into the <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">cell nucleus</a> by gene therapy. The <a href="https://en.wikipedia.org/wiki/Mitochondrial_DNA" title="Mitochondrial DNA">mitochondrial DNA</a> experiences a high degree of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mutagenic" title="Mutagenic">mutagenic</a> damage because most <a href="https://en.wikipedia.org/wiki/Radical_(chemistry)" title="Radical (chemistry)">free radicals</a> are generated in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria">mitochondria</a>. A copy of the mitochondrial DNA located in the <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">nucleus</a> will be better protected from free radicals, and there will be better <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA repair</a> when damage occurs. All mitochondrial <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">proteins</a> would then be imported into the mitochondria.</li><li>For <a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a> (the most lethal consequence of mutations) the strategy is to use <a href="https://en.wikipedia.org/wiki/Gene_therapy" title="Gene therapy">gene therapy</a> to delete the <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">genes</a> for <a href="https://en.wikipedia.org/wiki/Telomerase" title="Telomerase">telomerase</a>
and to eliminate telomerase-independent mechanisms of turning normal
cells into "immortal" cancer cells. To compensate for the loss of
telomerase in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cells" title="Stem cells">stem cells</a> we would introduce new stem cells every decade or so.</li></ol>
<p>In 2009, Aubrey de Grey co-founded the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SENS_Foundation" title="SENS Foundation">SENS Foundation</a> to expedite progress in the above-listed areas.
</p>
<h2><span class="mw-headline" id="Scientific_journal">Scientific journal</span></h2><ul><li><i><a href="https://en.wikipedia.org/wiki/Rejuvenation_Research" title="Rejuvenation Research">Rejuvenation Research</a></i> Editor: <a href="https://en.wikipedia.org/wiki/Aubrey_de_Grey" title="Aubrey de Grey">Aubrey de Grey</a>. Publisher: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mary_Ann_Liebert,_Inc." title="Mary Ann Liebert, Inc.">Mary Ann Liebert, Inc.</a> ISSN 1549-1684 – Published Bimonthly.</li></ul>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-86938228147813856822024-03-28T09:47:00.005-04:002024-03-28T09:47:37.679-04:00American Philosophical Society<div aria-labelledby="firstHeading" class="vector-body ve-init-mw-desktopArticleTarget-targetContainer" data-mw-ve-target-container="" id="bodyContent"><div class="vector-body-before-content"><div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div>
<div id="contentSub"><div id="mw-content-subtitle"></div></div>
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<div class="hatnote navigation-not-searchable" role="note"><a href="https://en.wikipedia.org/wiki/American_Philosophical_Society">https://en.wikipedia.org/wiki/American_Philosophical_Society</a><br /></div>
<p>The <b>American Philosophical Society</b> (<b>APS</b>) is an American scholarly organization and <a href="https://en.wikipedia.org/wiki/Learned_society" title="Learned society">learned society</a> founded in 1743 in <a href="https://en.wikipedia.org/wiki/Philadelphia" title="Philadelphia">Philadelphia</a> that promotes knowledge in the <a href="https://en.wikipedia.org/wiki/Humanities" title="Humanities">humanities</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Natural_sciences" title="Natural sciences">natural sciences</a> through research, professional meetings, publications, library resources, and community outreach. It was founded by <a href="https://en.wikipedia.org/wiki/Benjamin_Franklin" title="Benjamin Franklin">Benjamin Franklin</a> and is considered the first learned society in the United States.
</p><p><a href="https://en.wikipedia.org/wiki/Philosophical_Hall" title="Philosophical Hall">Philosophical Hall</a>, the society's headquarters and a museum, is located just east of <a href="https://en.wikipedia.org/wiki/Independence_Hall" title="Independence Hall">Independence Hall</a> in <a href="https://en.wikipedia.org/wiki/Independence_National_Historical_Park" title="Independence National Historical Park">Independence National Historical Park</a>. In 1965, in recognition of the building's history, it was designated a <a href="https://en.wikipedia.org/wiki/National_Historic_Landmark" title="National Historic Landmark">National Historic Landmark</a>.
</p><p>The society has about 1,000 elected members. As of April 2020,
5,710 members had been inducted since its creation. Through research
grants, published journals, the American Philosophical Society Museum,
an extensive library, and regular meetings, the society supports a
variety of disciplines in the humanities and the sciences.
</p>
<h2><span class="mw-headline" id="History">History</span></h2></div></div></div><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Feke_-_Benjamin_Franklin.png"><img class="mw-file-element" data-file-height="952" data-file-width="750" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/ad/Feke_-_Benjamin_Franklin.png/220px-Feke_-_Benjamin_Franklin.png" width="315" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Benjamin_Franklin" title="Benjamin Franklin">Benjamin Franklin</a> in 1746</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:American_Philosophical_Society_-_Library_Hall_(53590617275).jpg"><img class="mw-file-element" data-file-height="3544" data-file-width="4725" height="300" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c8/American_Philosophical_Society_-_Library_Hall_%2853590617275%29.jpg/220px-American_Philosophical_Society_-_Library_Hall_%2853590617275%29.jpg" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Library_Company_of_Philadelphia" title="Library Company of Philadelphia">Library Hall</a> in 2024</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:American_Philosophical_Society_Thomas_Jefferson_Garden.jpg"><img class="mw-file-element" data-file-height="3024" data-file-width="4032" height="300" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/56/American_Philosophical_Society_Thomas_Jefferson_Garden.jpg/220px-American_Philosophical_Society_Thomas_Jefferson_Garden.jpg" width="400" /></a><figcaption>Thomas Jefferson Garden adjacent to Library Hall</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Franklin_Hall_meeting_preparation.jpg"><img class="mw-file-element" data-file-height="2448" data-file-width="3264" height="300" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/26/Franklin_Hall_meeting_preparation.jpg/220px-Franklin_Hall_meeting_preparation.jpg" width="400" /></a><figcaption>Franklin Hall at the American Philosophical Hall, named for <a href="https://en.wikipedia.org/wiki/Benjamin_Franklin" title="Benjamin Franklin">Benjamin Franklin</a>, the organization's founder</figcaption></figure>
<p>The American Philosophical Society was founded as the <b>Philosophical Society</b> in 1743 by <a href="https://en.wikipedia.org/wiki/Benjamin_Franklin" title="Benjamin Franklin">Benjamin Franklin</a>, <a href="https://en.wikipedia.org/wiki/James_Alexander_(lawyer)" title="James Alexander (lawyer)">James Alexander</a>, <a href="https://en.wikipedia.org/wiki/Francis_Hopkinson" title="Francis Hopkinson">Francis Hopkinson</a>, <a href="https://en.wikipedia.org/wiki/John_Bartram" title="John Bartram">John Bartram</a>, <a href="https://en.wikipedia.org/wiki/Philip_Syng" title="Philip Syng">Philip Syng Jr.</a>, and others as an offshoot of an earlier club, the <a href="https://en.wikipedia.org/wiki/Junto_(club)" title="Junto (club)">Junto</a>.
</p><p>Early members included: <a href="https://en.wikipedia.org/wiki/Benjamin_Franklin" title="Benjamin Franklin">Benjamin Franklin</a>, <a href="https://en.wikipedia.org/wiki/John_Dickinson" title="John Dickinson">John Dickinson</a>, <a href="https://en.wikipedia.org/wiki/George_Washington" title="George Washington">George Washington</a>, <a href="https://en.wikipedia.org/wiki/John_Adams" title="John Adams">John Adams</a>, <a href="https://en.wikipedia.org/wiki/Thomas_Jefferson" title="Thomas Jefferson">Thomas Jefferson</a>, <a href="https://en.wikipedia.org/wiki/Alexander_Hamilton" title="Alexander Hamilton">Alexander Hamilton</a>, <a href="https://en.wikipedia.org/wiki/James_McHenry" title="James McHenry">James McHenry</a>, <a href="https://en.wikipedia.org/wiki/Thomas_Paine" title="Thomas Paine">Thomas Paine</a>, <a href="https://en.wikipedia.org/wiki/David_Rittenhouse" title="David Rittenhouse">David Rittenhouse</a>, <a href="https://en.wikipedia.org/wiki/Peter_Stephen_Du_Ponceau" title="Peter Stephen Du Ponceau">Peter Stephen Du Ponceau</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nicholas_Biddle_(banker)" title="Nicholas Biddle (banker)">Nicholas Biddle</a>, <a href="https://en.wikipedia.org/wiki/Owen_Biddle_Sr." title="Owen Biddle Sr.">Owen Biddle</a>, <a href="https://en.wikipedia.org/wiki/Benjamin_Rush" title="Benjamin Rush">Benjamin Rush</a>, <a href="https://en.wikipedia.org/wiki/James_Madison" title="James Madison">James Madison</a>, <a href="https://en.wikipedia.org/wiki/Michael_Hillegas" title="Michael Hillegas">Michael Hillegas</a>, <a href="https://en.wikipedia.org/wiki/John_Marshall" title="John Marshall">John Marshall</a>, <a href="https://en.wikipedia.org/wiki/Charles_Pettit" title="Charles Pettit">Charles Pettit</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/John_Andrews_(clergyman)" title="John Andrews (clergyman)">John Andrews</a>.
</p><p>It was common at the time for intellectual societies to invite
members from around the world, where the society recruited members from
other countries, including <a href="https://en.wikipedia.org/wiki/Alexander_von_Humboldt" title="Alexander von Humboldt">Alexander von Humboldt</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Marquis_de_Lafayette" title="Marquis de Lafayette">Marquis de Lafayette</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Baron_von_Steuben" title="Baron von Steuben">Baron von Steuben</a>, <a href="https://en.wikipedia.org/wiki/Tadeusz_Ko%C5%9Bciuszko" title="Tadeusz Kościuszko">Tadeusz Kościuszko</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Princess_Dashkova" title="Princess Dashkova">Princess Dashkova</a>. The society lapsed into inactivity by 1746, but was revived in 1767.
</p><p>On January 2, 1769, the society united with the American Society for Promoting Useful Knowledge under the name <b>American Philosophical Society Held at Philadelphia for Promoting Useful Knowledge</b>. Franklin was elected the first president.
During this time, the society maintained a standing Committee on
American Improvements; one of its investigations was to study the
prospects for a canal to connect the <a href="https://en.wikipedia.org/wiki/Chesapeake_Bay" title="Chesapeake Bay">Chesapeake Bay</a> and the <a href="https://en.wikipedia.org/wiki/Delaware_River" title="Delaware River">Delaware River</a>. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chesapeake_and_Delaware_Canal" title="Chesapeake and Delaware Canal">Chesapeake and Delaware Canal</a>, which had been proposed by Thomas Gilpin, Sr., was built in the 1820s.
</p><p>Following the <a href="https://en.wikipedia.org/wiki/American_Revolutionary_War" title="American Revolutionary War">American Revolutionary War</a>, the society looked for leadership to <a href="https://en.wikipedia.org/wiki/Francis_Hopkinson" title="Francis Hopkinson">Francis Hopkinson</a>, one of the signatories of the <a href="https://en.wikipedia.org/wiki/United_States_Declaration_of_Independence" title="United States Declaration of Independence">United States Declaration of Independence</a>.
Under his influence, the society received land from the government of
Pennsylvania, along with a plot of land in Philadelphia, where
Philosophical Hall now stands.
</p><p><a href="https://en.wikipedia.org/wiki/Charles_Darwin" title="Charles Darwin">Charles Darwin</a>, <a href="https://en.wikipedia.org/wiki/Robert_Frost" title="Robert Frost">Robert Frost</a>, <a href="https://en.wikipedia.org/wiki/Louis_Pasteur" title="Louis Pasteur">Louis Pasteur</a>, <a href="https://en.wikipedia.org/wiki/Elizabeth_Cabot_Agassiz" title="Elizabeth Cabot Agassiz">Elizabeth Cabot Agassiz</a>, <a href="https://en.wikipedia.org/wiki/John_James_Audubon" title="John James Audubon">John James Audubon</a>, <a href="https://en.wikipedia.org/wiki/Linus_Pauling" title="Linus Pauling">Linus Pauling</a>, <a href="https://en.wikipedia.org/wiki/Margaret_Mead" title="Margaret Mead">Margaret Mead</a>, <a href="https://en.wikipedia.org/wiki/Maria_Mitchell" title="Maria Mitchell">Maria Mitchell</a>, and <a href="https://en.wikipedia.org/wiki/Thomas_Edison" title="Thomas Edison">Thomas Edison</a> were all prominent members of the society.
</p><p>Many members of the <a href="https://en.wikipedia.org/wiki/Society_of_the_Cincinnati" title="Society of the Cincinnati">Society of the Cincinnati</a> were among the APS's first board members and contributors; the APS and SOC still maintain an informal, collegial relationship.
</p>
<h2><span class="mw-headline" id="Membership">Membership</span></h2><p>Membership
of the APS "honors extraordinary accomplishments in all fields." It has
about 1,000 elected members, comprising about 840 "resident" members
(United States citizens or those working or living in the United States)
and about 160 "international" members. As of April 2020 it had elected 5,710 members since its foundation.
</p><p>Over that history, 208 members have been from <a href="https://en.wikipedia.org/wiki/Harvard_University" title="Harvard University">Harvard University</a>, 115 from <a href="https://en.wikipedia.org/wiki/Princeton_University" title="Princeton University">Princeton University</a>, 88 from <a href="https://en.wikipedia.org/wiki/Stanford_University" title="Stanford University">Stanford University</a>, and 84 from the <a href="https://en.wikipedia.org/wiki/University_of_California,_Berkeley" title="University of California, Berkeley">University of California, Berkeley</a>. Ten academic institutions have each been affiliated with 50 or more members:
</p>
<table border="1">
<thead><tr>
<th class="headerSort" role="columnheader button" tabindex="0" title="Sort ascending">Institution
</th>
<th class="headerSort" data-sort-type="number" role="columnheader button" tabindex="0" title="Sort ascending">Members (1743–2021)
</th></tr></thead><tbody>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Harvard_University" title="Harvard University">Harvard</a>
</td>
<td>208
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Princeton_University" title="Princeton University">Princeton</a>
</td>
<td>115
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Stanford_University" title="Stanford University">Stanford</a>
</td>
<td>88
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/University_of_California,_Berkeley" title="University of California, Berkeley">Berkeley</a>
</td>
<td>84
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Columbia_University" title="Columbia University">Columbia</a>
</td>
<td>73
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/University_of_Chicago" title="University of Chicago">Chicago</a>
</td>
<td>68
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/University_of_Pennsylvania" title="University of Pennsylvania">Penn</a>
</td>
<td>64
</td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Yale" title="Yale">Yale</a>
</td>
<td>59
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Massachusetts_Institute_of_Technology" title="Massachusetts Institute of Technology">MIT</a>
</td>
<td>57
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/New_York_University" title="New York University">NYU</a>
</td>
<td>53
</td></tr></tbody><tfoot></tfoot></table>
<div class="reflist">
</div>
<h2><span class="mw-headline" id="Awards">Awards</span></h2><p>In 1786, the society established the <a href="https://en.wikipedia.org/wiki/Magellanic_Premium" title="Magellanic Premium">Magellanic Premium</a>, a prize for achievement in "navigation, <a href="https://en.wikipedia.org/wiki/Astronomy" title="Astronomy">astronomy</a>,
or natural philosophy," the oldest scientific prize awarded by an
American institution, which it still awards. Other awards include the
Barzun Prize for <a href="https://en.wikipedia.org/wiki/Cultural_history" title="Cultural history">cultural history</a>, the Judson Daland Prize for Outstanding Achievement in Clinical Investigation, the <a href="https://en.wikipedia.org/wiki/Benjamin_Franklin_Medal_(American_Philosophical_Society)" title="Benjamin Franklin Medal (American Philosophical Society)">Benjamin Franklin Medal</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lashley_Award" title="Lashley Award">Lashley Award</a> for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurobiology" title="Neurobiology">neurobiology</a>, the Lewis Award, and the Thomas Jefferson Medal for distinguished achievement in the arts, humanities, or social sciences.
</p>
<h2><span class="mw-headline" id="Publications">Publications</span></h2><p>The society has published the <i>Transactions of the American Philosophical Society</i> since 1771. Five issues appear each year. The <i><a href="https://en.wikipedia.org/wiki/Proceedings_of_the_American_Philosophical_Society" title="Proceedings of the American Philosophical Society">Proceedings</a></i> have appeared since 1838; they publish the papers delivered at the society's biannual meetings. The society has also published <a href="https://en.wikipedia.org/wiki/The_Papers_of_Benjamin_Franklin" title="The Papers of Benjamin Franklin">The Papers of Benjamin Franklin</a>, <a href="https://en.wikipedia.org/wiki/Joseph_Henry" title="Joseph Henry">Joseph Henry</a>, <a href="https://en.wikipedia.org/wiki/William_Penn" title="William Penn">William Penn</a>, and <a href="https://en.wikipedia.org/wiki/Meriwether_Lewis" title="Meriwether Lewis">Meriwether Lewis</a> and <a href="https://en.wikipedia.org/wiki/William_Clark" title="William Clark">William Clark</a>. <a href="https://en.wikipedia.org/wiki/Jane_Aitken" title="Jane Aitken">Jane Aitken</a> bound 400 volumes for the society.
</p><p>The society also has an expansive archive on framer of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/U.S._constitution" title="U.S. constitution">U.S. constitution</a> <a href="https://en.wikipedia.org/wiki/John_Dickinson" title="John Dickinson">John Dickinson</a>.
</p><p>APS has a collection of indigenous language documents from around
the United States including the ACLS Collection (American Council of
Learned Societies Committee on Native American Languages, American
Philosophical Society) recordings of the <a href="https://en.wikipedia.org/wiki/Ottawa_dialect" title="Ottawa dialect">Odawa language</a> from northern Michigan. APS has created a guide
to help provide broad coverage of the Native American and Indigenous
archival collections at the Library & Museum of the American
Philosophical Society. These materials date from 1553 to 2020 and
include manuscript, audio, and visual materials relating to Indigenous
peoples throughout the Americas.
</p><p>The society also has a collection of manuscripts on the history
of the British colonies, Revolutionary War, the history of American
science, quantum physics, Charles Darwin and evolution, genetics and the
history of technology.
</p>
<h2><span class="mw-headline" id="Buildings">Buildings</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Philosophical_NHL.jpg"><img class="mw-file-element" data-file-height="3840" data-file-width="5760" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/2e/Philosophical_NHL.jpg/240px-Philosophical_NHL.jpg" width="400" /></a><figcaption>National Historic Landmark Plaque</figcaption></figure>
<h3><span class="mw-headline" id="Philosophical_Hall">Philosophical Hall</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Philosophical_Hall" title="Philosophical Hall">Philosophical Hall</a></div>
<p><a href="https://en.wikipedia.org/wiki/Philosophical_Hall" title="Philosophical Hall">Philosophical Hall</a>, at 104 South Fifth Street, Philadelphia, between <a href="https://en.wikipedia.org/wiki/Chestnut_Street_(Philadelphia)" title="Chestnut Street (Philadelphia)">Chestnut</a> and <a href="https://en.wikipedia.org/wiki/Walnut_Street_(Philadelphia)" title="Walnut Street (Philadelphia)">Walnut</a> Streets, immediately south of <a href="https://en.wikipedia.org/wiki/Old_City_Hall_(Philadelphia)" title="Old City Hall (Philadelphia)">Old City Hall</a>, was built in 1785–1789 to house the society and designed by Samuel Vaughan in the <a href="https://en.wikipedia.org/wiki/Federal_architecture" title="Federal architecture">Federal style</a>. A third floor was added in 1890 to accommodate the expanding library, but was removed in 1948–1950, when the building was restored to its original appearance for the creation of <a href="https://en.wikipedia.org/wiki/Independence_National_Historical_Park" title="Independence National Historical Park">Independence National Historical Park</a>.
In 2001, it was opened to the public as The American Philosophical
Society Museum, hosting revolving, thematic exhibitions that explore
intersections of history, art, and science. The museum features works of
art, scientific instruments, original manuscripts, rare books, natural
history specimens, and curiosities of all kinds from the APS's own
collections, along with objects on loan from other institutions.
</p>
<h3><span class="mw-headline" id="Library_Hall">Library Hall</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:American_Philosophical_Society_Library_Hall_reading_room.jpg"><img class="mw-file-element" data-file-height="3024" data-file-width="4032" height="300" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b5/American_Philosophical_Society_Library_Hall_reading_room.jpg/240px-American_Philosophical_Society_Library_Hall_reading_room.jpg" width="400" /></a><figcaption>Reading room for researchers at <a href="https://en.wikipedia.org/wiki/Library_Company_of_Philadelphia" title="Library Company of Philadelphia">Library Hall</a> in 2019</figcaption></figure>
<p>In 1789–90, the <a href="https://en.wikipedia.org/wiki/Library_Company_of_Philadelphia" title="Library Company of Philadelphia">Library Company of Philadelphia</a>
(LCP) built its headquarters directly across 5th Street from APS. In
1884 LCP sold its building, which was demolished for the expansion of
the Drexel & Company Building in 1887. This building was demolished
in the mid-1950s, during the creation of Independence National
Historical Park.
</p><p>APS built a library on the site in 1958 and recreated the façade of the old LCP building.
</p>
<h3><span class="mw-headline" id="Benjamin_Franklin_Hall">Benjamin Franklin Hall</span></h3><p>APS restored the former Farmers' & Mechanics' Bank building at 425–29 <a href="https://en.wikipedia.org/wiki/Chestnut_Street_(Philadelphia)" title="Chestnut Street (Philadelphia)">Chestnut Street</a>, which was built in 1854–55 to the design of John M. Gries in the <a href="https://en.wikipedia.org/wiki/Italianate_architecture" title="Italianate architecture">Italianate style</a>, to serve as a lecture hall. It is the site of meetings and most major events the society hosts.
</p>
<h3><span class="mw-headline" id="Richardson_Hall">Richardson Hall</span></h3>The <a href="https://en.wikipedia.org/wiki/Constance_Coleman_Richardson" title="Constance Coleman Richardson">Constance C.</a> and <a href="https://en.wikipedia.org/wiki/Edgar_Preston_Richardson" title="Edgar Preston Richardson">Edgar P. Richardson</a>
Hall at 431 Chestnut Street, immediately west of Benjamin Franklin
Hall, is the former Pennsylvania Company for Insurances on Lives and
Granting Annuities Building, which was built in 1871–1873 and designed
by <a href="https://en.wikipedia.org/wiki/Addison_Hutton" title="Addison Hutton">Addison Hutton</a>. It contains offices and the Consortium for History of Science, Technology and Medicine.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-52217224957161165362024-03-28T09:33:00.008-04:002024-03-28T09:33:50.007-04:00Immortality<div aria-labelledby="firstHeading" class="vector-body ve-init-mw-desktopArticleTarget-targetContainer" data-mw-ve-target-container="" id="bodyContent"><div class="vector-body-before-content"><div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div>
<div id="contentSub"><div id="mw-content-subtitle"></div></div>
<div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Immortality">https://en.wikipedia.org/wiki/Immortality</a><br />
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Fountain_of_Eternal_Life_crop.jpg"><img class="mw-file-element" data-file-height="786" data-file-width="589" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/3f/Fountain_of_Eternal_Life_crop.jpg/220px-Fountain_of_Eternal_Life_crop.jpg" width="299" /></a><figcaption>The <i><a href="https://en.wikipedia.org/wiki/Fountain_of_Eternal_Life" title="Fountain of Eternal Life">Fountain of Eternal Life</a></i> in <a href="https://en.wikipedia.org/wiki/Cleveland" title="Cleveland">Cleveland</a>, Ohio, United States, is described as symbolizing "Man rising above death, reaching upward to God and toward Peace."</figcaption></figure>
<p><b>Immortality</b> is the concept of eternal life. Some <a href="https://en.wikipedia.org/wiki/Species" title="Species">species</a> possess <a href="https://en.wikipedia.org/wiki/Biological_immortality" title="Biological immortality">biological immortality</a>.
</p><p>Some scientists, <a href="https://en.wikipedia.org/wiki/Futurist" title="Futurist">futurists</a>
and philosophers have theorized about the immortality of the human
body, with some suggesting that human immortality may be achievable in
the first few decades of the 21st century with the help of certain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Technologies" title="Technologies">technologies</a> such as <a href="https://en.wikipedia.org/wiki/Mind_uploading" title="Mind uploading">mind uploading</a> (<a href="https://en.wikipedia.org/wiki/Digital_immortality" title="Digital immortality">digital immortality</a>). Other advocates believe that <a href="https://en.wikipedia.org/wiki/Life_extension" title="Life extension">life extension</a>
is a more achievable goal in the short term, with immortality awaiting
further research breakthroughs. The absence of aging would provide
humans with biological immortality, but not invulnerability to death by
disease or <a href="https://en.wikipedia.org/wiki/Major_trauma" title="Major trauma">injury</a>.
Whether the process of internal immortality is delivered within the
upcoming years depends chiefly on research (and in neuron research in
the case of internal immortality through an immortalized cell line) in
the former view and perhaps is an awaited goal in the latter case.
</p><p>From at least the <a href="https://en.wikipedia.org/wiki/Ancient_Mesopotamian_religion" title="Ancient Mesopotamian religion">ancient Mesopotamians</a>,
there has been a conviction that gods may be physically immortal, and
that this is also a state that the gods at times offer humans. For <a href="https://en.wikipedia.org/wiki/Christianity" title="Christianity">Christianity</a> the conviction that God may offer physical immortality with the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Resurrection_of_the_flesh" title="Resurrection of the flesh">resurrection of the flesh</a> at the end of time, has traditionally been at the very crux of its beliefs. What form an unending human life would take, or whether an immaterial <a href="https://en.wikipedia.org/wiki/Soul" title="Soul">soul</a> exists and possesses immortality, has been a major point of focus of religion,
as well as the subject of speculation and debate. In religious
contexts, immortality is often stated to be one of the promises of
divinities to human beings who perform <a href="https://en.wikipedia.org/wiki/Virtue" title="Virtue">virtue</a> or follow <a href="https://en.wikipedia.org/wiki/Divine_law" title="Divine law">divine law</a>.
</p>
<h2><span class="mw-headline" id="Definitions">Definitions</span></h2></div></div></div>
<h3><span class="mw-headline" id="Scientific">Scientific</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Anti-aging_movement" title="Anti-aging movement">Anti-aging movement</a></div>
<p><a href="https://en.wikipedia.org/wiki/Life_extension" title="Life extension">Life extension</a> technologies claim to be developing a path to complete <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rejuvenation_(aging)" title="Rejuvenation (aging)">rejuvenation</a>. <a href="https://en.wikipedia.org/wiki/Cryonics" title="Cryonics">Cryonics</a>
holds out the hope that the dead can be revived in the future,
following sufficient medical advancements. While, as shown with
creatures such as <a href="https://en.wikipedia.org/wiki/Hydra_(genus)" title="Hydra (genus)">hydra</a> and <a href="https://en.wikipedia.org/wiki/Planarian" title="Planarian">Planarian</a> worms, it is indeed possible for a creature to be <a href="https://en.wikipedia.org/wiki/Biological_immortality" title="Biological immortality">biologically immortal</a>,
these are animals which are physiologically very different from humans,
and it is not known if something comparable will ever be possible for
humans.
</p>
<h3><span class="mw-headline" id="Religious">Religious</span></h3><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Soul" title="Soul">Soul</a> and <a href="https://en.wikipedia.org/wiki/Resurrection" title="Resurrection">Resurrection</a></div>
<p>Immortality in religion refers usually to either the belief in physical immortality or a more spiritual <i><a href="https://en.wikipedia.org/wiki/Afterlife" title="Afterlife">afterlife</a></i>.
In traditions such as ancient Egyptian beliefs, Mesopotamian beliefs
and ancient Greek beliefs, the immortal gods consequently were
considered to have physical bodies. In Mesopotamian and Greek religion,
the gods also made certain men and women physically immortal,<sup> </sup>whereas in Christianity, many believe that all true believers will be <a href="https://en.wikipedia.org/wiki/Resurrection" title="Resurrection">resurrected</a> to physical immortality. Similar beliefs that physical immortality is possible are held by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rastafari_movement" title="Rastafari movement">Rastafarians</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rebirthing-Breathwork" title="Rebirthing-Breathwork">Rebirthers</a>.
</p>
<h2><span class="mw-headline" id="Physical_immortality">Physical immortality</span></h2><p>Physical
immortality is a state of life that allows a person to avoid death and
maintain conscious thought. It can mean the unending existence of a
person from a physical source other than organic life, such as a
computer.
</p><p>Pursuit of physical immortality before the advent of modern science included <a href="https://en.wikipedia.org/wiki/Alchemy" title="Alchemy">alchemists</a>, who sought to create the <a href="https://en.wikipedia.org/wiki/Philosopher%27s_stone" title="Philosopher's stone">Philosopher's Stone</a>, and various cultures' legends such as the <a href="https://en.wikipedia.org/wiki/Fountain_of_Youth" title="Fountain of Youth">Fountain of Youth</a> or the <a href="https://en.wikipedia.org/wiki/Peaches_of_Immortality" title="Peaches of Immortality">Peaches of Immortality</a> inspiring attempts at discovering an <a href="https://en.wikipedia.org/wiki/Elixir_of_life" title="Elixir of life">elixir of life</a>.
</p><p>Modern scientific trends, such as <a href="https://en.wikipedia.org/wiki/Cryonics" title="Cryonics">cryonics</a>, <a href="https://en.wikipedia.org/wiki/Digital_immortality" title="Digital immortality">digital immortality</a>, breakthroughs in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rejuvenation_(aging)" title="Rejuvenation (aging)">rejuvenation</a>, or predictions of an impending <a href="https://en.wikipedia.org/wiki/Technological_singularity" title="Technological singularity">technological singularity</a>, to achieve genuine human physical immortality, must still overcome all causes of death to succeed.
</p>
<h3><span class="mw-headline" id="Causes_of_death">Causes of death</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Death" title="Death">Death</a></div>
<p>There are three main causes of death: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aging" title="Aging">natural aging</a>, <a href="https://en.wikipedia.org/wiki/Disease" title="Disease">disease</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physical_trauma" title="Physical trauma">injury</a>.
Such issues can be resolved with the solutions provided in research to
any end providing such alternate theories at present that require
unification.
</p>
<h4><span class="mw-headline" id="Aging">Aging</span></h4><p><a href="https://en.wikipedia.org/wiki/Aubrey_de_Grey" title="Aubrey de Grey">Aubrey de Grey</a>, a leading researcher in the field, defines <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aging" title="Aging">aging</a> as "a collection of cumulative changes to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Molecular" title="Molecular">molecular</a> and <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cellular</a> structure of an adult <a href="https://en.wikipedia.org/wiki/Organism" title="Organism">organism</a>, which result in essential <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Metabolic" title="Metabolic">metabolic</a> processes, but which also, once they progress far enough, increasingly disrupt metabolism, resulting in <a href="https://en.wikipedia.org/wiki/Pathology" title="Pathology">pathology</a> and death." The current causes of aging in humans are cell loss (without replacement), <a href="https://en.wikipedia.org/wiki/DNA_damage_theory_of_aging" title="DNA damage theory of aging">DNA damage</a>, <a href="https://en.wikipedia.org/wiki/Oncology" title="Oncology">oncogenic</a> <a href="https://en.wikipedia.org/wiki/Cell_nucleus" title="Cell nucleus">nuclear</a> <a href="https://en.wikipedia.org/wiki/Mutation" title="Mutation">mutations</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epimutation" title="Epimutation">epimutations</a>, cell <a href="https://en.wikipedia.org/wiki/Senescence" title="Senescence">senescence</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria">mitochondrial</a> mutations, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lysosomal" title="Lysosomal">lysosomal</a> aggregates, extracellular aggregates, random extracellular cross-linking, <a href="https://en.wikipedia.org/wiki/Immune_system" title="Immune system">immune system</a> decline, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Endocrine" title="Endocrine">endocrine</a> changes. Eliminating aging would require finding a solution to each of these causes, a program de Grey calls <a href="https://en.wikipedia.org/wiki/Strategies_for_engineered_negligible_senescence" title="Strategies for engineered negligible senescence">engineered negligible senescence</a>. There is also a huge body of knowledge indicating that change is characterized by the loss of molecular fidelity.
</p>
<h4><span class="mw-headline" id="Disease">Disease</span></h4><p>Disease
is theoretically surmountable by technology. In short, it is an
abnormal condition affecting the body of an organism, something the body
should not typically have to deal with its natural make up. Human understanding of <a href="https://en.wikipedia.org/wiki/Genetics" title="Genetics">genetics</a>
is leading to cures and treatments for a myriad of previously incurable
diseases. The mechanisms by which other diseases do damage are becoming
better understood. Sophisticated methods of detecting diseases early
are being developed. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Preventative_medicine" title="Preventative medicine">Preventative medicine</a> is becoming better understood. Neurodegenerative diseases like <a href="https://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease">Parkinson's</a> and <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's</a> may soon be curable with the use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Stem_cells" title="Stem cells">stem cells</a>. Breakthroughs in <a href="https://en.wikipedia.org/wiki/Cell_biology" title="Cell biology">cell biology</a> and <a href="https://en.wikipedia.org/wiki/Telomere" title="Telomere">telomere</a> research are leading to treatments for cancer. <a href="https://en.wikipedia.org/wiki/Vaccine" title="Vaccine">Vaccines</a> are being researched for AIDS and <a href="https://en.wikipedia.org/wiki/Tuberculosis" title="Tuberculosis">tuberculosis</a>. Genes associated with <a href="https://en.wikipedia.org/wiki/Type_1_diabetes" title="Type 1 diabetes">type 1 diabetes</a>
and certain types of cancer have been discovered, allowing for new
therapies to be developed. Artificial devices attached directly to the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a> may restore sight to the blind. Drugs are being developed to treat a myriad of other diseases and ailments.
</p>
<h4><span class="mw-headline" id="Trauma">Trauma</span></h4><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physical_trauma" title="Physical trauma">Physical trauma</a>
would remain as a threat to perpetual physical life, as an otherwise
immortal person would still be subject to unforeseen accidents or
catastrophes. The speed and quality of <a href="https://en.wikipedia.org/wiki/Paramedic" title="Paramedic">paramedic</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Disaster_relief_operation" title="Disaster relief operation">response</a> remains a determining factor in surviving severe trauma. A body that could automatically repair itself from severe trauma, such as speculated uses for <a href="https://en.wikipedia.org/wiki/Nanotechnology" title="Nanotechnology">nanotechnology</a>,
would mitigate this factor. The brain cannot be risked to trauma if a
continuous physical life is to be maintained. This aversion to trauma
risk to the brain would naturally result in significant behavioral
changes that would render physical immortality undesirable for some
people.
</p>
<h4><span class="mw-headline" id="Environmental_change">Environmental change</span></h4>
<p>Organisms otherwise unaffected by these causes of death would still
face the problem of obtaining sustenance (whether from currently
available agricultural processes or from hypothetical future
technological processes) in the face of changing availability of
suitable resources as environmental conditions change. After avoiding
aging, disease, and trauma, death through resource limitation is still
possible, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hypoxia_(medical)" title="Hypoxia (medical)">hypoxia</a> or <a href="https://en.wikipedia.org/wiki/Starvation" title="Starvation">starvation</a>.
</p><p>If there is no limitation on the degree of gradual mitigation of risk then it is possible that the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cumulative_probability" title="Cumulative probability">cumulative probability</a> of death over an infinite horizon is less than <a href="https://en.wikipedia.org/wiki/Certainty" title="Certainty">certainty</a>, even when the risk of fatal trauma <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hazard_rate" title="Hazard rate">in any finite period</a> is greater than zero. Mathematically, this is an aspect of achieving <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Indefinite_lifespan#Actuarial_escape_velocity" title="Indefinite lifespan">'actuarial escape velocity'</a>.
</p>
<h3><span class="mw-headline" id="Biological_immortality">Biological immortality</span></h3><figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Telomere_caps.gif"><img class="mw-file-element" data-file-height="471" data-file-width="600" height="315" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4a/Telomere_caps.gif/220px-Telomere_caps.gif" width="400" /></a><figcaption>Human <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a> (grey) capped by telomeres (white)</figcaption></figure>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Biological_immortality" title="Biological immortality">Biological immortality</a></div>
<p>Biological immortality is an absence of aging. Specifically it is the absence of a sustained increase in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rate_of_mortality" title="Rate of mortality">rate of mortality</a>
as a function of chronological age. A cell or organism that does not
experience aging, or ceases to age at some point, is biologically
immortal.
</p><p><a href="https://en.wikipedia.org/wiki/Biologist" title="Biologist">Biologists</a> have chosen the word "immortal" to designate cells that are not limited by the <a href="https://en.wikipedia.org/wiki/Hayflick_limit" title="Hayflick limit">Hayflick limit</a>, where cells no longer divide because of <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA damage</a> or shortened <a href="https://en.wikipedia.org/wiki/Telomere" title="Telomere">telomeres</a>. The first and still most widely used immortal cell line is <a href="https://en.wikipedia.org/wiki/HeLa" title="HeLa">HeLa</a>, developed from cells taken from the malignant cervical tumor of <a href="https://en.wikipedia.org/wiki/Henrietta_Lacks" title="Henrietta Lacks">Henrietta Lacks</a> without her consent in 1951. Prior to the 1961 work of <a href="https://en.wikipedia.org/wiki/Leonard_Hayflick" title="Leonard Hayflick">Leonard Hayflick</a>, there was the erroneous belief fostered by <a href="https://en.wikipedia.org/wiki/Alexis_Carrel" title="Alexis Carrel">Alexis Carrel</a> that all normal <a href="https://en.wikipedia.org/wiki/Somatic_(biology)" title="Somatic (biology)">somatic</a>
cells are immortal. By preventing cells from reaching senescence one
can achieve biological immortality; telomeres, a "cap" at the end of
DNA, are thought to be the cause of cell aging. Every time a cell
divides the telomere becomes a bit shorter; when it is finally worn
down, the cell is unable to split and dies. <a href="https://en.wikipedia.org/wiki/Telomerase" title="Telomerase">Telomerase</a>
is an enzyme which rebuilds the telomeres in stem cells and cancer
cells, allowing them to replicate an infinite number of times.
No definitive work has yet demonstrated that telomerase can be used in
human somatic cells to prevent healthy tissues from aging. On the other
hand, scientists hope to be able to grow organs with the help of stem
cells, allowing organ transplants without the risk of rejection, another
step in extending human life expectancy. These technologies are the
subject of ongoing research, and are not yet realized.
</p>
<h4><span class="mw-headline" id="Biologically_immortal_species">Biologically immortal species</span></h4><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/List_of_longest-living_organisms" title="List of longest-living organisms">List of longest-living organisms</a></div>
<p>Life defined as biologically immortal is still susceptible to causes
of death besides aging, including disease and trauma, as defined above.
Notable immortal species include:
</p>
<ul><li><i>Bacteria</i> – Bacteria reproduce through <a href="https://en.wikipedia.org/wiki/Fission_(biology)" title="Fission (biology)">binary fission</a>.
A parent bacterium splits itself into two identical daughter cells
which eventually then split themselves in half. This process repeats,
thus making the bacterium essentially immortal. A 2005 <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PLoS_Biology" title="PLoS Biology">PLoS Biology</a> paper
suggests that after each division the daughter cells can be identified
as the older and the younger, and the older is slightly smaller, weaker,
and more likely to die than the younger.</li><li><i><a href="https://en.wikipedia.org/wiki/Turritopsis_dohrnii" title="Turritopsis dohrnii">Turritopsis dohrnii</a></i>, a jellyfish (phylum <a href="https://en.wikipedia.org/wiki/Cnidaria" title="Cnidaria">Cnidaria</a>, class <a href="https://en.wikipedia.org/wiki/Hydrozoa" title="Hydrozoa">Hydrozoa</a>, order <a href="https://en.wikipedia.org/wiki/Anthoathecata" title="Anthoathecata">Anthoathecata</a>), after becoming a sexually mature adult, can transform itself back into a <a href="https://en.wikipedia.org/wiki/Polyp_(zoology)" title="Polyp (zoology)">polyp</a> using the cell conversion process of <a href="https://en.wikipedia.org/wiki/Transdifferentiation" title="Transdifferentiation">transdifferentiation</a>. <i>Turritopsis dohrnii</i> repeats this cycle, meaning that it may have an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Indefinite_lifespan" title="Indefinite lifespan">indefinite lifespan</a>. Its immortal adaptation has allowed it to spread from its original habitat in the Caribbean to "all over the world".</li><li><i><a href="https://en.wikipedia.org/wiki/Hydra_(genus)" title="Hydra (genus)">Hydra</a></i> is a <a href="https://en.wikipedia.org/wiki/Genus" title="Genus">genus</a> belonging to the phylum <a href="https://en.wikipedia.org/wiki/Cnidaria" title="Cnidaria">Cnidaria</a>, the class <a href="https://en.wikipedia.org/wiki/Hydrozoa" title="Hydrozoa">Hydrozoa</a> and the order <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anthomedusae" title="Anthomedusae">Anthomedusae</a>. They are simple fresh-water <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Predatory" title="Predatory">predatory</a> animals possessing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Symmetry_(biology)#Radial_symmetry" title="Symmetry (biology)">radial symmetry</a>.</li></ul>
<h4><span class="mw-headline" id="Evolution_of_aging">Evolution of aging</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Evolution_of_aging" title="Evolution of aging">Evolution of aging</a></div>
<p>As the existence of biologically immortal species demonstrates, there is no <a href="https://en.wikipedia.org/wiki/Second_law_of_thermodynamics" title="Second law of thermodynamics">thermodynamic</a> necessity for senescence: a defining feature of life is that it takes in <a href="https://en.wikipedia.org/wiki/Gibbs_free_energy" title="Gibbs free energy">free energy</a> from the environment and unloads its <a href="https://en.wikipedia.org/wiki/Entropy" title="Entropy">entropy</a>
as waste. Living systems can even build themselves up from seed, and
routinely repair themselves. Aging is therefore presumed to be a
byproduct of <a href="https://en.wikipedia.org/wiki/Evolution" title="Evolution">evolution</a>,
but why mortality should be selected for remains a subject of research
and debate. Programmed cell death and the telomere "end replication
problem" are found even in the earliest and simplest of organisms. This may be a tradeoff between selecting for cancer and selecting for aging.
</p><p>Modern theories on the evolution of aging include the following:
</p>
<ul><li>Mutation accumulation is a theory formulated by <a href="https://en.wikipedia.org/wiki/Peter_Medawar" title="Peter Medawar">Peter Medawar</a>
in 1952 to explain how evolution would select for aging. Essentially,
aging is never selected against, as organisms have offspring before the
mortal mutations surface in an individual.</li><li><a href="https://en.wikipedia.org/wiki/Pleiotropy" title="Pleiotropy">Antagonistic pleiotropy</a> is a theory proposed as an alternative by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/George_C._Williams_(biologist)" title="George C. Williams (biologist)">George C. Williams</a>,
a critic of Medawar, in 1957. In antagonistic pleiotropy, genes carry
effects that are both beneficial and detrimental. In essence this refers
to genes that offer benefits early in life, but exact a cost later on,
i.e. decline and death.</li><li>The disposable soma theory was proposed in 1977 by <a href="https://en.wikipedia.org/wiki/Tom_Kirkwood" title="Tom Kirkwood">Thomas Kirkwood</a>,
which states that an individual body must allocate energy for
metabolism, reproduction, and maintenance, and must compromise when
there is food scarcity. Compromise in allocating energy to the repair
function is what causes the body gradually to deteriorate with age,
according to Kirkwood.</li></ul>
<h4><span class="mw-headline" id="Immortality_of_the_germline">Immortality of the germline</span></h4><p>Individual
organisms ordinarily age and die, while the germlines which connect
successive generations are potentially immortal. The basis for this
difference is a fundamental problem in biology. The Russian biologist
and historian <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Zhores_A._Medvedev" title="Zhores A. Medvedev">Zhores A. Medvedev</a> considered that the accuracy of <a href="https://en.wikipedia.org/wiki/Genome" title="Genome">genome</a> replicative and other synthetic systems alone cannot explain the immortality of <a href="https://en.wikipedia.org/wiki/Germline" title="Germline">germlines</a>. Rather Medvedev thought that known features of the biochemistry and genetics of <a href="https://en.wikipedia.org/wiki/Sexual_reproduction" title="Sexual reproduction">sexual reproduction</a> indicate the presence of unique information maintenance and restoration processes at the different stages of <a href="https://en.wikipedia.org/wiki/Gametogenesis" title="Gametogenesis">gametogenesis</a>. In particular, Medvedev considered that the most important opportunities for information maintenance of <a href="https://en.wikipedia.org/wiki/Germ_cell" title="Germ cell">germ cells</a> are created by <a href="https://en.wikipedia.org/wiki/Genetic_recombination" title="Genetic recombination">recombination during meiosis</a> and <a href="https://en.wikipedia.org/wiki/DNA_repair" title="DNA repair">DNA repair</a>; he saw these as processes within the germ cells that were capable of restoring the integrity of <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> and <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a> from the types of damage that cause irreversible aging in <a href="https://en.wikipedia.org/wiki/Somatic_cell" title="Somatic cell">somatic cells</a>.
</p>
<h3><span class="mw-headline" id="Prospects_for_human_biological_immortality">Prospects for human biological immortality</span></h3><h4><span class="mw-headline" id="Life-extending_substances">Life-extending substances</span></h4><p>Some scientists believe that boosting the amount or proportion of <a href="https://en.wikipedia.org/wiki/Telomerase" title="Telomerase">telomerase</a> in the body, a naturally forming enzyme that helps maintain the protective caps at the ends of <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosomes</a>,
could prevent cells from dying and so may ultimately lead to extended,
healthier lifespans. A team of researchers at the Spanish National
Cancer Centre (<a href="https://en.wikipedia.org/wiki/Madrid" title="Madrid">Madrid</a>) tested the hypothesis on mice. It was found that those mice which were "<a href="https://en.wikipedia.org/wiki/Genetic_engineering" title="Genetic engineering">genetically engineered</a> to produce 10 times the normal levels of telomerase lived 50% longer than normal mice".
</p><p>In normal circumstances, without the presence of telomerase, if a
cell divides repeatedly, at some point all the progeny will reach their
<a href="https://en.wikipedia.org/wiki/Hayflick_limit" title="Hayflick limit">Hayflick limit</a>. With the presence of telomerase, each dividing cell can replace the lost bit of <a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a>,
and any single cell can then divide unbounded. While this unbounded
growth property has excited many researchers, caution is warranted in
exploiting this property, as exactly this same unbounded growth is a
crucial step in enabling cancerous growth. If an organism can replicate
its body cells faster, then it would theoretically stop aging.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryonic_stem_cells" title="Embryonic stem cells">Embryonic stem cells</a>
express telomerase, which allows them to divide repeatedly and form the
individual. In adults, telomerase is highly expressed in cells that
need to divide regularly (e.g., in the immune system), whereas most <a href="https://en.wikipedia.org/wiki/Somatic_(biology)" title="Somatic (biology)">somatic</a> cells express it only at very low levels in a cell-cycle dependent manner.
</p>
<h4><span id="Technological_immortality.2C_biological_machines.2C_and_.22swallowing_the_doctor.22"></span><span class="mw-headline" id="Technological_immortality,_biological_machines,_and_"swallowing_the_doctor"">Technological immortality, biological machines, and "swallowing the doctor"</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Molecular_machine" title="Molecular machine">Molecular machine</a></div>
<p>Technological immortality is the prospect for much longer life spans
made possible by scientific advances in a variety of fields:
nanotechnology, emergency room procedures, genetics, <a href="https://en.wikipedia.org/wiki/Biological_engineering" title="Biological engineering">biological engineering</a>, <a href="https://en.wikipedia.org/wiki/Regenerative_medicine" title="Regenerative medicine">regenerative medicine</a>, <a href="https://en.wikipedia.org/wiki/Microbiology" title="Microbiology">microbiology</a>,
and others. Contemporary life spans in the advanced industrial
societies are already markedly longer than those of the past because of
better nutrition, availability of health care, standard of living and
bio-medical scientific advances.
Technological immortality predicts further progress for the same
reasons over the near term. An important aspect of current scientific
thinking about immortality is that some combination of <a href="https://en.wikipedia.org/wiki/Human_cloning" title="Human cloning">human cloning</a>, cryonics or nanotechnology will play an essential role in extreme life extension. <a href="https://en.wikipedia.org/wiki/Robert_Freitas" title="Robert Freitas">Robert Freitas</a>, a nanorobotics theorist, suggests tiny medical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanorobot" title="Nanorobot">nanorobots</a> could be created to go through human bloodstreams, find dangerous things like cancer cells and bacteria, and destroy them.
Freitas anticipates that gene-therapies and nanotechnology will
eventually make the human body effectively self-sustainable and capable
of living indefinitely in empty space, short of severe brain trauma.
This supports the theory that we will be able to continually create
biological or synthetic replacement parts to replace damaged or dying
ones. Future advances in <a href="https://en.wikipedia.org/wiki/Nanomedicine" title="Nanomedicine">nanomedicine</a> could give rise to <a href="https://en.wikipedia.org/wiki/Life_extension#Nanotechnology" title="Life extension">life extension</a> through the repair of many processes thought to be responsible for aging. <a href="https://en.wikipedia.org/wiki/K._Eric_Drexler" title="K. Eric Drexler">K. Eric Drexler</a>, one of the founders of <a href="https://en.wikipedia.org/wiki/Nanotechnology" title="Nanotechnology">nanotechnology</a>, postulated cell repair devices, including ones operating within cells and using as yet hypothetical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological_machine" title="Biological machine">biological machines</a>, in his 1986 book <a href="https://en.wikipedia.org/wiki/Engines_of_Creation" title="Engines of Creation">Engines of Creation</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Raymond_Kurzweil" title="Raymond Kurzweil">Raymond Kurzweil</a>, a <a href="https://en.wikipedia.org/wiki/Futurist" title="Futurist">futurist</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transhumanist" title="Transhumanist">transhumanist</a>, stated in his book <i><a href="https://en.wikipedia.org/wiki/The_Singularity_Is_Near" title="The Singularity Is Near">The Singularity Is Near</a></i> that he believes that advanced medical <a href="https://en.wikipedia.org/wiki/Nanorobotics" title="Nanorobotics">nanorobotics</a> could completely remedy the effects of aging by 2030. According to <a href="https://en.wikipedia.org/wiki/Richard_Feynman" title="Richard Feynman">Richard Feynman</a>, it was his former graduate student and collaborator <a href="https://en.wikipedia.org/wiki/Albert_Hibbs" title="Albert Hibbs">Albert Hibbs</a> who originally suggested to him (circa 1959) the idea of a <i>medical</i> use for Feynman's theoretical micromachines (see <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological_machine" title="Biological machine">biological machine</a>).
Hibbs suggested that certain repair machines might one day be reduced
in size to the point that it would, in theory, be possible to (as
Feynman put it) "swallow the doctor". The idea was incorporated into
Feynman's 1959 essay <i><a href="https://en.wikipedia.org/wiki/There%27s_Plenty_of_Room_at_the_Bottom" title="There's Plenty of Room at the Bottom">There's Plenty of Room at the Bottom</a>.</i>
</p>
<h4><span class="mw-headline" id="Cryonics">Cryonics</span></h4>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Cryonics" title="Cryonics">Cryonics</a></div>
<p><a href="https://en.wikipedia.org/wiki/Cryonics" title="Cryonics">Cryonics</a>,
the practice of preserving organisms (either intact specimens or only
their brains) for possible future revival by storing them at cryogenic
temperatures where metabolism and decay are almost completely stopped,
can be used to 'pause' for those who believe that life extension
technologies will not develop sufficiently within their lifetime.
Ideally, cryonics would allow clinically dead people to be brought back
in the future after cures to the patients' diseases have been discovered
and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Rejuvenation_(aging)" title="Rejuvenation (aging)">aging is reversible</a>. Modern cryonics procedures use a process called <a href="https://en.wikipedia.org/wiki/Cryopreservation#Vitrification" title="Cryopreservation">vitrification</a> which creates a glass-like state rather than <a href="https://en.wikipedia.org/wiki/Freezing" title="Freezing">freezing</a>
as the body is brought to low temperatures. This process reduces the
risk of ice crystals damaging the cell-structure, which would be
especially detrimental to cell structures in the brain, as their minute
adjustment evokes the individual's mind.
</p>
<h4><span class="mw-headline" id="Mind-to-computer_uploading">Mind-to-computer uploading</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Mind_uploading" title="Mind uploading">Mind uploading</a></div>
<p>One idea that has been advanced involves <a href="https://en.wikipedia.org/wiki/Mind_uploading" title="Mind uploading">uploading</a> an individual's habits and memories via <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Direct_mind-computer_interface" title="Direct mind-computer interface">direct mind-computer interface</a>. The individual's memory may be loaded to a computer or to a new organic body. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Extropian" title="Extropian">Extropian</a> <a href="https://en.wikipedia.org/wiki/Futures_studies" title="Futures studies">futurists</a> like Moravec and <a href="https://en.wikipedia.org/wiki/Ray_Kurzweil" title="Ray Kurzweil">Kurzweil</a> have proposed that, thanks to <a href="https://en.wikipedia.org/wiki/Exponential_growth" title="Exponential growth">exponentially growing</a> computing power, it will someday be possible to <a href="https://en.wikipedia.org/wiki/Mind_uploading" title="Mind uploading">upload human consciousness</a> onto a computer system, and exist indefinitely in a virtual environment.
</p><p>This could be accomplished via advanced cybernetics, where
computer hardware would initially be installed in the brain to help sort
memory or accelerate thought processes. Components would be added
gradually until the person's entire brain functions were handled by
artificial devices, avoiding sharp transitions that would lead to issues
of <a href="https://en.wikipedia.org/wiki/Identity_(social_science)" title="Identity (social science)">identity</a>,
thus running the risk of the person to be declared dead and thus not be
a legitimate owner of his or her property. After this point, the human
body could be treated as an optional accessory and the program
implementing the person could be transferred to any sufficiently
powerful computer.
</p><p>Another possible mechanism for mind upload is to perform a
detailed scan of an individual's original, organic brain and simulate
the entire structure in a computer. What level of detail such scans and
simulations would need to achieve to emulate awareness, and whether the
scanning process would destroy the brain, is still to be determined.
</p><p>It is suggested that achieving immortality through this mechanism
would require specific consideration to be given to the role of <a href="https://en.wikipedia.org/wiki/Consciousness" title="Consciousness">consciousness</a> in the functions of the <a href="https://en.wikipedia.org/wiki/Mind" title="Mind">mind</a>.
An uploaded mind would only be a copy of the original mind, and not the
conscious mind of the living entity associated in such a transfer.
Without a simultaneous upload of consciousness, the original living
entity remains mortal, thus not achieving true immortality.
Research on <a href="https://en.wikipedia.org/wiki/Neural_correlates_of_consciousness" title="Neural correlates of consciousness">neural correlates of consciousness</a>
is yet inconclusive on this issue. Whatever the route to mind upload,
persons in this state could then be considered essentially immortal,
short of loss or traumatic destruction of the machines that maintained
them.
</p>
<h4><span class="mw-headline" id="Cybernetics">Cybernetics</span></h4><table class="box-Unreferenced_section plainlinks metadata ambox ambox-content ambox-Unreferenced" role="presentation"><tbody><tr><td class="mbox-image"><div class="mbox-image-div"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Question_book-new.svg"><img alt="" class="mw-file-element" data-file-height="399" data-file-width="512" height="39" src="https://upload.wikimedia.org/wikipedia/en/thumb/9/99/Question_book-new.svg/50px-Question_book-new.svg.png" width="50" /></a></span></div></td><td class="mbox-text"><div class="mbox-text-span">This section <b>does not <a href="https://en.wikipedia.org/wiki/Wikipedia:Citing_sources" title="Wikipedia:Citing sources">cite</a> any <a href="https://en.wikipedia.org/wiki/Wikipedia:Verifiability" title="Wikipedia:Verifiability">sources</a></b>.<span class="hide-when-compact"> Please help <a href="https://en.wikipedia.org/wiki/Special:EditPage/Immortality" title="Special:EditPage/Immortality">improve this section</a> by <a href="https://en.wikipedia.org/wiki/Help:Referencing_for_beginners" title="Help:Referencing for beginners">adding citations to reliable sources</a>. Unsourced material may be challenged and <a href="https://en.wikipedia.org/wiki/Wikipedia:Verifiability#Burden_of_evidence" title="Wikipedia:Verifiability">removed</a>.</span> <span class="date-container"><i>(<span class="date">November 2022</span>)</i></span><span class="hide-when-compact"><i> (<small><a href="https://en.wikipedia.org/wiki/Help:Maintenance_template_removal" title="Help:Maintenance template removal">Learn how and when to remove this template message</a></small>)</i></span></div></td></tr></tbody></table>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Cyborg" title="Cyborg">Cyborg</a></div>
<p>Transforming a human into a <a href="https://en.wikipedia.org/wiki/Cyborg" title="Cyborg">cyborg</a> can include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Brain_implants" title="Brain implants">brain implants</a> or extracting a human processing unit and placing it in a robotic life-support system.
Even replacing biological organs with robotic ones could increase life
span (e.g. pace makers) and depending on the definition, many
technological upgrades to the body, like genetic modifications or the
addition of nanobots would qualify an individual as a cyborg. Some
people believe that such modifications would make one impervious to
aging and disease and theoretically immortal unless killed or destroyed.
</p>
<h4><span class="mw-headline" id="Digital_immortality">Digital immortality</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Digital_immortality" title="Digital immortality">Digital immortality</a></div>
<h2><span class="mw-headline" id="Religious_views">Religious views</span></h2><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Afterlife" title="Afterlife">Afterlife</a> and <a href="https://en.wikipedia.org/wiki/Soul" title="Soul">Soul</a></div>
<p>As late as 1952, the editorial staff of the <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/A_Syntopicon:_An_Index_to_The_Great_Ideas" title="A Syntopicon: An Index to The Great Ideas">Syntopicon</a></i> found in their compilation of the <a href="https://en.wikipedia.org/wiki/Great_Books_of_the_Western_World" title="Great Books of the Western World">Great Books of the Western World</a>,
that "The philosophical issue concerning immortality cannot be
separated from issues concerning the existence and nature of man's
soul." Thus, the vast majority of speculation on immortality before the 21st century was regarding the nature of the afterlife.
</p>
<h3><span class="mw-headline" id="Abrahamic_religion">Abrahamic religion</span></h3><p>The viewpoints of <a href="https://en.wikipedia.org/wiki/Christianity" title="Christianity">Christianity</a>, <a href="https://en.wikipedia.org/wiki/Islam" title="Islam">Islam</a>, and <a href="https://en.wikipedia.org/wiki/Judaism" title="Judaism">Judaism</a> regarding the concept of immortality diverge as each <a href="https://en.wikipedia.org/wiki/Faith" title="Faith">faith</a> system encapsulates unique <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Theological" title="Theological">theological</a> interpretations and doctrines on the enduring <a href="https://en.wikipedia.org/wiki/Human_nature" title="Human nature">human nature</a> <a href="https://en.wikipedia.org/wiki/Soul" title="Soul">soul</a> or <a href="https://en.wikipedia.org/wiki/Spirituality" title="Spirituality">spirit</a>.
</p>
<h4><span class="mw-headline" id="Christianity">Christianity</span></h4><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/Eternal_life_(Christianity)" title="Eternal life (Christianity)">Eternal life (Christianity)</a>, <a href="https://en.wikipedia.org/wiki/Christian_conditionalism" title="Christian conditionalism">Christian conditionalism</a>, <a href="https://en.wikipedia.org/wiki/Christian_mortalism" title="Christian mortalism">Christian mortalism</a>, and <a href="https://en.wikipedia.org/wiki/Universal_resurrection" title="Universal resurrection">Universal resurrection</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Holbein_Danse_Macabre_3.jpg"><img class="mw-file-element" data-file-height="1279" data-file-width="1000" height="281" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/51/Holbein_Danse_Macabre_3.jpg/220px-Holbein_Danse_Macabre_3.jpg" width="220" /></a><figcaption>Adam and Eve condemned to mortality. <a href="https://en.wikipedia.org/wiki/Hans_Holbein_the_Younger" title="Hans Holbein the Younger">Hans Holbein the Younger</a>, <i>Danse Macabre</i>, 16th century</figcaption></figure>
<p><a href="https://en.wikipedia.org/wiki/Christianity" title="Christianity">Christian theology</a> holds that <a href="https://en.wikipedia.org/wiki/Adam_and_Eve" title="Adam and Eve">Adam and Eve</a> lost physical immortality for themselves and all their descendants through <a href="https://en.wikipedia.org/wiki/Fall_of_man" title="Fall of man">the Fall</a>, although this initial "imperishability of the bodily frame of man" was "a preternatural condition".
</p><p>Christians who profess the <a href="https://en.wikipedia.org/wiki/Nicene_Creed" title="Nicene Creed">Nicene Creed</a> believe that every dead person (whether they believed in Christ or not) will be resurrected from the dead at the <a href="https://en.wikipedia.org/wiki/Second_Coming" title="Second Coming">Second Coming</a>; this belief is known as <a href="https://en.wikipedia.org/wiki/Universal_resurrection" title="Universal resurrection">universal resurrection</a>. <a href="https://en.wikipedia.org/wiki/Paul_the_Apostle" title="Paul the Apostle">Paul the Apostle</a>, in following his past life as a <a href="https://en.wikipedia.org/wiki/Pharisees" title="Pharisees">Pharisee</a> (a Jewish social movement that held to a future physical resurrection),
proclaims an amalgamated view of resurrected believers where both the
physical and the spiritual are rebuilt in the likeness of
post-resurrection Christ, who "will transform our lowly body to be like
his glorious body" (ESV).
This thought mirrors Paul's depiction of believers having been "buried
therefore with him [that is, Christ] by baptism into death" (ESV).
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/N.T._Wright" title="N.T. Wright">N.T. Wright</a>, a theologian and former <a href="https://en.wikipedia.org/wiki/Bishop_of_Durham" title="Bishop of Durham">Bishop of Durham</a>, has said many people forget the physical aspect of what Jesus promised. He told <a href="https://en.wikipedia.org/wiki/Time_(magazine)" title="Time (magazine)">Time</a>: "Jesus' resurrection marks the beginning of a restoration that he will complete upon <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Second_Coming_of_Christ" title="Second Coming of Christ">his return</a>. Part of this will be the <a href="https://en.wikipedia.org/wiki/Universal_resurrection" title="Universal resurrection">resurrection of all the dead</a>, who will 'awake', be embodied and participate in the renewal. Wright says <a href="https://en.wikipedia.org/wiki/John_Polkinghorne" title="John Polkinghorne">John Polkinghorne</a>,
a physicist and a priest, has put it this way: 'God will download our
software onto his hardware until the time he gives us new hardware to
run the software again for ourselves.' That gets to two things nicely:
that the period after death (the <a href="https://en.wikipedia.org/wiki/Intermediate_state_(Christianity)" title="Intermediate state (Christianity)">Intermediate state</a>)
is a period when we are in God's presence but not active in our own
bodies, and also that the more important transformation will be when we
are again embodied and administering <a class="mw-redirect" href="https://en.wikipedia.org/wiki/World_to_Come" title="World to Come">Christ's kingdom</a>." This kingdom will consist of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/World_to_Come" title="World to Come">Heaven and Earth "joined together in a new creation"</a>, he said.
</p><p>Christian apocrypha include immortal human figures such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cartaphilus" title="Cartaphilus">Cartaphilus</a> who were cursed with physical immortality for various transgressions against Christ during the Passion. The medieval <a href="https://en.wikipedia.org/wiki/Waldensians" title="Waldensians">Waldensians</a> believed in the immortality of the soul. Leaders of sects such as <a href="https://en.wikipedia.org/wiki/John_Asgill" title="John Asgill">John Asgill</a> and <a href="https://en.wikipedia.org/wiki/John_Wroe" title="John Wroe">John Wroe</a> taught followers that physical immortality was possible.
</p><p>Many Patristic writers have connected the immortal rational soul
to the image of God found in Genesis 1:26. Among them is Athanasius of
Alexandria and Clement of Alexandria, who say that the immortal rational
soul itself is the image of God.
Even Early Christian Liturgies exhibit this connection between the
immortal rational soul and the creation of humanity in the image of God.
</p>
<h4><span class="mw-headline" id="Islam">Islam</span></h4><p>Islamic
dogma bears the concept of spiritual immortality within it; following
the death of a certain individual, it will be arbitrated consistent with
its beliefs as well as actions and will embark on the ever-lasting
place where they will abate.
The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Muslim" title="Muslim">Muslim</a> who holds the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Five_pillars_of_Islam" title="Five pillars of Islam">five pillars of Islam</a> will make an entrance into the <a href="https://en.wikipedia.org/wiki/Jannah" title="Jannah">Jannah</a>, where they will inhabit indefinitely.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Al-Baqarah" title="Al-Baqarah">Al-Baqarah</a>
(2:25):
"But give glad tidings to those who believe and work righteousness, that
their portion is gardens, beneath which rivers flow. Every time they
are fed with fruits therefrom, they say, 'Why, this is what we were fed
with before,' for they are given things in similitude; and they have
therein companions pure (and holy); and they abide therein forever."
</p><p>In contrast, the <a href="https://en.wikipedia.org/wiki/Kafir" title="Kafir">kafir</a> hold the contradictory notion that they abide in <a href="https://en.wikipedia.org/wiki/Jahannam" title="Jahannam">Jahannam</a> perpetually.
</p><p><a href="https://en.wikipedia.org/wiki/Angels_in_Islam" title="Angels in Islam">Angels in Islam</a>
are reckoned as immortals from the perspective of Islam but most people
believe is that the angels will die and that the Angel of Death will
die, but there is no clear text concerning this. Rather there are texts
which may indicate this, and there is the well known hadeeth (narration)
about the "trumpet", which is a munkar hadeeth (rejected report). alternatively, <a href="https://en.wikipedia.org/wiki/Jinn" title="Jinn">Jinn</a> have a long lifespan between 1000 and 1500. In some Muslim <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sufi" title="Sufi">Sufi</a> mystics, <a href="https://en.wikipedia.org/wiki/Khidr" title="Khidr">Khidr</a>
is given a long life but not immortality or there is more than a little
argument stated about the demise of khidr; however, it is the matter of
debate, and there is a fabrication point that goes around the Khidr drank from the <a href="https://en.wikipedia.org/wiki/Fountain_of_Life" title="Fountain of Life">fountain of Life</a>, which is thoroughly invalid. <a href="https://en.wikipedia.org/wiki/Jesus_in_Islam" title="Jesus in Islam">Jesus in Islam</a> was summoned to the sky by Allah's sanction to preserve him from the cross and endow him with long life until the advent of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dajjal" title="Dajjal">Dajjal</a>.
Dijjal is, additionally, given a long life. Jesus Christ dispatches the
Dajjal as he stays after 40 days, one like a year, one like a month,
one like a week, and the rest of his days like normal days. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Holy_Qur%27an" title="Holy Qur'an">Qur'an</a> repudiates <a href="https://en.wikipedia.org/wiki/Rejuvenation" title="Rejuvenation">rejuvenation</a> and physical immortality, stating it is inconceivable for humans to attain genuine <a href="https://en.wikipedia.org/wiki/Elixir_of_life" title="Elixir of life">elixir of life</a>.
</p><p>كُلُّ نَفْسٍ ذَائِقَةُ الْمَوْتِ
Every soul will taste death
— Quran 3:185
</p>
<figure class="mw-default-size"><span><span class="mw-tmh-player audio mw-file-element" style="width: 220px;"><a class="mw-tmh-play" href="https://en.wikipedia.org/wiki/File:Kullu_nafsin_ja_lekatul_maut_new_ringtone_2023_Arabic_ringtone_Arabic_Allah_sa_daro_virl_arabic.wav" role="button" title="Play audio"><span class="mw-tmh-play-icon"></span></a><span class="mw-tmh-duration mw-tmh-label"><span class="sr-only">Duration: 16 seconds.</span><span aria-hidden="true">0:16</span></span></span></span><a class="mw-file-magnify" href="https://en.wikipedia.org/wiki/File:Kullu_nafsin_ja_lekatul_maut_new_ringtone_2023_Arabic_ringtone_Arabic_Allah_sa_daro_virl_arabic.wav"></a><figcaption>It
symbolize the transient nature of life and challenge the concept of
immortality in the physical world. This phrase reflects the impermanence
of all things.</figcaption></figure>
<h4><span class="mw-headline" id="Judaism">Judaism</span></h4>
<p>The traditional concept of an immaterial and immortal soul distinct from the body was not found in Judaism before the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Babylonian_exile" title="Babylonian exile">Babylonian exile</a>, but developed as a result of interaction with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Persian_philosophy" title="Persian philosophy">Persian</a> and <a href="https://en.wikipedia.org/wiki/Hellenistic_philosophy" title="Hellenistic philosophy">Hellenistic philosophies</a>. Accordingly, the Hebrew word <i><a href="https://en.wikipedia.org/wiki/Nephesh" title="Nephesh">nephesh</a></i>, although translated as <i>"soul"</i> in some older English-language Bibles, actually has a meaning closer to "living being". <i>Nephesh</i> was rendered in the <a href="https://en.wikipedia.org/wiki/Septuagint" title="Septuagint">Septuagint</a> as <span class="texhtml mvar" style="font-style: italic;"> <span title="Ancient Greek (to 1453)-language text"><span lang="grc">ψυχή</span></span> </span> (<i>psūchê</i>), the Greek word for 'soul'.
</p><p>The only Hebrew word traditionally translated "soul" (<i>nephesh</i>) in English language Bibles refers to a living, breathing conscious body, rather than to an immortal soul.
In the New Testament, the Greek word traditionally translated "soul" (<span title="Ancient Greek (to 1453)-language text"><span lang="grc">ψυχή</span></span>) has substantially the same meaning as the Hebrew, without reference to an immortal soul.
<i>"Soul"</i> may refer either to the whole person, the self, as in "three thousand <i>souls</i>" were converted in <a class="external text" href="https://bible.oremus.org/?passage=Acts%202:41&version=nrsv" rel="nofollow">Acts 2:41</a> (see <a class="external text" href="https://bible.oremus.org/?passage=Acts%203:23&version=nrsv" rel="nofollow">Acts 3:23</a>).
</p><p>The <a href="https://en.wikipedia.org/wiki/Hebrew_Bible" title="Hebrew Bible">Hebrew Bible</a> speaks about <i><a href="https://en.wikipedia.org/wiki/Sheol" title="Sheol">Sheol</a></i> (שאול), originally a synonym of the grave – the repository of the dead or the cessation of existence, until the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Techiyat_hamaysim" title="Techiyat hamaysim">resurrection of the dead</a>. This doctrine of resurrection is mentioned explicitly only in <a class="external text" href="https://www.esv.org/Daniel+12:1" rel="nofollow">Daniel 12:1–4</a> although it may be implied in several other texts. New theories arose concerning Sheol during the <a href="https://en.wikipedia.org/wiki/Intertestamental_period" title="Intertestamental period">intertestamental period</a>.
</p><p>The views about immortality in Judaism is perhaps best exemplified by the various references to this in <a href="https://en.wikipedia.org/wiki/Second_Temple_period" title="Second Temple period">Second Temple period</a>. The concept of resurrection of the physical body is found in <span class="nowrap"><a href="https://en.wikipedia.org/wiki/2_Maccabees" title="2 Maccabees">2 Maccabees</a></span>, according to which it will happen through recreation of the flesh. Resurrection of the dead is specified in detail in the extra-canonical books of <a href="https://en.wikipedia.org/wiki/Book_of_Enoch" title="Book of Enoch">Enoch</a>, and in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Syriac_Apocalypse_of_Baruch" title="Syriac Apocalypse of Baruch">Apocalypse of Baruch</a>. According to the British scholar in ancient Judaism <a href="https://en.wikipedia.org/wiki/Philip_R._Davies" title="Philip R. Davies">P.R. Davies</a>, there is "little or no clear reference ... either to immortality or to resurrection from the dead" in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dead_Sea_scrolls" title="Dead Sea scrolls">Dead Sea scrolls</a> texts.
Both <a href="https://en.wikipedia.org/wiki/Josephus" title="Josephus">Josephus</a> and the <a href="https://en.wikipedia.org/wiki/New_Testament" title="New Testament">New Testament</a> record that the <a href="https://en.wikipedia.org/wiki/Sadducees" title="Sadducees">Sadducees</a> did not believe in an <a href="https://en.wikipedia.org/wiki/Afterlife" title="Afterlife">afterlife</a>,
but the sources vary on the beliefs of the <a href="https://en.wikipedia.org/wiki/Pharisees" title="Pharisees">Pharisees</a>.
The New Testament claims that the Pharisees believed in the
resurrection, but does not specify whether this included the flesh or
not. According to <a href="https://en.wikipedia.org/wiki/Josephus" title="Josephus">Josephus</a>, who himself was a Pharisee, the Pharisees held that only the soul was immortal and the souls of good people will be <a href="https://en.wikipedia.org/wiki/Reincarnation" title="Reincarnation">reincarnated</a> and "pass into other bodies", while "the souls of the wicked will suffer eternal punishment."
The <a href="https://en.wikipedia.org/wiki/Book_of_Jubilees" title="Book of Jubilees">Book of Jubilees</a> seems to refer to the resurrection of the soul only, or to a more general idea of an immortal soul.
</p><p><a href="https://en.wikipedia.org/wiki/Rabbinic_Judaism" title="Rabbinic Judaism">Rabbinic Judaism</a> claims that the righteous dead will be resurrected in the <a href="https://en.wikipedia.org/wiki/Messianic_Age" title="Messianic Age">Messianic Age</a>, with the coming of the <a href="https://en.wikipedia.org/wiki/Messiah_in_Judaism" title="Messiah in Judaism">messiah</a>.
They will then be granted immortality in a perfect world. The wicked
dead, on the other hand, will not be resurrected at all. This is not the
only Jewish belief about the afterlife. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tanakh" title="Tanakh">Tanakh</a> is not specific about the afterlife, so there are wide differences in views and explanations among believers.
</p>
<h3><span class="mw-headline" id="Dharmic_religions">Dharmic religions</span></h3><p>The perspectives on immortality within <a href="https://en.wikipedia.org/wiki/Hinduism" title="Hinduism">Hinduism</a> and <a href="https://en.wikipedia.org/wiki/Buddhism" title="Buddhism">Buddhism</a> exhibit nuanced differences, with each <a href="https://en.wikipedia.org/wiki/Spirituality" title="Spirituality">spiritual</a> <a href="https://en.wikipedia.org/wiki/Tradition" title="Tradition">tradition</a> offering distinctive <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Theological" title="Theological">theological</a> interpretations and doctrines concerning the <a href="https://en.wikipedia.org/wiki/Eternity" title="Eternity">eternal</a> essence of the <a class="new" href="https://en.wikipedia.org/w/index.php?title=Human_soul&action=edit&redlink=1" title="Human soul (page does not exist)">human soul</a> or <a href="https://en.wikipedia.org/wiki/Consciousness" title="Consciousness">consciousness</a>.
</p>
<h4><span class="mw-headline" id="Hinduism">Hinduism</span></h4><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Chiranjivi" title="Chiranjivi">Chiranjivi</a> and <a href="https://en.wikipedia.org/wiki/Naraka_(Hinduism)" title="Naraka (Hinduism)">Naraka (Hinduism)</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Reincarnation_AS.jpg"><img class="mw-file-element" data-file-height="592" data-file-width="409" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f3/Reincarnation_AS.jpg/220px-Reincarnation_AS.jpg" width="277" /></a><figcaption>Representation of a soul undergoing <i><a href="https://en.wikipedia.org/wiki/Reincarnation" title="Reincarnation">punarjanma</a></i>. Illustration from <i>Hinduism Today</i>, 2004</figcaption></figure>
<p><a href="https://en.wikipedia.org/wiki/Hinduism" title="Hinduism">Hindus</a> believe in an immortal soul which is <a href="https://en.wikipedia.org/wiki/Reincarnation" title="Reincarnation">reincarnated</a> after death. According to Hinduism, people repeat a process of life, death, and rebirth in a cycle called <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Samsara" title="Samsara">samsara</a></i>. If they live their life well, their <i><a href="https://en.wikipedia.org/wiki/Karma" title="Karma">karma</a></i>
improves and their station in the next life will be higher, and
conversely lower if they live their life poorly. After many life times
of perfecting its karma, the soul is freed from the cycle and lives in
perpetual bliss. There is no place of eternal torment in Hinduism,
although if a soul consistently lives very evil lives, it could work its
way down to the very bottom of the cycle.
</p><p>There are explicit renderings in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Upanishad" title="Upanishad">Upanishads</a>
alluding to a physically immortal state brought about by purification,
and sublimation of the 5 elements that make up the body. For example, in
the <a href="https://en.wikipedia.org/wiki/Shvetashvatara_Upanishad" title="Shvetashvatara Upanishad">Shvetashvatara Upanishad</a>
(Chapter 2, Verse 12), it is stated "When earth, water, fire, air and
sky arise, that is to say, when the five attributes of the elements,
mentioned in the books on yoga, become manifest then the yogi's body
becomes purified by the fire of yoga and he is free from illness, old
age and death."
</p><p>Another view of immortality is traced to the Vedic tradition by the interpretation of <a href="https://en.wikipedia.org/wiki/Maharishi_Mahesh_Yogi" title="Maharishi Mahesh Yogi">Maharishi Mahesh Yogi</a>:
</p>
<blockquote><p>
That man indeed whom these (contacts)<br />do not disturb, who is even-minded in<br />pleasure and pain, steadfast, he is fit<br />for immortality, O best of men.</p></blockquote>
<p>To Maharishi Mahesh Yogi, the verse means, "Once a man has become
established in the understanding of the permanent reality of life, his
mind rises above the influence of pleasure and pain. Such an unshakable
man passes beyond the influence of death and in the permanent phase of
life: he attains eternal life ... A man established in the understanding
of the unlimited abundance of absolute existence is naturally free from
existence of the relative order. This is what gives him the status of
immortal life."
</p><p>An Indian Tamil saint known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vallalar" title="Vallalar">Vallalar</a> claimed to have achieved immortality before disappearing forever from a locked room in 1874.
</p>
<h4><span class="mw-headline" id="Buddhism">Buddhism</span></h4>
<p>One of the three marks of existence in Buddhism is <a href="https://en.wikipedia.org/wiki/Anatt%C4%81" title="Anattā">anattā</a>, "non-self". This teaching states that the body does not have an eternal soul but is composed of five <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Skandhas" title="Skandhas">skandhas</a> or aggregates. Additionally, another mark of existence is impermanence, also called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anicca" title="Anicca">anicca</a>, which runs directly counter to concepts of immortality or permanence. According to one <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tibetan_Buddhist" title="Tibetan Buddhist">Tibetan Buddhist</a> teaching, <a href="https://en.wikipedia.org/wiki/Dzogchen" title="Dzogchen">Dzogchen</a>, individuals can transform the physical body into an immortal <a href="https://en.wikipedia.org/wiki/Body_of_light" title="Body of light">body of light</a> called the <a href="https://en.wikipedia.org/wiki/Rainbow_body" title="Rainbow body">rainbow body</a>.
</p>
<h3><span class="mw-headline" id="Ancient_religions">Ancient religions</span></h3><p>Within
the intricate tapestry of ancient religious ideologies, delve into a
profound contemplation of the concept of immortality. Simultaneously,
broaden the expanse of this intellectual exploration, allowing for a
more comprehensive examination of the subject matter.
</p>
<h4><span class="mw-headline" id="Ancient_Greek_religion">Ancient Greek religion</span></h4><p>Immortality in <a href="https://en.wikipedia.org/wiki/Ancient_Greek_religion" title="Ancient Greek religion">ancient Greek religion</a> originally always included an eternal union of body and soul as can be seen in <a href="https://en.wikipedia.org/wiki/Homer" title="Homer">Homer</a>, <a href="https://en.wikipedia.org/wiki/Hesiod" title="Hesiod">Hesiod</a>,
and various other ancient texts. The soul was considered to have an
eternal existence in Hades, but without the body the soul was considered
dead. Although almost everybody had nothing to look forward to but an
eternal existence as a disembodied dead soul, a number of men and women
were considered to have gained physical immortality and been brought to
live forever in either <a href="https://en.wikipedia.org/wiki/Elysium" title="Elysium">Elysium</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Islands_of_the_Blessed" title="Islands of the Blessed">Islands of the Blessed</a>, heaven, the ocean or literally right under the ground.
Among those humans made immortal were <a href="https://en.wikipedia.org/wiki/Amphiaraus" title="Amphiaraus">Amphiaraus</a>, <a href="https://en.wikipedia.org/wiki/Ganymede_(mythology)" title="Ganymede (mythology)">Ganymede</a>, <a href="https://en.wikipedia.org/wiki/Ino_(Greek_mythology)" title="Ino (Greek mythology)">Ino</a>, <a href="https://en.wikipedia.org/wiki/Iphigenia" title="Iphigenia">Iphigenia</a>, <a href="https://en.wikipedia.org/wiki/Menelaus" title="Menelaus">Menelaus</a>, <a href="https://en.wikipedia.org/wiki/Peleus" title="Peleus">Peleus</a>, and a great number of those who fought in the Trojan and Theban wars. <a href="https://en.wikipedia.org/wiki/Asclepius" title="Asclepius">Asclepius</a> was killed by Zeus, and by <a href="https://en.wikipedia.org/wiki/Apollo" title="Apollo">Apollo</a>'s request, was subsequently immortalized as a star.
</p><p>In <a href="https://en.wikipedia.org/wiki/Ancient_Greek_religion" title="Ancient Greek religion">ancient Greek religion</a> a number of men and women have been interpreted as being resurrected and made <a href="https://en.wikipedia.org/wiki/Immortality#Ancient_Greek_religion">immortal</a>. <a href="https://en.wikipedia.org/wiki/Achilles" title="Achilles">Achilles</a>, after being killed, was snatched from his funeral pyre by his divine mother <a href="https://en.wikipedia.org/wiki/Thetis" title="Thetis">Thetis</a> and brought to an immortal existence in either Leuce, the <a href="https://en.wikipedia.org/wiki/Elysium" title="Elysium">Elysian plains</a> or the <a href="https://en.wikipedia.org/wiki/Fortunate_Isles" title="Fortunate Isles">Islands of the Blessed</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Memnon_(mythology)" title="Memnon (mythology)">Memnon</a>, who was killed by Achilles, seems to have received a similar fate. <a href="https://en.wikipedia.org/wiki/Alcmene" title="Alcmene">Alcmene</a>, <a href="https://en.wikipedia.org/wiki/Castor_and_Pollux" title="Castor and Pollux">Castor</a>, <a href="https://en.wikipedia.org/wiki/Heracles" title="Heracles">Heracles</a>, and <a href="https://en.wikipedia.org/wiki/Melicertes" title="Melicertes">Melicertes</a>, are also among the figures interpreted to have been resurrected to physical immortality. According to <a href="https://en.wikipedia.org/wiki/Herodotus" title="Herodotus">Herodotus</a>'s <a href="https://en.wikipedia.org/wiki/Histories_(Herodotus)" title="Histories (Herodotus)"><i>Histories</i></a>, the seventh century BC sage <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aristeas_of_Proconnesus" title="Aristeas of Proconnesus">Aristeas of Proconnesus</a> was first found dead, after which his body disappeared from a locked room. He would reappear alive years later.
However, Greek attitudes towards resurrection were generally negative,
and the idea of resurrection was considered neither desirable nor
possible. For example, <a href="https://en.wikipedia.org/wiki/Asclepius" title="Asclepius">Asclepius</a> was killed by Zeus for using herbs to resurrect the dead, but by his father <a href="https://en.wikipedia.org/wiki/Apollo" title="Apollo">Apollo</a>'s request, was subsequently immortalized as a star.
</p><p>Writing his <i>Lives of Illustrious Men</i> (<a href="https://en.wikipedia.org/wiki/Parallel_Lives" title="Parallel Lives">Parallel Lives</a>) in the first century, the <a href="https://en.wikipedia.org/wiki/Middle_Platonism" title="Middle Platonism">Middle Platonic</a> philosopher <a href="https://en.wikipedia.org/wiki/Plutarch" title="Plutarch">Plutarch</a> in his chapter on <a href="https://en.wikipedia.org/wiki/Romulus" title="Romulus">Romulus</a>
gave an account of the king's mysterious disappearance and subsequent
deification, comparing it to Greek tales such as the physical
immortalization of Alcmene and Aristeas the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proconnesian" title="Proconnesian">Proconnesian</a>,
"for they say Aristeas died in a fuller's work-shop, and his friends
coming to look for him, found his body vanished; and that some presently
after, coming from abroad, said they met him traveling towards Croton".
Plutarch openly scorned such beliefs held in ancient Greek religion,
writing, "many such improbabilities do your fabulous writers relate,
deifying creatures naturally mortal."
Likewise, he writes that while something within humans comes from the
gods and returns to them after death, this happens "only when it is most
completely separated and set free from the body, and becomes altogether
pure, fleshless, and undefiled."
</p><p>The parallel between these traditional beliefs and the later resurrection of Jesus was not lost on early Christians, as <a href="https://en.wikipedia.org/wiki/Justin_Martyr" title="Justin Martyr">Justin Martyr</a> argued:
</p>
<dl><dd>"when we say ... Jesus Christ, our teacher, was crucified and
died, and rose again, and ascended into heaven, we propose nothing
different from what you believe regarding those whom you consider sons
of Zeus."</dd></dl>
<p>The philosophical idea of an immortal soul was a belief first appearing with either <a href="https://en.wikipedia.org/wiki/Pherecydes_of_Syros" title="Pherecydes of Syros">Pherecydes</a> or the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Orphics" title="Orphics">Orphics</a>, and most importantly advocated by <a href="https://en.wikipedia.org/wiki/Plato" title="Plato">Plato</a>
and his followers. This, however, never became the general norm in
Hellenistic thought. As may be witnessed even into the Christian era,
not least by the complaints of various philosophers over popular
beliefs, many or perhaps most traditional Greeks maintained the
conviction that certain individuals were resurrected from the dead and
made physically immortal and that others could only look forward to an
existence as disembodied and dead, though everlasting, souls.
</p>
<h4><span class="mw-headline" id="Zoroastrianism">Zoroastrianism</span></h4><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Zoroastrian" title="Zoroastrian">Zoroastrians</a>
believe that on the fourth day after death, the human soul leaves the
body and the body remains as an empty shell. Souls would go to either
heaven or hell; these concepts of the afterlife in Zoroastrianism may
have influenced Abrahamic religions. The Persian word for "immortal" is
associated with the month "Amurdad", meaning "deathless" in Persian, in
the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Iranian_calendar" title="Iranian calendar">Iranian calendar</a> (near the end of July). The month of Amurdad or <a href="https://en.wikipedia.org/wiki/Ameretat" title="Ameretat">Ameretat</a>
is celebrated in Persian culture as ancient Persians believed the
"Angel of Immortality" won over the "Angel of Death" in this month.
</p>
<h3><span class="mw-headline" id="Philosophical_religions">Philosophical religions</span></h3><p>Within
the realm of philosophical religious paradigms, engage in a profound
exploration of the concept of immortality. Simultaneously, expand the
breadth and depth of this intellectual inquiry to afford a more
intricate examination of the subject matter.
</p>
<h4><span class="mw-headline" id="Taoism">Taoism</span></h4><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Chinese_alchemy" title="Chinese alchemy">Chinese alchemy</a>, <a href="https://en.wikipedia.org/wiki/Taoism_and_death" title="Taoism and death">Taoism and death</a>, and <a href="https://en.wikipedia.org/wiki/Xian_(Taoism)" title="Xian (Taoism)">Xian (Taoism)</a></div>
<p>It is repeatedly stated in the <i><a href="https://en.wikipedia.org/wiki/L%C3%BCshi_Chunqiu" title="Lüshi Chunqiu">Lüshi Chunqiu</a></i> that death is unavoidable. <a href="https://en.wikipedia.org/wiki/Henri_Maspero" title="Henri Maspero">Henri Maspero</a> noted that many scholarly works frame Taoism as a school of thought focused on the quest for immortality. Isabelle Robinet asserts that Taoism is better understood as a <i>way of life</i> than as a religion, and that its adherents do not approach or view Taoism the way non-Taoist historians have done.
In the Tractate of Actions and their Retributions, a traditional
teaching, spiritual immortality can be rewarded to people who do a
certain amount of good deeds and live a simple, pure life. A list of
good deeds and sins are tallied to determine whether or not a mortal is
worthy. Spiritual immortality in this definition allows the soul to
leave the earthly realms of afterlife and go to pure realms in the
Taoist cosmology.
</p>
<h2><span class="mw-headline" id="Philosophical_arguments_for_the_immortality_of_the_soul">Philosophical arguments for the immortality of the soul</span></h2><h3><span class="mw-headline" id="Alcmaeon_of_Croton">Alcmaeon of Croton</span></h3><p><a href="https://en.wikipedia.org/wiki/Alcmaeon_of_Croton" title="Alcmaeon of Croton">Alcmaeon of Croton</a>
argued that the soul is continuously and ceaselessly in motion. The
exact form of his argument is unclear, but it appears to have influenced
Plato, Aristotle, and other later writers.
</p>
<h3><span class="mw-headline" id="Plato">Plato</span></h3><p><a href="https://en.wikipedia.org/wiki/Plato" title="Plato">Plato</a>'s <i><a href="https://en.wikipedia.org/wiki/Phaedo" title="Phaedo">Phaedo</a></i> advances four arguments for the soul's immortality:
</p>
<ul><li>The <a href="https://en.wikipedia.org/wiki/Phaedo#The_Cyclical_Argument" title="Phaedo">Cyclical Argument</a>, or Opposites Argument explains that <a href="https://en.wikipedia.org/wiki/Theory_of_forms" title="Theory of forms">Forms</a>
are eternal and unchanging, and as the soul always brings life, then it
must not die, and is necessarily "imperishable". As the body is mortal
and is subject to physical death, the soul must be its indestructible
opposite. Plato then suggests the analogy of fire and cold. If the form
of cold is imperishable, and fire, its opposite, was within close
proximity, it would have to withdraw intact as does the soul during
death. This could be likened to the idea of the opposite charges of
magnets.</li><li>The <a href="https://en.wikipedia.org/wiki/Anamnesis_(philosophy)" title="Anamnesis (philosophy)">Theory of Recollection</a>
explains that we possess some non-empirical knowledge (e.g. The Form of
Equality) at birth, implying the soul existed before birth to carry
that knowledge. Another account of the theory is found in Plato's <i><a href="https://en.wikipedia.org/wiki/Meno" title="Meno">Meno</a></i>, although in that case Socrates implies anamnesis (previous knowledge of everything) whereas he is not so bold in <i>Phaedo</i>.</li><li>The <a href="https://en.wikipedia.org/wiki/Phaedo#The_Affinity_Argument" title="Phaedo">Affinity Argument</a>,
explains that invisible, immortal, and incorporeal things are different
from visible, mortal, and corporeal things. Our soul is of the former,
while our body is of the latter, so when our bodies die and decay, our
soul will continue to live.</li><li>The <a href="https://en.wikipedia.org/wiki/Phaedo#The_Argument_from_Form_of_Life" title="Phaedo">Argument from Form of Life</a>
or The Final Argument explains that the Forms, incorporeal and static
entities, are the cause of all things in the world, and all things
participate in Forms. For example, beautiful things participate in the
Form of Beauty; the number four participates in the Form of the Even,
etc. The soul, by its very nature, participates in the Form of Life,
which means the soul can never die.</li></ul>
<h3><span class="mw-headline" id="Plotinus">Plotinus</span></h3><p><a href="https://en.wikipedia.org/wiki/Plotinus" title="Plotinus">Plotinus</a>
offers a version of the argument that Kant calls "The Achilles of
Rationalist Psychology". Plotinus first argues that the soul is <a href="https://en.wikipedia.org/wiki/Simple_(philosophy)" title="Simple (philosophy)">simple</a>,
then notes that a simple being cannot decompose. Many subsequent
philosophers have argued both that the soul is simple and that it must
be immortal. The tradition arguably culminates with <a href="https://en.wikipedia.org/wiki/Moses_Mendelssohn" title="Moses Mendelssohn">Moses Mendelssohn</a>'s <a href="https://en.wikipedia.org/wiki/Phaedon" title="Phaedon">Phaedon</a>.
</p>
<h3><span class="mw-headline" id="Metochites">Metochites</span></h3><p><a href="https://en.wikipedia.org/wiki/Theodore_Metochites" title="Theodore Metochites">Theodore Metochites</a>
argues that part of the soul's nature is to move itself, but that a
given movement will cease only if what causes the movement is separated
from the thing moved – an impossibility if they are one and the same.
</p>
<h3><span class="mw-headline" id="Avicenna">Avicenna</span></h3><p><a href="https://en.wikipedia.org/wiki/Avicenna" title="Avicenna">Avicenna</a> argued for the distinctness of the soul and the body, and the incorruptibility of the former.
</p>
<h3><span class="mw-headline" id="Aquinas">Aquinas</span></h3><p>The full argument for the immortality of the soul and <a href="https://en.wikipedia.org/wiki/Thomas_Aquinas" title="Thomas Aquinas">Thomas Aquinas</a>' elaboration of Aristotelian theory is found in Question 75 of the First Part of the <i><a href="https://en.wikipedia.org/wiki/Summa_Theologica" title="Summa Theologica">Summa Theologica</a></i>.
</p>
<h3><span class="mw-headline" id="Descartes">Descartes</span></h3><p><a href="https://en.wikipedia.org/wiki/Ren%C3%A9_Descartes" title="René Descartes">René Descartes</a>
endorses the claim that the soul is simple, and also that this entails
that it cannot decompose. Descartes does not address the possibility
that the soul might suddenly disappear.
</p>
<h3><span class="mw-headline" id="Leibniz">Leibniz</span></h3><p>In early work, <a href="https://en.wikipedia.org/wiki/Gottfried_Wilhelm_Leibniz" title="Gottfried Wilhelm Leibniz">Gottfried Wilhelm Leibniz</a>
endorses a version of the argument from the simplicity of the soul to
its immortality, but like his predecessors, he does not address the
possibility that the soul might suddenly disappear. In his <a href="https://en.wikipedia.org/wiki/Monadology" title="Monadology">monadology</a> he advances a sophisticated novel argument for the immortality of monads.
</p>
<h3><span class="mw-headline" id="Moses_Mendelssohn">Moses Mendelssohn</span></h3><p><a href="https://en.wikipedia.org/wiki/Moses_Mendelssohn" title="Moses Mendelssohn">Moses Mendelssohn</a>'s <i><a href="https://en.wikipedia.org/wiki/Phaedon" title="Phaedon">Phaedon</a></i>
is a defense of the simplicity and immortality of the soul. It is a
series of three dialogues, revisiting the Platonic dialogue <i><a href="https://en.wikipedia.org/wiki/Phaedo" title="Phaedo">Phaedo</a></i>, in which <a href="https://en.wikipedia.org/wiki/Socrates" title="Socrates">Socrates</a>
argues for the immortality of the soul, in preparation for his own
death. Many philosophers, including Plotinus, Descartes, and Leibniz,
argue that the soul is simple, and that because simples cannot decompose
they must be immortal. In the Phaedon, Mendelssohn addresses gaps in
earlier versions of this argument (an argument that Kant calls the
Achilles of Rationalist Psychology). The Phaedon contains an original
argument for the simplicity of the soul, and also an original argument
that simples cannot suddenly disappear. It contains further original
arguments that the soul must retain its rational capacities as long as
it exists.
</p>
<h2><span class="mw-headline" id="Ethics">Ethics</span></h2><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Life_extension#Ethics_and_politics" title="Life extension">Life extension § Ethics and politics</a></div>
<p>The possibility of clinical immortality raises a host of medical,
philosophical, and religious issues and ethical questions. These include
<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Persistent_vegetative_state" title="Persistent vegetative state">persistent vegetative states</a>, the nature of personality over time, technology to mimic or copy the mind or its processes, <a href="https://en.wikipedia.org/wiki/Human_enhancement#Inequality_and_Social_Disruption" title="Human enhancement">social and economic</a> disparities created by <a href="https://en.wikipedia.org/wiki/Longevity" title="Longevity">longevity</a>, and survival of the <a href="https://en.wikipedia.org/wiki/Heat_death_of_the_universe" title="Heat death of the universe">heat death of the universe</a>.
</p>
<h3><span class="mw-headline" id="Undesirability">Undesirability</span></h3><p>Physical immortality has also been imagined as a form of eternal torment, as in the myth of <a href="https://en.wikipedia.org/wiki/Tithonus" title="Tithonus">Tithonus</a>, or in <a href="https://en.wikipedia.org/wiki/Mary_Shelley" title="Mary Shelley">Mary Shelley</a>'s short story <i><a href="https://en.wikipedia.org/wiki/The_Mortal_Immortal" title="The Mortal Immortal">The Mortal Immortal</a></i>, where the protagonist lives to witness everyone he cares about die around him. For additional examples in fiction, see <a href="https://en.wikipedia.org/wiki/Immortality_in_fiction" title="Immortality in fiction">Immortality in fiction</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Shelly_Kagan" title="Shelly Kagan">Kagan</a> (2012)
argues that any form of human immortality would be undesirable. Kagan's
argument takes the form of a dilemma. Either our characters remain
essentially the same in an immortal afterlife, or they do not:
</p>
<ul><li>If our characters remain basically the same – that is, if we
retain more or less the desires, interests, and goals that we have now –
then eventually, over an infinite stretch of time, we will get bored
and find eternal life unbearably tedious.</li><li>If, on the other hand, our characters are radically changed – e.g.,
by God periodically erasing our memories or giving us rat-like brains
that never tire of certain simple pleasures – then such a person would
be too different from our current self for us to care much what happens
to them.</li></ul>
<p>Either way, Kagan argues, immortality is unattractive. The best
outcome, Kagan argues, would be for humans to live as long as they
desired and then to accept death gratefully as rescuing us from the
unbearable tedium of immortality.
</p>
<h2><span class="mw-headline" id="Sociology">Sociology</span></h2><p>If human beings were to achieve immortality, there would most likely be a change in the world's <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Social_structures" title="Social structures">social structures</a>. Sociologists argue that human beings' awareness of their own <a class="extiw" href="https://en.wiktionary.org/wiki/mortality" title="wikt:mortality">mortality</a> shapes their behavior.
With the advancements in medical technology in extending human life,
there may need to be serious considerations made about future social
structures. The world is already experiencing a global <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Demographic_shift" title="Demographic shift">demographic shift</a> of increasingly ageing populations with lower replacement rates.
The social changes that are made to accommodate this new population
shift may be able to offer insight on the possibility of an immortal
society.
</p><p>Sociology has a growing body of literature on the sociology of
immortality, which details the different attempts at reaching
immortality (whether actual or symbolic) and their prominence in the
21st century. These attempts include renewed attention to the dead in
the West, practices of online memorialization, and biomedical attempts to increase longevity.
These attempts at reaching immortality and their effects in societal
structures have led some to argue that we are becoming a "Postmortal
Society".<sup> </sup>Foreseen changes to societies derived from the pursuit of immortality
would encompass societal paradigms and worldviews, as well as the
institutional landscape. Similarly, different forms of reaching
immortality might entail a significant reconfiguration of societies,
from becoming more technologically oriented to becoming more aligned
with nature.
</p><p>Immortality would increase population growth, bringing with it many consequences as for example the impact of population growth on the environment and <a href="https://en.wikipedia.org/wiki/Planetary_boundaries" title="Planetary boundaries">planetary boundaries</a>.
</p>
<h2><span class="mw-headline" id="Politics">Politics</span></h2><p>Although some scientists state that radical life extension, delaying and stopping aging are achievable,
there are no international or national programs focused on stopping
aging or on radical life extension. In 2012 in Russia, and then in the
United States, Israel and the Netherlands, pro-immortality political
parties were launched. They aimed to provide political support to
anti-aging and radical life extension research and technologies and at
the same time transition to the next step, radical life extension, life
without aging, and finally, immortality and aim to make possible access
to such technologies to most currently living people.
</p><p>Some scholars critique the increasing support for immortality
projects. Panagiotis Pentaris speculates that defeating ageing as the
cause of death comes with a cost: "heightened stratification of humans
in society and a wider gap between social classes".
Others suggest that other immortality projects like transhumanist
digital immortality, radical life extension and cryonics are part of the
capitalist fabric of exploitation and control, which aims to extend privileged lives of the economic elite.
In this sense, immortality could become a political-economic
battleground for the twenty-first century between the haves and
have-nots.
</p>
<h2><span class="mw-headline" id="Symbols">Symbols</span></h2><figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Ankh-Symbol.svg"><img class="mw-file-element" data-file-height="815" data-file-width="450" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Ankh-Symbol.svg/80px-Ankh-Symbol.svg.png" width="221" /></a><figcaption>The ankh</figcaption></figure>
<p>There are numerous symbols representing immortality. The <a href="https://en.wikipedia.org/wiki/Ankh" title="Ankh">ankh</a> is an Egyptian symbol of life that holds connotations of immortality when depicted in the hands of the <a href="https://en.wikipedia.org/wiki/Category:Egyptian_deities" title="Category:Egyptian deities">gods</a> and <a href="https://en.wikipedia.org/wiki/Pharaoh" title="Pharaoh">pharaohs</a>, who were seen as having control over the journey of life. The <a href="https://en.wikipedia.org/wiki/M%C3%B6bius_strip" title="Möbius strip">Möbius strip</a> in the shape of a <a href="https://en.wikipedia.org/wiki/Trefoil_knot" title="Trefoil knot">trefoil knot</a>
is another symbol of immortality. Most symbolic representations of
infinity or the life cycle are often used to represent immortality
depending on the context they are placed in. Other examples include the <a href="https://en.wikipedia.org/wiki/Ouroboros" title="Ouroboros">Ouroboros</a>, the Chinese fungus of longevity, the <i>ten</i> <a href="https://en.wikipedia.org/wiki/Kanji" title="Kanji">kanji</a>, the <a href="https://en.wikipedia.org/wiki/Phoenix_(mythology)" title="Phoenix (mythology)">phoenix</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Peacock" title="Peacock">peacock</a> in Christianity, and the colors amaranth (in <a href="https://en.wikipedia.org/wiki/Western_culture" title="Western culture">Western culture</a>) and peach (in <a href="https://en.wikipedia.org/wiki/Chinese_culture" title="Chinese culture">Chinese culture</a>).
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-45730535989020517722024-03-28T09:02:00.005-04:002024-03-28T09:02:52.941-04:00Spinal disc herniation<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Spinal_disc_herniation">https://en.wikipedia.org/wiki/Spinal_disc_herniation</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Spinal disc herniation</th></tr><tr><th class="infobox-label" scope="row">Other names</th><td class="infobox-data">Slipped disc, bulging disc, ruptured disc, herniated disc, prolapsed disc, herniated <i>nucleus pulposus</i>, lumbar disc herniation</td></tr><tr><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Hernie_discale_L4_L5.png"><img class="mw-file-element" data-file-height="1049" data-file-width="688" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/84/Hernie_discale_L4_L5.png/220px-Hernie_discale_L4_L5.png" width="263" /></a></span></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Orthopedics" title="Orthopedics">Orthopedics</a>, <a href="https://en.wikipedia.org/wiki/Neurosurgery" title="Neurosurgery">neurosurgery</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Risk_factor" title="Risk factor">Risk factors</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Connective_tissue_disease" title="Connective tissue disease">Connective tissue disease</a></td></tr></tbody></table>
<p>A <b>spinal disc herniation</b> is an injury to the <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">intervertebral disc</a> between two spinal <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebrae" title="Vertebrae">vertebrae</a>, usually caused by excessive <a href="https://en.wikipedia.org/wiki/Strain_(injury)" title="Strain (injury)">strain</a> or trauma to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spine_(vertebral_column)" title="Spine (vertebral column)">spine</a>. It may result in <a href="https://en.wikipedia.org/wiki/Back_pain" title="Back pain">back pain</a>, pain or sensation in different parts of the body, and physical <a href="https://en.wikipedia.org/wiki/Disability" title="Disability">disability</a>. The most conclusive diagnostic tool for disc <a href="https://en.wikipedia.org/wiki/Hernia" title="Hernia">herniation</a> is <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRI" title="MRI">MRI</a>, and treatment may range from painkillers to surgery. Protection from disc herniation is best provided by <a href="https://en.wikipedia.org/wiki/Core_(anatomy)" title="Core (anatomy)">core</a> strength and an awareness of body mechanics including <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Good_posture" title="Good posture">good posture</a>.
</p><p>When a tear in the outer, fibrous ring of an intervertebral disc
allows the soft, central portion to bulge out beyond the damaged outer
rings, the disc is said to be herniated.
</p><p>Disc herniation is frequently associated with age-related degeneration of the outer ring, known as the <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Annulus_fibrosus_disci_intervertebralis" title="Annulus fibrosus disci intervertebralis">annulus fibrosus</a></i>, but is normally triggered by trauma or straining by lifting or twisting. Tears are almost always <a href="https://en.wikipedia.org/wiki/Anatomical_terms_of_location" title="Anatomical terms of location">posterolateral</a> (on the back sides) owing to relative narrowness of the <a href="https://en.wikipedia.org/wiki/Posterior_longitudinal_ligament" title="Posterior longitudinal ligament">posterior longitudinal ligament</a> relative to the <a href="https://en.wikipedia.org/wiki/Anterior_longitudinal_ligament" title="Anterior longitudinal ligament">anterior longitudinal ligament</a>. A tear in the disc ring may result in the release of chemicals causing <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a>, which can result in severe pain even in the absence of <a href="https://en.wikipedia.org/wiki/Nerve_root" title="Nerve root">nerve root</a> compression.
</p><p>Disc herniation is normally a further development of a previously existing <a href="https://en.wikipedia.org/wiki/Disc_protrusion" title="Disc protrusion">disc protrusion</a>, in which the outermost layers of the <i>annulus fibrosus</i>
are still intact, but can bulge when the disc is under pressure. In
contrast to a herniation, none of the central portion escapes beyond the
outer layers. Most minor herniations heal within several weeks.
Anti-inflammatory treatments for pain associated with disc herniation,
protrusion, bulge, or disc tear are generally effective. Severe
herniations may not heal of their own accord and may require surgery.
</p><p>The condition may be referred to as a <i>slipped disc</i>, but this term is not accurate as the spinal discs are firmly attached between the vertebrae and cannot "slip" out of place.
</p>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2></div></div></div><p>Typically, symptoms are experienced on one side of the body only.
</p><p>Symptoms of a herniated disc can vary depending on the location
of the herniation and the types of soft tissue involved. They can range
from little or no pain, if the disc is the only tissue injured, to
severe and unrelenting <a href="https://en.wikipedia.org/wiki/Neck_pain" title="Neck pain">neck pain</a> or <a href="https://en.wikipedia.org/wiki/Low_back_pain" title="Low back pain">low back pain</a>
that radiates into regions served by nerve roots which have been
irritated or impinged by the herniated material. Often, herniated discs
are not diagnosed immediately, as patients present with undefined pains
in the thighs, knees, or feet.
</p><p>Symptoms may include sensory changes such as numbness, tingling, <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">paresthesia</a>, and motor changes such as muscular weakness, paralysis, and affection of <a href="https://en.wikipedia.org/wiki/Reflex" title="Reflex">reflexes</a>. If the herniated disc is in the lumbar region, the patient may also experience <a href="https://en.wikipedia.org/wiki/Sciatica" title="Sciatica">sciatica</a> due to irritation of one of the nerve roots of the <a href="https://en.wikipedia.org/wiki/Sciatic_nerve" title="Sciatic nerve">sciatic nerve</a>.
Unlike a pulsating pain or pain that comes and goes, which can be
caused by muscle spasm, pain from a herniated disc is usually continuous
or at least continuous in a specific <a href="https://en.wikipedia.org/wiki/List_of_human_positions" title="List of human positions">position of the body</a>.
</p><p>It is possible to have a herniated disc without pain or noticeable symptoms if the extruded <i>nucleus pulposus</i>
material doesn't press on soft tissues or nerves. A small-sample study
examining the cervical spine in symptom-free volunteers found <a href="https://en.wikipedia.org/wiki/Focal_neurologic_signs" title="Focal neurologic signs">focal</a>
disc protrusions in 50% of participants, suggesting that a considerable
part of the population might have focal herniated discs in their
cervical region that do not cause noticeable symptoms.
</p><p>A herniated disc in the lumbar spine may cause radiating nerve
pain in the lower extremities or groin area and may sometimes be
associated with bowel or bladder incontinence.
</p><p>Typically, symptoms are experienced only on one side of the body,
but if a herniation is very large and presses on the nerves on both
sides within the spinal column or the <i><a href="https://en.wikipedia.org/wiki/Cauda_equina" title="Cauda equina">cauda equina</a></i>, both sides of the body may be affected, often with serious consequences. Compression of the <i>cauda equina</i>
can cause permanent nerve damage or paralysis which can result in loss
of bowel and bladder control and sexual dysfunction. This disorder is
called <a href="https://en.wikipedia.org/wiki/Cauda_equina_syndrome" title="Cauda equina syndrome">cauda equina syndrome</a>. Other complications include <a href="https://en.wikipedia.org/wiki/Chronic_pain" title="Chronic pain">chronic pain</a>.
</p>
<h2><span class="mw-headline" id="Cause">Cause</span></h2><p>When the
spine is straight, such as in standing or lying down, internal pressure
is equalized on all parts of the discs. While sitting or bending to
lift, internal pressure on a disc can move from 1.2 <a href="https://en.wikipedia.org/wiki/Bar_(unit)" title="Bar (unit)">bar</a> (17 <a href="https://en.wikipedia.org/wiki/Pound_per_square_inch" title="Pound per square inch">psi</a>) (lying down) to over 21 bar (300 psi) (lifting with a rounded back).
Herniation of the contents of the disc into the spinal canal often
occurs when the anterior side (stomach side) of the disc is compressed
while sitting or bending forward, and the contents (<i>nucleus pulposus</i>) get pressed against the tightly stretched and thinned membrane (<i>annulus fibrosus</i>)
on the posterior side (back side) of the disc. The combination of
membrane-thinning from stretching and increased internal pressure (14 to
21 bar (200 to 300 psi)) can result in the rupture of the confining
membrane. The jelly-like contents of the disc then move into the spinal
canal, pressing against the spinal nerves, which may produce intense and
potentially disabling pain and other symptoms.
</p><p>Some authors favour degeneration of the intervertebral disc as
the major cause of spinal disc herniation and cite trauma as a minor
cause. Disc degeneration occurs both in <a href="https://en.wikipedia.org/wiki/Degenerative_disc_disease" title="Degenerative disc disease">degenerative disc disease</a> and aging. With degeneration, the disc components – the <i>nucleus pulposus</i> and <i>annulus fibrosus</i>
– become exposed to altered loads. Specifically, the nucleus becomes
fibrous and stiff and less able to bear load. Excess load is transferred
to the <i>annulus</i>, which may then develop fissures as a result. If the fissures reach the periphery of the <i>annulus</i>, the nuclear material can pass through as a disc herniation.
</p><p>Mutations in several genes have been implicated in intervertebral disc degeneration. Probable candidate genes include <a href="https://en.wikipedia.org/wiki/Type_I_collagen" title="Type I collagen">type I collagen</a> (sp1 site), <a href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">type IX collagen</a>, <a href="https://en.wikipedia.org/wiki/Vitamin_D_receptor" title="Vitamin D receptor">vitamin D receptor</a>, <a href="https://en.wikipedia.org/wiki/Aggrecan" title="Aggrecan">aggrecan</a>, <a href="https://en.wikipedia.org/wiki/Asporin" title="Asporin">asporin</a>, <a href="https://en.wikipedia.org/wiki/MMP3" title="MMP3">MMP3</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interleukin-1" title="Interleukin-1">interleukin-1</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interleukin-6" title="Interleukin-6">interleukin-6</a> <a href="https://en.wikipedia.org/wiki/Gene_polymorphism" title="Gene polymorphism">polymorphisms</a>. Mutation in genes – such as <a href="https://en.wikipedia.org/wiki/MMP2" title="MMP2">MMP2</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/THBS2" title="THBS2">THBS2</a>
– that encode for proteins and enzymes involved in the regulation of
the extracellular matrix has been shown to contribute to lumbar disc
herniation.
</p><p>Disc herniations can result from general wear and tear, such as weightlifting training, constant sitting or squatting, driving, or a sedentary lifestyle. Herniations can also result from the lifting of heavy loads.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Professional_athlete" title="Professional athlete">Professional athletes</a>, especially those playing <a href="https://en.wikipedia.org/wiki/Contact_sport" title="Contact sport">contact sports</a>, such as <a href="https://en.wikipedia.org/wiki/American_football" title="American football">American football</a>, <a href="https://en.wikipedia.org/wiki/Rugby_football" title="Rugby football">Rugby</a>, <a href="https://en.wikipedia.org/wiki/Ice_hockey" title="Ice hockey">ice hockey</a>, and <a href="https://en.wikipedia.org/wiki/Wrestling" title="Wrestling">wrestling</a>,
are known to be prone to disc herniations as well as some limited
contact sports that require repetitive flexion and compression such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Soccer" title="Soccer">soccer</a>, <a href="https://en.wikipedia.org/wiki/Baseball" title="Baseball">baseball</a>, <a href="https://en.wikipedia.org/wiki/Basketball" title="Basketball">basketball</a>, and <a href="https://en.wikipedia.org/wiki/Volleyball" title="Volleyball">volleyball</a>.
Within athletic contexts, herniation is often the result of sudden
blunt impacts against, or abrupt bending or torsional movements of, the
lower back.
</p>
<h2><span class="mw-headline" id="Pathophysiology">Pathophysiology</span></h2><p>The majority of spinal disc herniations occur in the <a href="https://en.wikipedia.org/wiki/Lumbar_vertebrae" title="Lumbar vertebrae">lumbar</a> spine (95% at L4–L5 or L5–S1). The second most common site is the <a href="https://en.wikipedia.org/wiki/Cervical_vertebrae" title="Cervical vertebrae">cervical</a> region (C5–C6, C6–C7). The <a href="https://en.wikipedia.org/wiki/Thoracic_vertebrae" title="Thoracic vertebrae">thoracic</a> region accounts for only 1–2% of cases. Herniations usually occur postero-laterally, at the points where the <i>annulus fibrosus</i> is relatively thin and is not reinforced by the posterior or anterior longitudinal ligament.
In the cervical spine, a symptomatic postero-lateral herniation between
two vertebrae will impinge on the nerve which exits the spinal canal
between those two vertebrae on that side.
So, for example, a right postero-lateral herniation of the disc between
vertebrae C5 and C6 will impinge on the right C6 spinal nerve. The rest
of the spinal cord, however, is oriented differently, so a symptomatic
postero-lateral herniation between two vertebrae will impinge on the
nerve exiting at the next intervertebral level down.
</p>
<p><span class="anchor" id="lumbar"></span> </p><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Blausen_0484_HerniatedLumbarDisc.png"><img class="mw-file-element" data-file-height="1500" data-file-width="1500" height="220" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/da/Blausen_0484_HerniatedLumbarDisc.png/220px-Blausen_0484_HerniatedLumbarDisc.png" width="220" /></a><figcaption>Herniated lumbar disc</figcaption></figure>
<p>Lumbar disc herniations occur in the back, most often between the
fourth and fifth lumbar vertebral bodies or between the fifth and the <a href="https://en.wikipedia.org/wiki/Sacrum" title="Sacrum">sacrum</a>. Here, symptoms can be felt in the lower back, <a href="https://en.wikipedia.org/wiki/Buttocks" title="Buttocks">buttocks</a>, <a href="https://en.wikipedia.org/wiki/Thigh" title="Thigh">thigh</a>, <a href="https://en.wikipedia.org/wiki/Perineum" title="Perineum">anal/genital region</a> (via the <a href="https://en.wikipedia.org/wiki/Perineal_nerve" title="Perineal nerve">perineal nerve</a>), and may radiate into the foot and/or <a href="https://en.wikipedia.org/wiki/Toe" title="Toe">toe</a>. The <a href="https://en.wikipedia.org/wiki/Sciatic_nerve" title="Sciatic nerve">sciatic nerve</a> is the most commonly affected nerve, causing symptoms of <a href="https://en.wikipedia.org/wiki/Sciatica" title="Sciatica">sciatica</a>. The <a href="https://en.wikipedia.org/wiki/Femoral_nerve" title="Femoral nerve">femoral nerve</a>
can also be affected and cause the patient to experience a numb,
tingling feeling throughout one or both legs and even feet or a burning
feeling in the hips and legs.
A herniation in the lumbar region often compresses the nerve root
exiting at the level below the disc. Thus, a herniation of the L4–5 disc
compresses the L5 nerve root, only if the herniation is posterolateral.
</p>
<h3><span class="mw-headline" id="Cervical_disc_herniation">Cervical disc herniation</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:06_Cervical_MRI_scan_R_T1WFSE_G_T2WfrFSE_STIR_B.jpg"><img class="mw-file-element" data-file-height="512" data-file-width="512" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/5a/06_Cervical_MRI_scan_R_T1WFSE_G_T2WfrFSE_STIR_B.jpg/220px-06_Cervical_MRI_scan_R_T1WFSE_G_T2WfrFSE_STIR_B.jpg" width="400" /></a><figcaption>Herniated disc at C6–C7 level</figcaption></figure>
<p>Cervical disc herniations occur in the neck, most often between the
fifth and sixth (C5–6) and the sixth and seventh (C6–7) cervical
vertebral bodies. There is an increased susceptibility amongst older
(60+) patients to herniations higher in the neck, especially at C3–4. Symptoms of cervical herniations may be felt in the back of the skull, the neck, shoulder girdle, <a href="https://en.wikipedia.org/wiki/Scapula" title="Scapula">scapula</a>, arm, and hand. The nerves of the <a href="https://en.wikipedia.org/wiki/Cervical_plexus" title="Cervical plexus">cervical plexus</a> and <a href="https://en.wikipedia.org/wiki/Brachial_plexus" title="Brachial plexus">brachial plexus</a> can be affected.
</p>
<h3><span class="mw-headline" id="Intradural_disc_herniation">Intradural disc herniation</span></h3><p>Intradural
disc herniation is a rare form of disc herniation with an incidence of
0.2–2.2%. Pre-operative imaging can be helpful for diagnosis, but
intra-operative findings are required for confirmation.
</p>
<h3><span class="mw-headline" id="Inflammation">Inflammation</span></h3><p>It
is increasingly recognized that back pain resulting from disc
herniation is not always due solely to compression of the spinal cord or
nerve roots, but may also be caused by chemical inflammation.<sup> </sup>There is evidence that points to a specific inflammatory mediator in back pain: an inflammatory molecule, called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha" title="Tumor necrosis factor alpha">tumor necrosis factor alpha</a> (TNF), is released not only by a herniated disc, but also in cases of disc tear (<i>annulus</i> tear) by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Facet_joints" title="Facet joints">facet joints</a>, and in <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>. In addition to causing pain and inflammation, TNF may contribute to disc degeneration.
</p>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><h3><span class="mw-headline" id="Terminology">Terminology</span></h3><p>Terms commonly used to describe the condition include <i>herniated disc</i>, <i>prolapsed disc</i>, <i>ruptured disc</i>, and <i>slipped disc</i>. Other conditions that are closely related include <a href="https://en.wikipedia.org/wiki/Disc_protrusion" title="Disc protrusion">disc protrusion</a>, <a href="https://en.wikipedia.org/wiki/Radiculopathy" title="Radiculopathy">radiculopathy</a> (pinched nerve), <a href="https://en.wikipedia.org/wiki/Sciatica" title="Sciatica">sciatica</a>, disc disease, disc degeneration, <a href="https://en.wikipedia.org/wiki/Degenerative_disc_disease" title="Degenerative disc disease">degenerative disc disease</a>, and black disc (a totally degenerated spinal disc).
</p><p>The popular term <i>slipped disc</i> is a misnomer, as the
intervertebral discs are tightly sandwiched between two vertebrae to
which they are attached, and cannot actually "slip", or even get out of
place. The disc is actually grown together with the adjacent vertebrae
and can be squeezed, stretched and twisted, all in small degrees. It can
also be torn, ripped, herniated, and degenerated, but it cannot "slip". Some authors consider that the term <i>slipped disc</i> is harmful, as it leads to an incorrect idea of what has occurred and thus of the likely outcome. However, during growth, one vertebral body can slip relative to an adjacent vertebral body, a deformity called <a href="https://en.wikipedia.org/wiki/Spondylolisthesis" title="Spondylolisthesis">spondylolisthesis</a>.
</p><p>Spinal disc herniation is known in Latin as <i>prolapsus disci intervertebralis</i>.
</p>
<dl><dt></dt></dl>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Lumbar_Disc_Lesions_Classification.jpg" title="Lumbar disc lesions, classification"><img alt="Lumbar disc lesions, classification" class="mw-file-element" data-file-height="503" data-file-width="467" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Lumbar_Disc_Lesions_Classification.jpg/111px-Lumbar_Disc_Lesions_Classification.jpg" width="370" /></a></span></div>
<div class="gallerytext">Lumbar disc lesions, classification</div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:ACDF_coronal_english.png" title="Normal situation and spinal disc herniation in cervical vertebrae"><img alt="Normal situation and spinal disc herniation in cervical vertebrae" class="mw-file-element" data-file-height="1394" data-file-width="3256" height="170" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/ACDF_coronal_english.png/120px-ACDF_coronal_english.png" width="400" /></a></span></div>
<div class="gallerytext">Normal situation and spinal disc herniation in cervical vertebrae</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Herniated_Disc.png" title="Illustration depicting herniated disc and spinal nerve compression"><img alt="Illustration depicting herniated disc and spinal nerve compression" class="mw-file-element" data-file-height="1024" data-file-width="768" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/35/Herniated_Disc.png/90px-Herniated_Disc.png" width="300" /></a></span></div>
<div class="gallerytext">Illustration depicting herniated disc and spinal nerve compression</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Disc_prolapse.png" title="Nucleus herniating through tear in annulus (with MRI)[9]"><img alt="Nucleus herniating through tear in annulus (with MRI)[9]" class="mw-file-element" data-file-height="409" data-file-width="399" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Disc_prolapse.png/117px-Disc_prolapse.png" width="390" /></a></span></div>
<div class="gallerytext">Nucleus herniating through tear in <i>annulus</i> (with MRI)</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Disc_herniation_-_Degeneration_Prolapse_Extrusion_Sequestration_--_Smart-Servier.jpg" title="Illustration showing disc degeneration, prolapse, extrusion and sequestration"><img alt="Illustration showing disc degeneration, prolapse, extrusion and sequestration" class="mw-file-element" data-file-height="5760" data-file-width="10240" height="227" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a1/Disc_herniation_-_Degeneration_Prolapse_Extrusion_Sequestration_--_Smart-Servier.jpg/120px-Disc_herniation_-_Degeneration_Prolapse_Extrusion_Sequestration_--_Smart-Servier.jpg" width="400" /></a></span></div>
<div class="gallerytext">Illustration showing disc degeneration, prolapse, extrusion and sequestration</div>
</li></ul>
<h3><span class="mw-headline" id="Physical_examination">Physical examination</span></h3><p>Diagnosis of spinal disc herniation is made by a practitioner on the basis of a patient's history and symptoms, and by <a href="https://en.wikipedia.org/wiki/Physical_examination" title="Physical examination">physical examination</a>.
During an evaluation, tests may be performed to confirm or rule out
other possible causes with similar symptoms – spondylolisthesis,
degeneration, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumor" title="Tumor">tumors</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Metastases" title="Metastases">metastases</a> and space-occupying <a href="https://en.wikipedia.org/wiki/Lesion" title="Lesion">lesions</a>, for instance – as well as to evaluate the efficacy of potential treatment options.
</p>
<h4><span class="mw-headline" id="Straight_leg_raise">Straight leg raise</span></h4><p>The <a href="https://en.wikipedia.org/wiki/Straight_leg_raise" title="Straight leg raise">straight leg raise</a>
is often used as a preliminary test for possible disc herniation in the
lumbar region. A variation is to lift the leg while the patient is
sitting. However, this reduces the <a href="https://en.wikipedia.org/wiki/Sensitivity_and_specificity" title="Sensitivity and specificity">sensitivity</a> of the test.
A Cochrane review published in 2010 found that individual diagnostic
tests including the straight leg raising test, absence of tendon
reflexes, or muscle weakness were not very accurate when conducted in
isolation.
</p>
<h4><span class="mw-headline" id="Spinal_imaging">Spinal imaging</span></h4><ul><li><a href="https://en.wikipedia.org/wiki/Projectional_radiography" title="Projectional radiography">Projectional radiography</a>
(X-ray imaging). Traditional plain X-rays are limited in their ability
to image soft tissues such as discs, muscles, and nerves, but they are
still used to confirm or exclude other possibilities such as tumors,
infections, fractures, etc. In spite of their limitations, X-rays play a
relatively inexpensive role in confirming the suspicion of the presence
of a herniated disc. If a suspicion is thus strengthened, other methods
may be used to provide final confirmation.</li></ul>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:L5S1_prolapsed_intervertibral_disc_PID.jpg" title="Narrowed space between L5 and S1 vertebrae, indicating probable prolapsed intervertebral disc – a classic picture"><img alt="Narrowed space between L5 and S1 vertebrae, indicating probable prolapsed intervertebral disc – a classic picture" class="mw-file-element" data-file-height="1600" data-file-width="1200" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b3/L5S1_prolapsed_intervertibral_disc_PID.jpg/90px-L5S1_prolapsed_intervertibral_disc_PID.jpg" width="300" /></a></span></div>
<div class="gallerytext">Narrowed space between L5 and S1 vertebrae, indicating probable prolapsed intervertebral disc – a classic picture</div>
</li></ul>
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Computed_tomography" title="Computed tomography">Computed tomographyscan</a>
is the most sensitive imaging modality to examine the bony structures
of the spine. CT imaging allows for the evaluation of calcified
herniated discs or any pathological process that may result in bone loss
or destruction. It is deficient for the visualization of nerve roots,
making it unsuitable in the diagnoses of radiculopathy.</li><li><a href="https://en.wikipedia.org/wiki/Magnetic_resonance_imaging" title="Magnetic resonance imaging">Magnetic resonance imaging</a>
is the gold standard study for confirming a suspected LDH. With a
diagnostic accuracy of 97%, it is the most sensitive study to visualize a
herniated disc due to its significant ability in soft tissue
visualization. MRI also has higher inter-observer reliability than other
imaging modalities. It suggests disc herniation when it shows an
increased T2-weighted signal at the posterior 10% of the disc.
Degenerative disc diseases have shown a correlation with Modic type 1
changes. When evaluating for postoperative lumbar radiculopathies, the
recommendation is that the MRI is performed with contrast unless
otherwise contraindicated. MRI is more effective than CT in
distinguishing inflammatory, malignant, or inflammatory etiologies of
LDH. It is indicated relatively early in the course of evaluation (<8
weeks) when the patient presents with relative indications like
significant pain, neurological motor deficits, and cauda equina
syndrome. Diffusion tensor imaging is a type of MRI sequence used for
detecting microstructural changes in the nerve root. It may be
beneficial in understanding the changes that occur after herniated
lumbar disc compresses a nerve root, and might help in differentiating
the patients that need surgical intervention. In patients with a high
suspicion of radiculopathy due to lumbar disc herniation, yet the MRI is
equivocal or negative, nerve conduction studies are indicated. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/MRI#T1_and_T2" title="MRI">T2</a>-weighted images allow for clear visualization of protruded disc material in the spinal canal.</li></ul>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:C5-C6-herniation.jpg" title="MRI scan of cervical disc herniation between C5 and C6 vertebrae"><img alt="MRI scan of cervical disc herniation between C5 and C6 vertebrae" class="mw-file-element" data-file-height="1133" data-file-width="1024" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/58/C5-C6-herniation.jpg/108px-C5-C6-herniation.jpg" width="360" /></a></span></div>
<div class="gallerytext">MRI scan of cervical disc herniation between C5 and C6 vertebrae</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:C6-C7-disc-herniation-cevical-mri-scan.jpg" title="MRI scan of cervical disc herniation between C6 and C7 vertebrae"><img alt="MRI scan of cervical disc herniation between C6 and C7 vertebrae" class="mw-file-element" data-file-height="934" data-file-width="998" height="373" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/83/C6-C7-disc-herniation-cevical-mri-scan.jpg/120px-C6-C7-disc-herniation-cevical-mri-scan.jpg" width="400" /></a></span></div>
<div class="gallerytext">MRI scan of cervical disc herniation between C6 and C7 vertebrae</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:L4-l5-disc-herniation.png" title="MRI scan of large herniation (on the right) of the disc between L4 and L5 vertebrae"><img alt="MRI scan of large herniation (on the right) of the disc between L4 and L5 vertebrae" class="mw-file-element" data-file-height="538" data-file-width="423" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/63/L4-l5-disc-herniation.png/94px-L4-l5-disc-herniation.png" width="313" /></a></span></div>
<div class="gallerytext">MRI scan of large herniation (on the right) of the disc between L4 and L5 vertebrae</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Severe_herniation_of_L4-L5_disc.png" title="A rather severe herniation of the L4–L5 disc"><img alt="A rather severe herniation of the L4–L5 disc" class="mw-file-element" data-file-height="340" data-file-width="320" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9c/Severe_herniation_of_L4-L5_disc.png/113px-Severe_herniation_of_L4-L5_disc.png" width="377" /></a></span></div>
<div class="gallerytext">A rather severe herniation of the L4–L5 disc</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Herniated-Disc.jpg" title="Example of a herniated disc at L5–S1 in the lumbar spine"><img alt="Example of a herniated disc at L5–S1 in the lumbar spine" class="mw-file-element" data-file-height="510" data-file-width="410" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/91/Herniated-Disc.jpg/96px-Herniated-Disc.jpg" width="320" /></a></span></div>
<div class="gallerytext">Example of a herniated disc at L5–S1 in the lumbar spine</div>
</li></ul>
<ul><li><a href="https://en.wikipedia.org/wiki/Myelography" title="Myelography">Myelography</a>.
An X-ray of the spinal canal following injection of a contrast material
into the surrounding cerebrospinal fluid spaces will reveal
displacement of the contrast material. It can show the presence of
structures that can cause pressure on the spinal cord or nerves, such as
herniated discs, tumors, or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bone_spur" title="Bone spur">bone spurs</a>.
Because myelography involves the injection of foreign substances, MRI
scans are now preferred for most patients. Myelograms still provide
excellent outlines of space-occupying lesions, especially when combined
with CT scanning (CT myelography). CT myelography is the imaging
modality of choice to visualize herniated discs in patients with
contraindications for an MRI. However, due to its invasiveness, the
assistance of a trained radiologist is required. Myelography is
associated with risks like post-spinal headache, meningeal infection,
and radiation exposure. Recent advances with a multidetector CT scan
have made the diagnostic level of it nearly equal to the MRI.</li><li>The presence and severity of <a href="https://en.wikipedia.org/wiki/Myelopathy" title="Myelopathy">myelopathy</a> can be evaluated by means of <a href="https://en.wikipedia.org/wiki/Transcranial_magnetic_stimulation" title="Transcranial magnetic stimulation">transcranial magnetic stimulation</a> (TMS), a neurophysiological method that measures the time required for a neural impulse to cross the <a href="https://en.wikipedia.org/wiki/Pyramidal_tracts" title="Pyramidal tracts">pyramidal tracts</a>, starting from the <a href="https://en.wikipedia.org/wiki/Cerebral_cortex" title="Cerebral cortex">cerebral cortex</a> and ending at the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anterior_horn_cells" title="Anterior horn cells">anterior horn cells</a> of the cervical, thoracic, or lumbar spinal cord. This measurement is called the <i>central conduction time</i> (<i>CCT</i>). TMS can aid physicians to:</li></ul>
<dl><dd><ul><li>determine if myelopathy exists</li><li>identify the level of the spinal cord where myelopathy is located.
This is especially useful in cases where more than two lesions may be
responsible for the clinical symptoms and signs, such as in patients
with two or more cervical disc hernias</li><li>assess the progression of myelopathy with time, for example before and after cervical spine surgery</li><li>TMS can also help in the differential diagnosis of different causes of pyramidal tract damage.</li></ul></dd></dl>
<ul><li><a href="https://en.wikipedia.org/wiki/Electromyography" title="Electromyography">Electromyography</a> and <a href="https://en.wikipedia.org/wiki/Nerve_conduction_study" title="Nerve conduction study">nerve conduction studies</a>
(EMG/NCS) measure the electrical impulses along nerve roots, peripheral
nerves, and muscle tissue. Tests can indicate if there is ongoing nerve
damage, if the nerves are in a state of healing from a past injury, or
if there is another site of nerve compression. EMG/NCS studies are
typically used to pinpoint the sources of nerve dysfunction <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Distal" title="Distal">distal</a> to the spine.</li></ul>
<h4><span class="mw-headline" id="Differential_diagnosis">Differential diagnosis</span></h4><p>Tests may be required to <a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">distinguish</a> spinal disc herniations from other conditions with similar symptoms.
</p>
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Discogenic_pain" title="Discogenic pain">Discogenic pain</a></li><li>Mechanical pain</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myofascial" title="Myofascial">Myofascial</a> pain</li><li><a href="https://en.wikipedia.org/wiki/Abscess" title="Abscess">Abscess</a></li><li><a href="https://en.wikipedia.org/wiki/Aortic_dissection" title="Aortic dissection">Aortic dissection</a></li><li><a href="https://en.wikipedia.org/wiki/Discitis" title="Discitis">Discitis</a> or <a href="https://en.wikipedia.org/wiki/Osteomyelitis" title="Osteomyelitis">osteomyelitis</a></li><li><a href="https://en.wikipedia.org/wiki/Hematoma" title="Hematoma">Hematoma</a></li><li>Mass lesion or <a href="https://en.wikipedia.org/wiki/Malignancy" title="Malignancy">malignancy</a></li><li>Benign tumor like <a href="https://en.wikipedia.org/wiki/Schwannoma" title="Schwannoma">neurinoma</a> or <a href="https://en.wikipedia.org/wiki/Meningioma" title="Meningioma">meningeoma</a></li><li><a href="https://en.wikipedia.org/wiki/Myocardial_infarction" title="Myocardial infarction">Myocardial infarction</a></li><li><a href="https://en.wikipedia.org/wiki/Sacroiliac_joint_dysfunction" title="Sacroiliac joint dysfunction">Sacroiliac joint dysfunction</a></li><li><a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">Spinal stenosis</a></li><li><a href="https://en.wikipedia.org/wiki/Spondylosis" title="Spondylosis">Spondylosis</a> or <a href="https://en.wikipedia.org/wiki/Spondylolisthesis" title="Spondylolisthesis">spondylolisthesis</a></li></ul>
<h2><span class="mw-headline" id="Treatment">Treatment</span></h2><p>In
the majority of cases spinal disc herniation can be treated successfully
conservatively, without surgical removal of the herniated material. <a href="https://en.wikipedia.org/wiki/Sciatica" title="Sciatica">Sciatica</a>
is a set of symptoms associated with disc herniation. A study on
sciatica showed that about one-third of patients with sciatica recover
within two weeks after presentation using conservative measures alone,
and about three-quarters of patients recovered after three months of
conservative treatment. However the study did not indicate the number of individuals with sciatica that had disc herniations.
</p><p>Initial treatment usually consists of <a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">nonsteroidal anti-inflammatory drugs</a>
(NSAIDs), but long-term use of NSAIDs for people with persistent back
pain is complicated by their possible cardiovascular and
gastrointestinal toxicity.
</p><p><a href="https://en.wikipedia.org/wiki/Epidural_steroid_injection" title="Epidural steroid injection">Epidural corticosteroid injections</a> provide a slight and questionable short-term improvement for those with sciatica, but are of no long-term benefit. Complications occur in up to 17% of cases when injections are performed on the neck, though most are minor. In 2014, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/US_Food_and_Drug_Administration" title="US Food and Drug Administration">US Food and Drug Administration</a>
(FDA) suggested that the "injection of corticosteroids into the
epidural space of the spine may result in rare but serious adverse
events, including loss of vision, stroke, paralysis, and death", and
that "the effectiveness and safety of epidural administration of
corticosteroids have not been established, and FDA has not approved
corticosteroids for this use".
</p>
<h3><span class="mw-headline" id="Lumbar_disc_herniation">Lumbar disc herniation</span></h3><p>Non-surgical
methods of treatment are usually attempted first. Pain medications may
be prescribed to alleviate acute pain and allow the patient to begin
exercising and stretching. There are a number of non-surgical methods
used in attempts to relieve the condition. They are considered <a href="https://en.wikipedia.org/wiki/Indication_(medicine)" title="Indication (medicine)">indicated</a>, <a href="https://en.wikipedia.org/wiki/Contraindication" title="Contraindication">contraindicated</a>, relatively contraindicated, or inconclusive, depending on the safety profile of their <a href="https://en.wikipedia.org/wiki/Risk%E2%80%93benefit_ratio" title="Risk–benefit ratio">risk–benefit ratio</a> and on whether they may or may not help:
</p>
<h4><span class="mw-headline" id="Indicated">Indicated</span></h4><ul><li>Education on proper body mechanics</li><li><a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">Physical therapy</a> to address mechanical factors, and may include modalities to temporarily relieve pain (i.e. <a href="https://en.wikipedia.org/wiki/Traction_(orthopedics)" title="Traction (orthopedics)">traction</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electrical_stimulation" title="Electrical stimulation">electrical stimulation</a>, <a href="https://en.wikipedia.org/wiki/Massage" title="Massage">massage</a>)</li><li><a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">Nonsteroidal anti-inflammatory drugs</a> (NSAIDs)</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Weight_control" title="Weight control">Weight control</a></li><li><a href="https://en.wikipedia.org/wiki/Spinal_manipulation" title="Spinal manipulation">Spinal manipulation</a>.
Moderate quality evidence suggests that spinal manipulation is more
effective than placebo for the treatment of acute (less than 3 months
duration) lumbar disc herniation and acute sciatica.
The same study also found "low to very low" evidence for its usefulness
in treating chronic lumbar symptoms (more than 3 months) and "the
quality of evidence for ... cervical spine-related extremity symptoms of
any duration is low or very low". A 2006 review of published research
states that spinal manipulation "is likely to be safe when used by
appropriately-trained practitioners", and research currently suggests that spinal manipulation is safe for the treatment of disc-related pain.</li></ul>
<h4><span class="mw-headline" id="Contraindicated">Contraindicated</span></h4><ul><li>Spinal manipulation is contraindicated when the etiology of the herniation is the result of a Motor Vehicle Collision (MVC) </li><li><a href="https://en.wikipedia.org/wiki/Spinal_manipulation" title="Spinal manipulation">Spinal manipulation</a> is contraindicated for disc herniations when there are progressive neurological deficits such as with <i>cauda equina</i> syndrome.</li><li>A review of non-surgical <a href="https://en.wikipedia.org/wiki/Spinal_decompression" title="Spinal decompression">spinal decompression</a>
found shortcomings in most published studies and concluded that there
was only "very limited evidence in the scientific literature to support
the effectiveness of non-surgical spinal decompression therapy". Its use and marketing have been very controversial.</li></ul>
<h4><span class="mw-headline" id="Surgery">Surgery</span></h4><p>Surgery
may be useful when a herniated disc is causing significant pain
radiating into the leg, significant leg weakness, bladder problems, or
loss of bowel control.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Discectomy" title="Discectomy">Discectomy</a> (the partial removal of a disc that is causing leg pain) can provide pain relief sooner than non-surgical treatments.</li><li><a href="https://en.wikipedia.org/wiki/Discectomy#Endoscopic_discectomy" title="Discectomy">Small endoscopic discectomy</a> (called <i>nano-endoscopic discectomy</i>) is non-invasive and does not cause <a href="https://en.wikipedia.org/wiki/Failed_back_syndrome" title="Failed back syndrome">failed back syndrome</a>.</li><li>Invasive <a href="https://en.wikipedia.org/wiki/Discectomy#Microdiscectomy" title="Discectomy">microdiscectomy</a>
with a one-inch skin opening has not been shown to result in a
significantly different outcome from larger-opening discectomy with
respect to pain. It might however have less risk of infection.</li><li><a href="https://en.wikipedia.org/wiki/Failed_back_syndrome" title="Failed back syndrome">Failed back syndrome</a>
is a significant, potentially disabling, result that can arise
following invasive spine surgery to treat disc herniation. Smaller spine
procedures such as <i>endoscopic transforaminal lumbar discectomy</i> cannot cause failed back syndrome, because no bone is removed.</li><li>The presence of <a href="https://en.wikipedia.org/wiki/Cauda_equina_syndrome" title="Cauda equina syndrome"><i>cauda equina</i> syndrome</a>
(in which there is incontinence, weakness, and genital numbness) is
considered a medical emergency requiring immediate attention and
possibly surgical decompression.</li></ul>
<p>When different forms of surgical treatments including (discetomy,
microdiscectomy, and chemonucleolysis) were compared evidence was
suggestive rather than conclusive. A Cochrane review from 2007 reported:
"surgical discectomy for carefully selected patients with sciatica due
to a prolapsed lumbar disc appears to provide faster relief from the
acute attack than non‐surgical management. However, any positive or
negative effects on the lifetime natural history of the underlying disc
disease are unclear. Microdiscectomy gives broadly comparable results to
standard discectomy. There is insufficient evidence on other surgical
techniques to draw firm conclusions." Regarding the role of surgery for failed medical therapy in people without a significant neurological deficit, a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cochrane_review" title="Cochrane review">Cochrane review</a> concluded that "limited evidence is now available to support some aspects of surgical practice".
</p><p>Following surgery, rehabilitation programmes are often
implemented. There is wide variation in what these programmes entail. A
Cochrane review found low- to very low-quality evidence that patients
who participated in high-intensity exercise programmes had slightly less
short term pain and disability compared to low-intensity exercise
programmes. There was no difference between supervised and home exercise
programmes.
</p>
<h2><span class="mw-headline" id="Epidemiology">Epidemiology</span></h2><p>Disc
herniation can occur in any disc in the spine, but the two most common
forms are lumbar disc herniation and cervical disc herniation. The
former is the most common, causing <a href="https://en.wikipedia.org/wiki/Low_back_pain" title="Low back pain">low back pain</a> (lumbago) and often leg pain as well, in which case it is commonly referred to as <a href="https://en.wikipedia.org/wiki/Sciatica" title="Sciatica">sciatica</a>.
Lumbar disc herniation occurs 15 times more often than cervical (neck)
disc herniation, and it is one of the most common causes of low back
pain. The cervical discs are affected 8% of the time and the
upper-to-mid-back (thoracic) discs only 1–2% of the time.
</p><p>The following locations have no discs and are therefore exempt
from the risk of disc herniation: the upper two cervical intervertebral
spaces, the <a href="https://en.wikipedia.org/wiki/Sacrum" title="Sacrum">sacrum</a>, and the <a href="https://en.wikipedia.org/wiki/Coccyx" title="Coccyx">coccyx</a>. Most disc herniations occur when a person is in their thirties or forties when the <i>nucleus pulposus</i> is still a gelatin-like substance. With age the <i>nucleus pulposus</i> changes ("dries out") and the risk of herniation is greatly reduced. After age 50 or 60, <a href="https://en.wikipedia.org/wiki/Osteoarthritis" title="Osteoarthritis">osteoarthritic</a> degeneration (spondylosis) or <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a> are more likely causes of low back pain or leg pain.
</p>
<ul><li>4.8% of males and 2.5% of females older than 35 experience sciatica during their lifetime.</li><li>Of all individuals, 60% to 80% experience back pain during their lifetime.</li><li>In 14%, pain lasts more than two weeks.</li><li>Generally, males have a slightly higher incidence than females.</li></ul>
<h2><span class="mw-headline" id="Prevention">Prevention</span></h2><p>Because there are various causes of back injuries, prevention must be comprehensive. Back injuries are predominant in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Manual_labor" title="Manual labor">manual labor</a>, so the majority of <a href="https://en.wikipedia.org/wiki/Low_back_pain" title="Low back pain">low back pain</a> prevention methods have been applied primarily toward <a href="https://en.wikipedia.org/wiki/Biomechanics" title="Biomechanics">biomechanics</a>. Prevention must come from multiple sources such as education, proper body mechanics, and <a href="https://en.wikipedia.org/wiki/Physical_fitness" title="Physical fitness">physical fitness</a>.
</p>
<h3><span class="mw-headline" id="Education">Education</span></h3><p>Education should emphasize not lifting beyond one's capabilities and giving the body a rest after strenuous effort. Over time, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Poor_posture" title="Poor posture">poor posture</a> can cause the intervertebral disc to tear or become damaged. Striving to maintain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neutral_spine" title="Neutral spine">proper posture</a> and body alignment will aid in preventing disc degradation.
</p>
<h3><span class="mw-headline" id="Exercise">Exercise</span></h3><p>Exercises that enhance back strength may also be used to prevent <a href="https://en.wikipedia.org/wiki/Back_injury" title="Back injury">back injuries</a>. Back exercises include the prone push-ups/press-ups, upper back extension, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transverse_abdominis" title="Transverse abdominis">transverse abdominis</a>
bracing, and floor bridges. If pain is present in the back, it can mean
that the stabilization muscles of the back are weak and a person needs
to train the trunk musculature. Other preventative measures are to lose
weight and not to work oneself past fatigue. Signs of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatigue_(medical)" title="Fatigue (medical)">fatigue</a> include <a href="https://en.wikipedia.org/wiki/Tremor" title="Tremor">shaking</a>,
poor coordination, muscle burning, and loss of the transverse abdominal
brace. Heavy lifting should be done with the legs performing the work,
and not the back.
</p><p>Swimming is a common tool used in strength training. The usage of
lumbar-sacral support belts may restrict movement at the spine and
support the back during lifting.</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-13953633902837020412024-03-28T08:36:00.001-04:002024-03-28T08:36:15.137-04:00Surgery<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Surgery">https://en.wikipedia.org/wiki/Surgery</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><div class="thumb tmulti tright"><div class="thumbinner multiimageinner" style="max-width: 304px; width: 304px;"><div class="trow"><div class="tsingle" style="max-width: 302px; width: 302px;"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Cardiac_surgery_operating_room.jpg"><img alt="" class="mw-file-element" data-file-height="705" data-file-width="1237" height="228" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/2e/Cardiac_surgery_operating_room.jpg/300px-Cardiac_surgery_operating_room.jpg" width="400" /></a></span></div></div></div><div class="trow"><div class="tsingle" style="max-width: 302px; width: 302px;"><div class="thumbimage"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:%D0%9D%D0%B5%D0%B9%D1%80%D0%BE%D1%85%D0%B8%D1%80%D1%83%D1%80%D0%B3%D0%B8%D1%87%D0%B5%D1%81%D0%BA%D0%B0%D1%8F_%D0%BE%D0%BF%D0%B5%D1%80%D0%B0%D1%86%D0%B8%D1%8F_%D0%B2_%D0%98%D0%BD%D1%81%D1%82%D0%B8%D1%82%D1%83%D1%82%D0%B5_%D0%A1%D0%BA%D0%BB%D0%B8%D1%84%D0%BE%D1%81%D0%BE%D0%B2%D1%81%D0%BA%D0%BE%D0%B3%D0%BE.jpg"><img alt="" class="mw-file-element" data-file-height="2504" data-file-width="3664" height="273" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e1/%D0%9D%D0%B5%D0%B9%D1%80%D0%BE%D1%85%D0%B8%D1%80%D1%83%D1%80%D0%B3%D0%B8%D1%87%D0%B5%D1%81%D0%BA%D0%B0%D1%8F_%D0%BE%D0%BF%D0%B5%D1%80%D0%B0%D1%86%D0%B8%D1%8F_%D0%B2_%D0%98%D0%BD%D1%81%D1%82%D0%B8%D1%82%D1%83%D1%82%D0%B5_%D0%A1%D0%BA%D0%BB%D0%B8%D1%84%D0%BE%D1%81%D0%BE%D0%B2%D1%81%D0%BA%D0%BE%D0%B3%D0%BE.jpg/300px-%D0%9D%D0%B5%D0%B9%D1%80%D0%BE%D1%85%D0%B8%D1%80%D1%83%D1%80%D0%B3%D0%B8%D1%87%D0%B5%D1%81%D0%BA%D0%B0%D1%8F_%D0%BE%D0%BF%D0%B5%D1%80%D0%B0%D1%86%D0%B8%D1%8F_%D0%B2_%D0%98%D0%BD%D1%81%D1%82%D0%B8%D1%82%D1%83%D1%82%D0%B5_%D0%A1%D0%BA%D0%BB%D0%B8%D1%84%D0%BE%D1%81%D0%BE%D0%B2%D1%81%D0%BA%D0%BE%D0%B3%D0%BE.jpg" width="400" /></a></span></div></div></div><div class="trow" style="display: flex;"><div class="thumbcaption">Surgeons conducting operations</div></div></div></div>
<p><b>Surgery</b> is a <a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">medical specialty</a> that uses manual and/or instrumental techniques to diagnose or treat <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pathological" title="Pathological">pathological</a> conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (i.e., malabsorption created by <a href="https://en.wikipedia.org/wiki/Bariatric_surgery" title="Bariatric surgery">bariatric surgery</a> such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gastric_bypass" title="Gastric bypass">gastric bypass</a>), to reconstruct or improve aesthetics and appearance (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cosmetic_surgery" title="Cosmetic surgery">cosmetic surgery</a>), or to remove unwanted <a href="https://en.wikipedia.org/wiki/Tissue_(biology)" title="Tissue (biology)">tissues</a> (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Body_fat" title="Body fat">body fat</a>, <a href="https://en.wikipedia.org/wiki/Gland" title="Gland">glands</a>, <a href="https://en.wikipedia.org/wiki/Scar" title="Scar">scars</a> or <a href="https://en.wikipedia.org/wiki/Skin_tag" title="Skin tag">skin tags</a>) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Foreign_bodies" title="Foreign bodies">foreign bodies</a>. The subject receiving the surgery is typically a <a href="https://en.wikipedia.org/wiki/Person" title="Person">person</a> (i.e. a <a href="https://en.wikipedia.org/wiki/Patient" title="Patient">patient</a>), but can also be a non-human <a href="https://en.wikipedia.org/wiki/Animal" title="Animal">animal</a> (i.e. <a href="https://en.wikipedia.org/wiki/Veterinary_surgery" title="Veterinary surgery">veterinary surgery</a>).
</p><p>The act of performing surgery may be called a <b>surgical procedure</b> or <b>surgical operation</b>, or simply "surgery" or "operation". In this context, the verb "operate" means to perform surgery. The adjective <b>surgical</b> means pertaining to surgery; e.g. <a href="https://en.wikipedia.org/wiki/Surgical_instrument" title="Surgical instrument">surgical instruments</a>, <a href="https://en.wikipedia.org/wiki/Operating_theater" title="Operating theater">surgical facility</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Surgical_nurse" title="Surgical nurse">surgical nurse</a>. Most surgical procedures are performed by a pair of operators: a <a href="https://en.wikipedia.org/wiki/Surgeon" title="Surgeon">surgeon</a> who is the main operator performing the surgery, and a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Surgical_assistant" title="Surgical assistant">surgical assistant</a> who provides in-procedure manual assistance during surgery. Modern surgical operations typically require a <b>surgical team</b> that typically consists of the surgeon, the surgical assistant, an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anaesthetist" title="Anaesthetist">anaesthetist</a> (often also complemented by an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anaesthetic_nurse" title="Anaesthetic nurse">anaesthetic nurse</a>), a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Scrub_nurse" title="Scrub nurse">scrub nurse</a> (who handles <a href="https://en.wikipedia.org/wiki/Asepsis" title="Asepsis">sterile</a> equipment), a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Circulating_nurse" title="Circulating nurse">circulating nurse</a> and a <a href="https://en.wikipedia.org/wiki/Surgical_technologist" title="Surgical technologist">surgical technologist</a>, while procedures that mandate <a href="https://en.wikipedia.org/wiki/Cardiopulmonary_bypass" title="Cardiopulmonary bypass">cardiopulmonary bypass</a> will also have a <a href="https://en.wikipedia.org/wiki/Perfusionist" title="Perfusionist">perfusionist</a>. All surgical procedures are considered <i>invasive</i> and often require a period of <i>postoperative</i> care (sometimes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intensive_care" title="Intensive care">intensive care</a>) for the patient to recover from the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Iatrogenic" title="Iatrogenic">iatrogenic</a> trauma inflicted by the procedure. The duration of surgery can span from several minutes to tens of hours depending on the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Specialty_(medicine)" title="Specialty (medicine)">specialty</a>, the nature of the condition, the target <a class="extiw" href="https://en.wiktionary.org/wiki/body_part" title="wikt:body part">body parts</a>
involved and the circumstance of each procedure, but most surgeries are
designed to be one-off interventions that are typically not intended as
an ongoing or repeated type of treatment.
</p><p>In British colloquialism, the term "surgery" can also refer to the facility where surgery is performed, or simply the <a href="https://en.wikipedia.org/wiki/Doctor%27s_office" title="Doctor's office">office</a>/<a href="https://en.wikipedia.org/wiki/Clinic" title="Clinic">clinic</a> of a <a href="https://en.wikipedia.org/wiki/Physician" title="Physician">physician</a>, <a href="https://en.wikipedia.org/wiki/Dentist" title="Dentist">dentist</a> or <a href="https://en.wikipedia.org/wiki/Veterinarian" title="Veterinarian">veterinarian</a>.
</p>
<h2><span class="mw-headline" id="Definitions">Definitions</span></h2></div></div></div><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Leikkaus_Punaisen_ristin_sairaalassa_Tampereella_(26875894332).jpg"><img class="mw-file-element" data-file-height="2465" data-file-width="3924" height="251" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/eb/Leikkaus_Punaisen_ristin_sairaalassa_Tampereella_%2826875894332%29.jpg/220px-Leikkaus_Punaisen_ristin_sairaalassa_Tampereella_%2826875894332%29.jpg" width="400" /></a><figcaption>Surgery underway at the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Red_Cross" title="Red Cross">Red Cross</a> Hospital in <a href="https://en.wikipedia.org/wiki/Tampere" title="Tampere">Tampere</a>, <a href="https://en.wikipedia.org/wiki/Finland" title="Finland">Finland</a> during the 1918 <a href="https://en.wikipedia.org/wiki/Finnish_Civil_War" title="Finnish Civil War">Finnish Civil War</a>.</figcaption></figure>
<p>As a general rule, a procedure is considered surgical when it
involves cutting of a person's tissues or closure of a previously
sustained wound. Other procedures that do not necessarily fall under
this rubric, such as <a href="https://en.wikipedia.org/wiki/Angioplasty" title="Angioplasty">angioplasty</a> or <a href="https://en.wikipedia.org/wiki/Endoscopy" title="Endoscopy">endoscopy</a>, may be considered surgery if they involve "common" surgical procedure or settings, such as use of <a href="https://en.wikipedia.org/wiki/Antiseptic" title="Antiseptic">antiseptic</a> measures and sterile fields, <a href="https://en.wikipedia.org/wiki/Sedation" title="Sedation">sedation</a>/<a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">anesthesia</a>, proactive <a href="https://en.wikipedia.org/wiki/Hemostasis" title="Hemostasis">hemostasis</a>, typical <a href="https://en.wikipedia.org/wiki/Surgical_instrument" title="Surgical instrument">surgical instruments</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Suturing" title="Suturing">suturing</a> or <a href="https://en.wikipedia.org/wiki/Surgical_staple" title="Surgical staple">stapling</a>.
All forms of surgery are considered invasive procedures; the so-called
"noninvasive surgery" ought to be more appropriately called <a href="https://en.wikipedia.org/wiki/Minimally_invasive_procedure" title="Minimally invasive procedure">minimally invasive procedures</a>, which usually refers to a procedure that utilize natural orifices (e.g. most <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urological" title="Urological">urological</a> procedures) or does not penetrate the structure being excised (e.g. endoscopic <a href="https://en.wikipedia.org/wiki/Polypectomy" title="Polypectomy">polyp excision</a>, <a href="https://en.wikipedia.org/wiki/Rubber_band_ligation" title="Rubber band ligation">rubber band ligation</a>, <a href="https://en.wikipedia.org/wiki/LASIK" title="LASIK">laser eye surgery</a>), are <a href="https://en.wikipedia.org/wiki/Percutaneous" title="Percutaneous">percutaneous</a> (e.g. <a href="https://en.wikipedia.org/wiki/Arthroscopy" title="Arthroscopy">arthroscopy</a>, <a href="https://en.wikipedia.org/wiki/Catheter_ablation" title="Catheter ablation">catheter ablation</a>, <a href="https://en.wikipedia.org/wiki/Angioplasty" title="Angioplasty">angioplasty</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Valvuloplasty" title="Valvuloplasty">valvuloplasty</a>), or to a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Radiotherapy" title="Radiotherapy">radiosurgical</a> procedure (e.g. irradiation of a tumor).
</p>
<h3><span class="mw-headline" id="Types_of_surgery">Types of surgery</span></h3><p>Surgical
procedures are commonly categorized by urgency, type of procedure, body
system involved, the degree of invasiveness, and special
instrumentation.
</p>
<ul><li>Based on timing:
<ul><li><a href="https://en.wikipedia.org/wiki/Elective_surgery" title="Elective surgery">Elective surgery</a>
is done to correct a non-life-threatening condition, and is carried out
at the person's convenience, or to the surgeon's and the surgical
facility's availability.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Semi-elective_surgery" title="Semi-elective surgery">Semi-elective surgery</a>
is one that is better done early to avoid complications or potential
deterioration of the patient's condition, but such risk are sufficiently
low that the procedure can be postponed for a short period time.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Emergency_surgery" title="Emergency surgery">Emergency surgery</a> is surgery which must be done without any delay to prevent death or serious disabilities and/or loss of limbs and functions.</li></ul></li><li>Based on purpose:
<ul><li><a href="https://en.wikipedia.org/wiki/Exploratory_surgery" title="Exploratory surgery">Exploratory surgery</a> is performed to establish or aid a <a href="https://en.wikipedia.org/wiki/Diagnosis" title="Diagnosis">diagnosis</a>.</li><li>Therapeutic surgery is performed to treat a previously diagnosed condition.
<ul><li>Curative surgery is a therapeutic procedure done to permanently remove a pathology.</li></ul></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cosmetic_surgery" title="Cosmetic surgery">Cosmetic surgery</a> is done to subjectively improve the appearance of an otherwise normal structure.</li><li><a href="https://en.wikipedia.org/wiki/Bariatric_surgery" title="Bariatric surgery">Bariatric surgery</a> is done to assist <a href="https://en.wikipedia.org/wiki/Weight_loss" title="Weight loss">weight loss</a> when dietary and pharmaceutical methods alone have failed.</li></ul></li></ul>
<p><span class="anchor" id="Resection"></span>
</p>
<ul><li>By type of procedure:
<ul><li><b><a href="https://en.wikipedia.org/wiki/Amputation" title="Amputation">Amputation</a></b> involves removing an entire <a class="extiw" href="https://en.wiktionary.org/wiki/body_part" title="wikt:body part">body part</a>, usually a <a href="https://en.wikipedia.org/wiki/Limb_(anatomy)" title="Limb (anatomy)">limb</a> or <a href="https://en.wikipedia.org/wiki/Digit_(anatomy)" title="Digit (anatomy)">digit</a>; <a href="https://en.wikipedia.org/wiki/Castration" title="Castration">castration</a> is the amputation of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Testes" title="Testes">testes</a>; <a href="https://en.wikipedia.org/wiki/Circumcision" title="Circumcision">circumcision</a> is the removal of <a href="https://en.wikipedia.org/wiki/Foreskin" title="Foreskin">prepuce</a> from the <a href="https://en.wikipedia.org/wiki/Human_penis" title="Human penis">penis</a> or <a href="https://en.wikipedia.org/wiki/Clitoral_hood" title="Clitoral hood">clitoral hood</a> from the <a href="https://en.wikipedia.org/wiki/Clitoris" title="Clitoris">clitoris</a> (see <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Female_circumcision" title="Female circumcision">female circumcision</a>). <b><a href="https://en.wikipedia.org/wiki/Replantation" title="Replantation">Replantation</a></b> involves reattaching a severed body part.</li><li><b>Resection</b> is the removal of all or part of an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Internal_organ" title="Internal organ">internal organ</a> and/or <a href="https://en.wikipedia.org/wiki/Connective_tissue" title="Connective tissue">connective tissue</a>. A <a href="https://en.wikipedia.org/wiki/Segmental_resection" title="Segmental resection">segmental resection</a> specifically removes an independent vascular region of an organ such as a <a href="https://en.wikipedia.org/wiki/Lobes_of_liver" title="Lobes of liver">hepatic segment</a>, a <a href="https://en.wikipedia.org/wiki/Bronchopulmonary_segment" title="Bronchopulmonary segment">bronchopulmonary segment</a> or a <a href="https://en.wikipedia.org/wiki/Renal_lobe" title="Renal lobe">renal lobe</a>. <b>Excision</b> is the resection of only part of an organ, tissue or other body part (e.g. <a href="https://en.wikipedia.org/wiki/Skin" title="Skin">skin</a>) without discriminating specific vascular territories. <b>Exenteration</b> is the complete removal of all organs and <a href="https://en.wikipedia.org/wiki/Soft_tissue" title="Soft tissue">soft tissue</a> content (especially <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lymphoid_tissue" title="Lymphoid tissue">lymphoid tissues</a>) within a <a href="https://en.wikipedia.org/wiki/Body_cavity" title="Body cavity">body cavity</a>.</li><li><b><a href="https://en.wikipedia.org/wiki/Surgical_extirpation" title="Surgical extirpation">Extirpation</a></b> is the complete excision or surgical destruction of a body part.</li><li><b><a href="https://en.wikipedia.org/wiki/Ablation" title="Ablation">Ablation</a></b> is destruction of tissue through the use of energy-transmitting devices such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electrocautery" title="Electrocautery">electrocautery</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fulguration" title="Fulguration">fulguration</a>, <a href="https://en.wikipedia.org/wiki/Laser_ablation" title="Laser ablation">laser</a>, <a href="https://en.wikipedia.org/wiki/Focused_ultrasound" title="Focused ultrasound">focused ultrasound</a> or <a href="https://en.wikipedia.org/wiki/Cryoablation" title="Cryoablation">freezing</a>.</li><li><b>Repair</b> involves the direct closure or restoration of an injured, mutilated or deformed organ or body part, usually by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Suturing" title="Suturing">suturing</a> or <a href="https://en.wikipedia.org/wiki/Internal_fixation" title="Internal fixation">internal fixation</a>. <b><a href="https://en.wikipedia.org/wiki/Reconstructive_surgery" title="Reconstructive surgery">Reconstruction</a></b> is an extensive repair of a complex body part (such as <a href="https://en.wikipedia.org/wiki/Joint" title="Joint">joints</a>), often with some degrees of structural/functional replacement and commonly involves grafting and/or use of implants.</li><li><b><a href="https://en.wikipedia.org/wiki/Graft_(surgery)" title="Graft (surgery)">Grafting</a></b> is the relocation and establishment of a tissue from one part of the body to another. A <a href="https://en.wikipedia.org/wiki/Flap_(surgery)" title="Flap (surgery)">flap</a> is the relocation of a tissue without complete separation of its original attachment, and a <a href="https://en.wikipedia.org/wiki/Free_flap" title="Free flap">free flap</a> is a completely detached flap that carries an intact neurovascular structure ready for grafting onto a new location.</li><li><b><a href="https://en.wikipedia.org/wiki/Bypass_surgery" title="Bypass surgery">Bypass</a></b>
involves the relocation/grafting of a tubular structure onto another in
order to reroute the content flow of that target structure from a
specific segment directly to a more distal ("downstream") segment.</li><li><b><a href="https://en.wikipedia.org/wiki/Implant_(medicine)" title="Implant (medicine)">Implantation</a></b> is insertion of artificial <a href="https://en.wikipedia.org/wiki/Medical_device" title="Medical device">medical devices</a> to replace or augment existing tissue.</li><li><b><a href="https://en.wikipedia.org/wiki/Organ_transplantation" title="Organ transplantation">Transplantation</a></b>
is the replacement of an organ or body part by insertion of another
from a different human (or animal) into the person undergoing surgery. <b><a href="https://en.wikipedia.org/wiki/Organ_procurement" title="Organ procurement">Harvesting</a></b> is the resection of an organ or body part from a live human or animal (known as the <i><a href="https://en.wikipedia.org/wiki/Organ_donation" title="Organ donation">donor</a></i>) for transplantation into another patient (known as the <i>recipient</i>).</li></ul></li><li>By <a href="https://en.wikipedia.org/wiki/Organ_system" title="Organ system">organ system</a>:
Surgical specialties are traditionally and academically categorized by
the organ, organ system or body region involved. Examples include:
<ul><li><a href="https://en.wikipedia.org/wiki/Cardiac_surgery" title="Cardiac surgery">Cardiac surgery</a> — the <a href="https://en.wikipedia.org/wiki/Heart" title="Heart">heart</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mediastinal" title="Mediastinal">mediastinal</a> <a href="https://en.wikipedia.org/wiki/Great_vessels" title="Great vessels">great vessels</a>;</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thoracic_surgery" title="Thoracic surgery">Thoracic surgery</a> — the <a href="https://en.wikipedia.org/wiki/Thoracic_cavity" title="Thoracic cavity">thoracic cavity</a> including the <a href="https://en.wikipedia.org/wiki/Lung" title="Lung">lungs</a>;</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gastrointestinal_surgery" title="Gastrointestinal surgery">Gastrointestinal surgery</a> — the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Digestive_tract" title="Digestive tract">digestive tract</a> and its accessory organs;</li><li><a href="https://en.wikipedia.org/wiki/Vascular_surgery" title="Vascular surgery">Vascular surgery</a> — the extra-mediastinal great vessels and peripheral <a href="https://en.wikipedia.org/wiki/Circulatory_system" title="Circulatory system">circulatory system</a>;</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urological_surgery" title="Urological surgery">Urological surgery</a> — the <a href="https://en.wikipedia.org/wiki/Genitourinary_system" title="Genitourinary system">genitourinary system</a>;</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/ENT_surgery" title="ENT surgery">ENT surgery</a> — <a href="https://en.wikipedia.org/wiki/Ear" title="Ear">ear</a>, <a href="https://en.wikipedia.org/wiki/Nose" title="Nose">nose</a> and <a href="https://en.wikipedia.org/wiki/Throat" title="Throat">throat</a>, also known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Head_and_neck_surgery" title="Head and neck surgery">head and neck surgery</a> when including the <a href="https://en.wikipedia.org/wiki/Neck" title="Neck">neck</a> region;</li><li><a href="https://en.wikipedia.org/wiki/Oral_and_maxillofacial_surgery" title="Oral and maxillofacial surgery">Oral and maxillofacial surgery</a> — the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oral_cavity" title="Oral cavity">oral cavity</a>, jaws, and face;</li><li><a href="https://en.wikipedia.org/wiki/Neurosurgery" title="Neurosurgery">Neurosurgery</a> — the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>, and;</li><li><a href="https://en.wikipedia.org/wiki/Orthopedic_surgery" title="Orthopedic surgery">Orthopedic surgery</a> — the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Musculoskeletal_system" title="Musculoskeletal system">musculoskeletal system</a>.</li></ul></li><li>By degree of invasiveness of surgical procedures:
<ul><li>Conventional <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Open_surgery" title="Open surgery">open surgery</a> (such as a <a href="https://en.wikipedia.org/wiki/Laparotomy" title="Laparotomy">laparotomy</a>) requires a large incision to access the area of interest, and directly exposes the internal body cavity to the outside.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Minimally-invasive_procedures" title="Minimally-invasive procedures">Minimally-invasive surgery</a> involves much smaller surface incisions or even natural orifices (<a href="https://en.wikipedia.org/wiki/Nostril" title="Nostril">nostril</a>, <a href="https://en.wikipedia.org/wiki/Mouth" title="Mouth">mouth</a>, <a href="https://en.wikipedia.org/wiki/Anus" title="Anus">anus</a> or <a href="https://en.wikipedia.org/wiki/Urethra" title="Urethra">urethra</a>) to insert miniaturized instruments within a body cavity or structure, as in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Laparoscopic_surgery" title="Laparoscopic surgery">laparoscopic surgery</a> or <a href="https://en.wikipedia.org/wiki/Angioplasty" title="Angioplasty">angioplasty</a>.</li><li>Hybrid surgery uses a combination of open and minimally-invasive
techniques, and may include hand ports or larger incisions to assist
with performance of elements of the procedure.</li></ul></li><li>By equipment used:
<ul><li><a href="https://en.wikipedia.org/wiki/Laser_surgery" title="Laser surgery">Laser surgery</a> involves use of <a href="https://en.wikipedia.org/wiki/Laser_ablation" title="Laser ablation">laser ablation</a> to divide tissue instead of a <a href="https://en.wikipedia.org/wiki/Scalpel" title="Scalpel">scalpel</a>, <a href="https://en.wikipedia.org/wiki/Scissors" title="Scissors">scissors</a> or similar sharp-edged instruments.</li><li><a href="https://en.wikipedia.org/wiki/Cryosurgery" title="Cryosurgery">Cryosurgery</a> uses low-temperature <a href="https://en.wikipedia.org/wiki/Cryoablation" title="Cryoablation">cryoablation</a> to freeze and destroy a target tissue.</li><li><a href="https://en.wikipedia.org/wiki/Electrosurgery" title="Electrosurgery">Electrosurgery</a> involves use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electrocautery" title="Electrocautery">electrocautery</a> to cut and coagulate tissue.</li><li><a href="https://en.wikipedia.org/wiki/Microsurgery" title="Microsurgery">Microsurgery</a> involves the use of an operating <a href="https://en.wikipedia.org/wiki/Microscope" title="Microscope">microscope</a> for the surgeon to see and manipulate small structures.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Endoscopic_surgery" title="Endoscopic surgery">Endoscopic surgery</a> uses <a href="https://en.wikipedia.org/wiki/Optical_instrument" title="Optical instrument">optical instruments</a>
to relay the image from inside an enclosed body cavity to the outside,
and the surgeon performs the procedure using specialized handheld
instruments inserted through <a href="https://en.wikipedia.org/wiki/Trocar" title="Trocar">trocars</a> placed through the body wall. Most modern endoscopic procedures are <i>video-assisted</i>, meaning the images are viewed on a <a href="https://en.wikipedia.org/wiki/Electronic_visual_display" title="Electronic visual display">display screen</a> rather than through the <a href="https://en.wikipedia.org/wiki/Eyepiece" title="Eyepiece">eyepiece</a> on the endoscope.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Robotic_surgery" title="Robotic surgery">Robotic surgery</a> makes use of <a href="https://en.wikipedia.org/wiki/Robotics" title="Robotics">robotics</a> such as the <a href="https://en.wikipedia.org/wiki/Da_Vinci_Surgical_System" title="Da Vinci Surgical System">Da Vinci</a> or the <a href="https://en.wikipedia.org/wiki/ZEUS_robotic_surgical_system" title="ZEUS robotic surgical system">ZEUS robotic surgical systems</a>, to <a href="https://en.wikipedia.org/wiki/Remote_control" title="Remote control">remotely control</a> endoscopic or minimally-invasive instruments.</li></ul></li></ul>
<h3><span class="mw-headline" id="Terminology">Terminology</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/List_of_surgical_procedures" title="List of surgical procedures">List of surgical procedures</a></div>
<ul><li>Resection and excisional procedures start with a <a href="https://en.wikipedia.org/wiki/Prefix" title="Prefix">prefix</a> for the target organ to be excised (cut out) and end in the <a href="https://en.wikipedia.org/wiki/Suffix" title="Suffix">suffix</a> <b>-ectomy</b>. For example, removal of part of the stomach would be called a subtotal gastrectomy.</li><li>Procedures involving cutting into an organ or tissue end in <b>-otomy</b>. A surgical procedure cutting through the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Abdominal" title="Abdominal">abdominal</a> wall to gain access to the <a href="https://en.wikipedia.org/wiki/Abdominal_cavity" title="Abdominal cavity">abdominal cavity</a> is a <a href="https://en.wikipedia.org/wiki/Laparotomy" title="Laparotomy">laparotomy</a>.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Minimally_invasive_surgery#Minimally_invasive_procedure" title="Minimally invasive surgery">Minimally invasive procedures</a>, involving small incisions through which an endoscope is inserted, end in -<b>oscopy</b>. For example, such surgery in the abdominal cavity is called <a href="https://en.wikipedia.org/wiki/Laparoscopy" title="Laparoscopy">laparoscopy</a>.</li><li>Procedures for formation of a permanent or semi-permanent opening called a <a href="https://en.wikipedia.org/wiki/Stoma_(medicine)" title="Stoma (medicine)">stoma</a> in the body end in <b>-ostomy</b>,
such as creation of a colostomy, a connection of colon and the
abdominal wall. This prefix is also used for connection between two
viscera, such as how an esophagojejunostomy refers to a connection
created between the esophagus and the jejunum.</li><li>Plastic and reconstruction procedures start with the name for the body part to be reconstructed and end in <b>-plasty</b>. For example, <i>rhino-</i> is a prefix meaning "nose", therefore a <i><a href="https://en.wikipedia.org/wiki/Rhinoplasty" title="Rhinoplasty">rhinoplasty</a></i> is a reconstructive or cosmetic surgery for the nose. A pyloroplasty refers to a type of reconstruction of the gastric pylorus.</li><li>Procedures that involve cutting the muscular layers of an organ end in <b>-myotomy</b>. A pyloromyotomy refers to cutting the muscular layers of the gastric pylorus.</li><li>Repair of a damaged or abnormal structure ends in <b>-orraphy</b>. This includes herniorrhaphy, another name for a hernia repair.</li><li>Reoperation, revision, or "redo" procedures refer to a planned or
unplanned return to the operating theater after a surgery is performed
to re-address an aspect of patient care. Unplanned reasons for
reoperation include postoperative <a href="https://en.wikipedia.org/wiki/Complication_(medicine)" title="Complication (medicine)">complications</a> such as <a href="https://en.wikipedia.org/wiki/Bleeding" title="Bleeding">bleeding</a> or hematoma formation, development of a <a href="https://en.wikipedia.org/wiki/Seroma" title="Seroma">seroma</a> or <a href="https://en.wikipedia.org/wiki/Abscess" title="Abscess">abscess</a>, anastomotic leak, tissue <a href="https://en.wikipedia.org/wiki/Necrosis" title="Necrosis">necrosis</a> requiring <a href="https://en.wikipedia.org/wiki/Debridement" title="Debridement">debridement</a> or excision, or in the case of malignancy, close or involved <a href="https://en.wikipedia.org/wiki/Resection_margin" title="Resection margin">resection margins</a>
that may require re-excision to avoid local recurrence. Reoperation can
be performed in the acute phase, or it can be also performed months to
years later if the surgery failed to solve the indicated problem.
Reoperation can also be planned as a staged operation where components
of the procedure are performed and/or reversed under separate
anesthesia.</li></ul>
<h2><span class="mw-headline" id="Description_of_surgical_procedure">Description of surgical procedure</span></h2><h3><span class="mw-headline" id="Setting">Setting</span></h3><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Inpatient" title="Inpatient">Inpatient</a>
surgery is performed in a hospital, and the person undergoing surgery
stays at least one night in the hospital after the surgery. <a href="https://en.wikipedia.org/wiki/Outpatient_surgery" title="Outpatient surgery">Outpatient surgery</a>
occurs in a hospital outpatient department or freestanding ambulatory
surgery center, and the person who had surgery is discharged the same
working day. Office-based surgery occurs in a physician's office, and the person is discharged the same day.
</p><p>At a <a href="https://en.wikipedia.org/wiki/Hospital" title="Hospital">hospital</a>, modern surgery is often performed in an <a href="https://en.wikipedia.org/wiki/Operating_theater" title="Operating theater">operating theater</a> using <a href="https://en.wikipedia.org/wiki/Surgical_instrument" title="Surgical instrument">surgical instruments</a>, an <a href="https://en.wikipedia.org/wiki/Operating_table" title="Operating table">operating table</a>,
and other equipment. Among United States hospitalizations for
non-maternal and non-neonatal conditions in 2012, more than one-fourth
of stays and half of hospital costs involved stays that included
operating room (OR) procedures. The environment and procedures used in surgery are governed by the principles of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Aseptic_technique" title="Aseptic technique">aseptic technique</a>:
the strict separation of "sterile" (free of microorganisms) things from
"unsterile" or "contaminated" things. All surgical instruments must be
<a href="https://en.wikipedia.org/wiki/Sterilization_(microbiology)" title="Sterilization (microbiology)">sterilized</a>,
and an instrument must be replaced or re-sterilized if it becomes
contaminated (i.e. handled in an unsterile manner, or allowed to touch
an unsterile surface). Operating room staff must wear sterile attire (<a href="https://en.wikipedia.org/wiki/Scrubs_(clothing)" title="Scrubs (clothing)">scrubs</a>,
a scrub cap, a sterile surgical gown, sterile latex or non-latex
polymer gloves and a surgical mask), and they must scrub hands and arms
with an approved disinfectant agent before each procedure.
</p>
<h3><span class="mw-headline" id="Preoperative_care">Preoperative care</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Preoperative_care" title="Preoperative care">Preoperative care</a></div>
<p>Prior to surgery, the person is given a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medical_examination" title="Medical examination">medical examination</a>, receives certain pre-operative tests, and their <a href="https://en.wikipedia.org/wiki/Physical_fitness" title="Physical fitness">physical status</a> is rated according to the <a href="https://en.wikipedia.org/wiki/ASA_physical_status_classification_system" title="ASA physical status classification system">ASA physical status classification system</a>.
If these results are satisfactory, the person requiring surgery signs a
consent form and is given a surgical clearance. If the procedure is
expected to result in significant blood loss, an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autologous" title="Autologous">autologous</a> <a href="https://en.wikipedia.org/wiki/Blood_donation" title="Blood donation">blood donation</a> may be made some weeks prior to surgery. If the surgery involves the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Digestive_system" title="Digestive system">digestive system</a>, the person requiring surgery may be instructed to perform a <a href="https://en.wikipedia.org/wiki/Whole_bowel_irrigation" title="Whole bowel irrigation">bowel prep</a> by drinking a solution of <a href="https://en.wikipedia.org/wiki/Polyethylene_glycol" title="Polyethylene glycol">polyethylene glycol</a> the night before the procedure. People preparing for surgery are also instructed to abstain from food or drink (an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nil_per_os" title="Nil per os">NPO order</a>
after midnight on the night before the procedure), to minimize the
effect of stomach contents on pre-operative medications and reduce the
risk of aspiration if the person vomits during or after the procedure.
</p><p>Some medical systems have a practice of routinely performing
chest x-rays before surgery. The premise behind this practice is that
the physician might discover some unknown medical condition which would
complicate the surgery, and that upon discovering this with the chest
x-ray, the physician would adapt the surgery practice accordingly. However, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Specialty_(medicine)" title="Specialty (medicine)">medical specialty</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Professional_organizations" title="Professional organizations">professional organizations</a> recommend against routine pre-operative <a href="https://en.wikipedia.org/wiki/Chest_radiograph" title="Chest radiograph">chest x-rays</a> for people who have an unremarkable medical history and presented with a physical exam which did not indicate a chest x-ray.
Routine x-ray examination is more likely to result in problems like
misdiagnosis, overtreatment, or other negative outcomes than it is to
result in a benefit to the person. Likewise, other tests including <a href="https://en.wikipedia.org/wiki/Complete_blood_count" title="Complete blood count">complete blood count</a>, <a href="https://en.wikipedia.org/wiki/Prothrombin_time" title="Prothrombin time">prothrombin time</a>, <a href="https://en.wikipedia.org/wiki/Partial_thromboplastin_time" title="Partial thromboplastin time">partial thromboplastin time</a>, <a href="https://en.wikipedia.org/wiki/Basic_metabolic_panel" title="Basic metabolic panel">basic metabolic panel</a>, and <a href="https://en.wikipedia.org/wiki/Urinalysis" title="Urinalysis">urinalysis</a> should not be done unless the results of these tests can help evaluate surgical risk.
</p>
<h3><span class="mw-headline" id="Preparing_for_surgery">Preparing for surgery</span></h3>
<p>A surgical team may include a surgeon, anesthetist, a circulating
nurse, and a "scrub tech", or surgical technician, as well as other
assistants who provide equipment and supplies as required. While
informed consent discussions may be performed in a clinic or acute care
setting, the pre-operative holding area is where documentation is
reviewed and where family members can also meet the surgical team.
Nurses in the preoperative holding area confirm orders and answer
additional questions of the family members of the patient prior to
surgery. In the pre-operative holding area, the person preparing for
surgery changes out of their street clothes and are asked to confirm the
details of his or her surgery as previously discussed during the
process of informed consent. A set of vital signs are recorded, a
peripheral <a href="https://en.wikipedia.org/wiki/Intravenous_therapy" title="Intravenous therapy">IV line</a> is placed, and pre-operative medications (antibiotics, sedatives, etc.) are given.
</p><p>When the patient enters the operating room and is appropriately
anesthetized, the team will then position the patient in an appropriate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Surgical_Positions" title="Surgical Positions">surgical position</a>. If hair is present at the surgical site, it is clipped (instead of shaving). The skin surface within the <a href="https://en.wikipedia.org/wiki/Operating_field" title="Operating field">operating field</a> is cleansed and prepared by applying an <a href="https://en.wikipedia.org/wiki/Antiseptic" title="Antiseptic">antiseptic</a> (typically <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chlorhexidine_gluconate" title="Chlorhexidine gluconate">chlorhexidine gluconate</a> in alcohol, as this is twice as effective as <a href="https://en.wikipedia.org/wiki/Povidone-iodine" title="Povidone-iodine">povidone-iodine</a> at reducing the risk of infection). Sterile drapes are then used to cover the borders of the <a href="https://en.wikipedia.org/wiki/Operating_field" title="Operating field">operating field</a>.
Depending on the type of procedure, the cephalad drapes are secured to
a pair of poles near the head of the bed to form an "ether screen",
which separate the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anesthetist" title="Anesthetist">anesthetist</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anesthesiologist" title="Anesthesiologist">anesthesiologist</a>'s working area (unsterile) from the surgical site (sterile).
</p><p><a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">Anesthesia</a> is administered to prevent <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>
from the trauma of cutting, tissue manipulation, application of thermal
energy, and suturing. Depending on the type of operation, anesthesia
may be provided <a href="https://en.wikipedia.org/wiki/Local_anesthesia" title="Local anesthesia">locally, regionally</a>, or as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/General_anesthesia" title="General anesthesia">general anesthesia</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_anesthesia" title="Spinal anesthesia">Spinal anesthesia</a>
may be used when the surgical site is too large or deep for a local
block, but general anesthesia may not be desirable. With local and
spinal anesthesia, the surgical site is anesthetized, but the person can
remain conscious or minimally sedated. In contrast, general anesthesia
may render the person unconscious and paralyzed during surgery. The
person is typically <a href="https://en.wikipedia.org/wiki/Intubation" title="Intubation">intubated</a> to protect their airway and placed on a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mechanical_ventilator" title="Mechanical ventilator">mechanical ventilator</a>, and anesthesia is produced by a combination of injected and inhaled agents. The choice of surgical method and <a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">anesthetic</a>
technique aims to solve the indicated problem, minimize the risk of
complications, optimize the time needed for recovery, and limit the <a href="https://en.wikipedia.org/wiki/Surgical_stress" title="Surgical stress">surgical stress</a> response.
</p>
<h3><span class="mw-headline" id="Intraoperative_phase">Intraoperative phase</span></h3><p>The intraoperative phase begins when the surgery subject is received in the surgical area (such as the <a href="https://en.wikipedia.org/wiki/Operating_theater" title="Operating theater">operating theater</a> or surgical <a href="https://en.wikipedia.org/wiki/Hospital#Departments_or_wards" title="Hospital">department</a>), and lasts until the subject is transferred to a recovery area (such as a <a href="https://en.wikipedia.org/wiki/Post-anesthesia_care_unit" title="Post-anesthesia care unit">post-anesthesia care unit</a>).
</p><p>An incision is made to access the surgical site. <a href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">Blood vessels</a> may be clamped or <a href="https://en.wikipedia.org/wiki/Cauterization" title="Cauterization">cauterized</a>
to prevent bleeding, and retractors may be used to expose the site or
keep the incision open. The approach to the surgical site may involve
several layers of incision and dissection, as in abdominal surgery,
where the incision must traverse skin, subcutaneous tissue, three layers
of muscle and then the peritoneum. In certain cases, <a href="https://en.wikipedia.org/wiki/Bone" title="Bone">bone</a> may be cut to further access the interior of the body; for example, cutting the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_skull" title="Human skull">skull</a> for <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> surgery or cutting the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_sternum" title="Human sternum">sternum</a> for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thoracic_surgery" title="Thoracic surgery">thoracic (chest) surgery</a> to open up the <a href="https://en.wikipedia.org/wiki/Rib_cage" title="Rib cage">rib cage</a>. Whilst in surgery <a href="https://en.wikipedia.org/wiki/Asepsis" title="Asepsis">aseptic technique</a>
is used to prevent infection or further spreading of the disease. The
surgeons' and assistants' hands, wrists and forearms are washed
thoroughly for at least 4 minutes to prevent germs getting into the
operative field, then sterile gloves are placed onto their hands. An
antiseptic solution is applied to the area of the person's body that
will be operated on. Sterile drapes are placed around the operative
site. Surgical masks are worn by the surgical team to avoid germs on
droplets of liquid from their mouths and noses from contaminating the
operative site.
</p><p>Work to correct the problem in body then proceeds. This work may involve:
<span class="anchor" id="excision"></span>
</p>
<ul><li>excision – cutting out an organ, tumor, or other tissue.</li><li><a href="https://en.wikipedia.org/wiki/Segmental_resection" title="Segmental resection">resection</a> – partial removal of an organ or other bodily structure.</li><li>reconnection of organs, tissues, etc., particularly if severed.
Resection of organs such as intestines involves reconnection. Internal <a href="https://en.wikipedia.org/wiki/Surgical_suture" title="Surgical suture">suturing</a>
or stapling may be used. Surgical connection between blood vessels or
other tubular or hollow structures such as loops of intestine is called <a href="https://en.wikipedia.org/wiki/Anastomosis" title="Anastomosis">anastomosis</a>.</li><li>reduction – the movement or realignment of a body part to its normal
position. e.g. Reduction of a broken nose involves the physical
manipulation of the bone or cartilage from their displaced state back to
their original position to restore normal airflow and aesthetics.</li><li><a href="https://en.wikipedia.org/wiki/Ligature_(medicine)" title="Ligature (medicine)">ligation</a> – tying off blood vessels, ducts, or "tubes".</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medical_grafting" title="Medical grafting">grafts</a>
– may be severed pieces of tissue cut from the same (or different) body
or flaps of tissue still partly connected to the body but resewn for
rearranging or restructuring of the area of the body in question.
Although grafting is often used in cosmetic surgery, it is also used in
other surgery. Grafts may be taken from one area of the person's body
and inserted to another area of the body. An example is <a href="https://en.wikipedia.org/wiki/Vascular_bypass" title="Vascular bypass">bypass surgery</a>,
where clogged blood vessels are bypassed with a graft from another part
of the body. Alternatively, grafts may be from other persons,
cadavers, or animals.</li><li>insertion of <a href="https://en.wikipedia.org/wiki/Prosthesis" title="Prosthesis">prosthetic</a>
parts when needed. Pins or screws to set and hold bones may be used.
Sections of bone may be replaced with prosthetic rods or other parts.
Sometimes a plate is inserted to replace a damaged area of skull. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Artificial_hip" title="Artificial hip">Artificial hip</a> replacement has become more common. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_pacemaker" title="Heart pacemaker">Heart pacemakers</a> or <a href="https://en.wikipedia.org/wiki/Heart_valve" title="Heart valve">valves</a> may be inserted. Many other types of <a href="https://en.wikipedia.org/wiki/Prosthesis" title="Prosthesis">prostheses</a> are used.</li><li>creation of a <a href="https://en.wikipedia.org/wiki/Stoma_(medicine)" title="Stoma (medicine)">stoma</a>, a permanent or semi-permanent opening in the body</li><li>in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Organ_transplant" title="Organ transplant">transplant</a>
surgery, the donor organ (taken out of the donor's body) is inserted
into the recipient's body and reconnected to the recipient in all
necessary ways (blood vessels, ducts, etc.).</li><li><a href="https://en.wikipedia.org/wiki/Arthrodesis" title="Arthrodesis">arthrodesis</a> – surgical connection of adjacent bones so the bones can grow together into one. <a href="https://en.wikipedia.org/wiki/Spinal_fusion" title="Spinal fusion">Spinal fusion</a> is an example of adjacent <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebrae" title="Vertebrae">vertebrae</a> connected allowing them to grow together into one piece.</li><li>modifying the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Digestive_tract" title="Digestive tract">digestive tract</a> in <a href="https://en.wikipedia.org/wiki/Bariatric_surgery" title="Bariatric surgery">bariatric surgery</a> for <a href="https://en.wikipedia.org/wiki/Weight_loss" title="Weight loss">weight loss</a>.</li><li>repair of a <a href="https://en.wikipedia.org/wiki/Fistula" title="Fistula">fistula</a>, <a href="https://en.wikipedia.org/wiki/Hernia" title="Hernia">hernia</a>, or <a href="https://en.wikipedia.org/wiki/Prolapse" title="Prolapse">prolapse</a>.</li><li>repair according to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ICD-10-PCS" title="ICD-10-PCS">ICD-10-PCS</a>,
in the Medical and Surgical Section 0, root operation Q, means
restoring, to the extent possible, a body part to its normal anatomic
structure and function. This definition, repair, is used only when the
method used to accomplish the repair is not one of the other root
operations. Examples would be <a href="https://en.wikipedia.org/wiki/Colostomy" title="Colostomy">colostomy</a> takedown, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Herniorrhaphy" title="Herniorrhaphy">herniorrhaphy</a> of a <a href="https://en.wikipedia.org/wiki/Hernia" title="Hernia">hernia</a>, and the <a href="https://en.wikipedia.org/wiki/Surgical_suture" title="Surgical suture">surgical suture</a> of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Laceration" title="Laceration">laceration</a>.</li><li>other procedures, including:</li></ul>
<dl><dd><ul><li>clearing clogged ducts, blood or other vessels</li><li>removal of calculi (stones)</li><li>draining of accumulated fluids</li><li><a href="https://en.wikipedia.org/wiki/Debridement" title="Debridement">debridement</a> – removal of dead, damaged, or diseased tissue</li></ul></dd></dl>
<p><a href="https://en.wikipedia.org/wiki/Blood_transfusion" title="Blood transfusion">Blood</a> or blood expanders may be administered to compensate for blood lost during surgery. Once the procedure is complete, <a href="https://en.wikipedia.org/wiki/Surgical_suture" title="Surgical suture">sutures</a> or <a href="https://en.wikipedia.org/wiki/Surgical_staple" title="Surgical staple">staples</a>
are used to close the incision. Once the incision is closed, the
anesthetic agents are stopped or reversed, and the person is taken off
ventilation and <a class="extiw" href="https://en.wiktionary.org/wiki/extubate" title="wikt:extubate">extubated</a> (if general anesthesia was administered).
</p>
<h3><span class="mw-headline" id="Postoperative_care">Postoperative care</span></h3><p>After completion of surgery, the person is transferred to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Post_anesthesia_care_unit" title="Post anesthesia care unit">post anesthesia care unit</a>
and closely monitored. When the person is judged to have recovered
from the anesthesia, he/she is either transferred to a surgical ward
elsewhere in the hospital or discharged home. During the post-operative
period, the person's general function is assessed, the outcome of the
procedure is assessed, and the surgical site is checked for signs of
infection. There are several risk factors associated with postoperative
complications, such as immune deficiency and obesity. Obesity has long
been considered a risk factor for adverse post-surgical outcomes. It has
been linked to many disorders such as obesity <a href="https://en.wikipedia.org/wiki/Hypoventilation" title="Hypoventilation">hypoventilation</a> syndrome, <a href="https://en.wikipedia.org/wiki/Atelectasis" title="Atelectasis">atelectasis</a> and pulmonary embolism, adverse cardiovascular effects, and wound healing complications.
If removable skin closures are used, they are removed after 7 to 10
days post-operatively, or after healing of the incision is well under
way. It is not uncommon for <a href="https://en.wikipedia.org/wiki/Drain_(surgery)" title="Drain (surgery)">surgical drains</a>
to be required to remove blood or fluid from the surgical wound during
recovery. Mostly these drains stay in until the volume tapers off, then
they are removed. These drains can become clogged, leading to <a href="https://en.wikipedia.org/wiki/Abscess" title="Abscess">abscess</a>.
</p><p>Postoperative therapy may include <a href="https://en.wikipedia.org/wiki/Adjuvant" title="Adjuvant">adjuvant</a> treatment such as <a href="https://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapy</a>, <a href="https://en.wikipedia.org/wiki/Radiation_therapy" title="Radiation therapy">radiation therapy</a>, or administration of <a href="https://en.wikipedia.org/wiki/Medication" title="Medication">medication</a> such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anti-rejection_medication" title="Anti-rejection medication">anti-rejection medication</a>
for transplants. For postoperative nausea and vomiting (PONV),
solutions like saline, water, controlled breathing placebo and
aromatherapy can be used in addition to medication. Other follow-up studies or <a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">rehabilitation</a>
may be prescribed during and after the recovery period. A recent
post-operative care philosophy has been early ambulation. Ambulation is
getting the patient moving around. This can be as simple as sitting up
or even walking around. The goal is to get the patient moving as early
as possible. It has been found to shorten the patient's length of stay.
Length of stay is the amount of time a patient spends in the hospital
after surgery before they are discharged. In a recent study done with lumbar decompressions, the patient's length of stay was decreased by 1–3 days.
</p><p>The use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibacterial" title="Antibacterial">topical antibiotics</a> on surgical wounds to reduce infection rates has been questioned. Antibiotic ointments are likely to irritate the skin, slow healing, and could increase risk of developing <a href="https://en.wikipedia.org/wiki/Contact_dermatitis" title="Contact dermatitis">contact dermatitis</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibiotic_resistance" title="Antibiotic resistance">antibiotic resistance</a>.
It has also been suggested that topical antibiotics should only be used
when a person shows signs of infection and not as a preventative. A systematic review published by <a href="https://en.wikipedia.org/wiki/Cochrane_(organisation)" title="Cochrane (organisation)">Cochrane (organisation)</a>
in 2016, though, concluded that topical antibiotics applied over
certain types of surgical wounds reduce the risk of surgical site
infections, when compared to no treatment or use of <a href="https://en.wikipedia.org/wiki/Antiseptic" title="Antiseptic">antiseptics</a>.
The review also did not find conclusive evidence to suggest that
topical antibiotics increased the risk of local skin reactions or
antibiotic resistance.
</p><p>Through a retrospective analysis of national administrative data,
the association between mortality and day of elective surgical
procedure suggests a higher risk in procedures carried out later in the
working week and on weekends. The odds of death were 44% and 82% higher
respectively when comparing procedures on a Friday to a weekend
procedure. This "weekday effect" has been postulated to be from several
factors including poorer availability of services on a weekend, and
also, decrease number and level of experience over a weekend.
</p><p>Postoperative pain affects an estimated 80% of people who underwent surgery.
While pain is expected after surgery, there is growing evidence that
pain may be inadequately treated in many people in the acute period
immediately after surgery. It has been reported that incidence of
inadequately controlled pain after surgery ranged from 25.1% to 78.4%
across all surgical disciplines.
There is insufficient evidence to determine if giving opioid pain
medication pre-emptively (before surgery) reduces postoperative pain the
amount of medication needed after surgery.
</p><p>Postoperative recovery has been defined as an energy‐requiring
process to decrease physical symptoms, reach a level of emotional
well‐being, regain functions, and re‐establish activities. Moreover, it has been identified that patients who have undergone surgery are often not fully recovered on discharge.
</p>
<h2><span class="mw-headline" id="Epidemiology">Epidemiology</span></h2><h3><span class="mw-headline" id="United_States">United States</span></h3><p>In
2011, of the 38.6 million hospital stays in U.S. hospitals, 29%
included at least one operating room procedure. These stays accounted
for 48% of the total $387 billion in hospital costs.
</p><p>The overall number of procedures remained stable from 2001 to
2011. In 2011, over 15 million operating room procedures were performed
in U.S. hospitals.
</p><p>Data from 2003 to 2011 showed that U.S. hospital costs were
highest for the surgical service line; the surgical service line costs
were $17,600 in 2003 and projected to be $22,500 in 2013. For hospital stays in 2012 in the United States, private insurance had the highest percentage of surgical expenditure. In 2012, mean hospital costs in the United States were highest for surgical stays.
</p>
<h2><span class="mw-headline" id="Special_populations">Special populations</span></h2><h3><span class="mw-headline" id="Elderly_people">Elderly people</span></h3><p>Older adults have widely varying physical health. <a href="https://en.wikipedia.org/wiki/Frailty_syndrome" title="Frailty syndrome">Frail elderly</a>
people are at significant risk of post-surgical complications and the
need for extended care. Assessment of older people before elective
surgery can accurately predict the person's recovery trajectories. One frailty scale uses five items: unintentional weight loss, <a href="https://en.wikipedia.org/wiki/Muscle_weakness" title="Muscle weakness">muscle weakness</a>,
exhaustion, low physical activity, and slowed walking speed. A healthy
person scores 0; a very frail person scores 5. Compared to non-frail
elderly people, people with intermediate frailty scores (2 or 3) are
twice as likely to have post-surgical complications, spend 50% more time
in the hospital, and are three times as likely to be discharged to a
skilled nursing facility instead of to their own homes.
People who are frail and elderly (score of 4 or 5) have even worse
outcomes, with the risk of being discharged to a nursing home rising to
twenty times the rate for non-frail elderly people.
</p>
<h3><span class="mw-headline" id="Children">Children</span></h3><p>Surgery
on children requires considerations that are not common in adult
surgery. Children and adolescents are still developing physically and
mentally making it difficult for them to make informed decisions and
give consent for surgical treatments. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bariatric_Surgery#Youth" title="Bariatric Surgery">Bariatric surgery in youth</a> is among the controversial topics related to surgery in children.
</p>
<div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Pediatric_surgery" title="Pediatric surgery">Pediatric surgery</a> and <a href="https://en.wikipedia.org/wiki/Pediatric_plastic_surgery" title="Pediatric plastic surgery">Pediatric plastic surgery</a></div>
<h3><span class="mw-headline" id="Vulnerable_populations">Vulnerable populations</span></h3><p>Doctors perform surgery with the consent of the person undergoing surgery. Some people are able to give better <a href="https://en.wikipedia.org/wiki/Informed_consent" title="Informed consent">informed consent</a> than others. Populations such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Incarceration" title="Incarceration">incarcerated persons</a>, <a href="https://en.wikipedia.org/wiki/Dementia" title="Dementia">people living with dementia</a>,
the mentally incompetent, persons subject to coercion, and other people
who are not able to make decisions with the same authority as others,
have special needs when making decisions about their personal
healthcare, including surgery.
</p>
<h2><span class="mw-headline" id="Global_surgery">Global surgery</span></h2><p>Global surgery has been defined as 'the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multidisciplinary" title="Multidisciplinary">multidisciplinary</a>
enterprise of providing improved and equitable surgical care to the
world's population, with its core belief as the issues of need, access
and quality". <a href="https://en.wikipedia.org/wiki/Halfdan_T._Mahler" title="Halfdan T. Mahler">Halfdan T. Mahler</a>, the 3rd Director-General of <a href="https://en.wikipedia.org/wiki/World_Health_Organization" title="World Health Organization">the World Health Organization (WHO)</a>,
first brought attention to the disparities in surgery and surgical care
in 1980 when he stated in his address to the World Congress of the
International College of Surgeons, "'the vast majority of the world's
population has no access whatsoever to skilled surgical care and little
is being done to find a solution.As such, surgical care globally has
been described as the 'neglected stepchild of global health,' a term
coined by <a href="https://en.wikipedia.org/wiki/Paul_Farmer" title="Paul Farmer">Paul Farmer</a> to highlight the urgent need for further work in this area. Furthermore, <a href="https://en.wikipedia.org/wiki/Jim_Yong_Kim" title="Jim Yong Kim">Jim Young Kim</a>, the former President of the <a href="https://en.wikipedia.org/wiki/World_Bank" title="World Bank">World Bank</a>,
proclaimed in 2014 that "surgery is an indivisible, indispensable part
of health care and of progress towards universal health coverage."
</p><p>In 2015, the Lancet Commission on Global Surgery (LCoGS)
published the landmark report titled "Global Surgery 2030: evidence and
solutions for achieving health, welfare, and economic development",
describing the large, pre-existing burden of surgical diseases in low-
and middle-income countries (LMICs) and future directions for increasing
universal access to safe surgery by the year 2030.
The Commission highlighted that about 5 billion people lack access to
safe and affordable surgical and anesthesia care and 143 million
additional procedures were needed every year to prevent further <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Morbidity" title="Morbidity">morbidity</a> and <a href="https://en.wikipedia.org/wiki/Mortality_rate" title="Mortality rate">mortality</a> from treatable surgical conditions as well as a $12.3 trillion loss in economic productivity by the year 2030.
This was especially true in the poorest countries, which account for
over one-third of the population but only 3.5% of all surgeries that
occur worldwide. It emphasized the need to significantly improve the capacity for Bellwether procedures – <a href="https://en.wikipedia.org/wiki/Laparotomy" title="Laparotomy">laparotomy</a>, <a href="https://en.wikipedia.org/wiki/Caesarean_section" title="Caesarean section">caesarean section</a>, <a href="https://en.wikipedia.org/wiki/Open_fracture" title="Open fracture">open fracture care</a>
– which are considered a minimum level of care that first-level
hospitals should be able to provide in order to capture the most basic
emergency surgical care.
In terms of the financial impact on the patients, the lack of adequate
surgical and anesthesia care has resulted in 33 million individuals
every year facing catastrophic health expenditure – the out-of-pocket
healthcare cost exceeding 40% of a given household's income.
</p><p>In alignment with the LCoGS call for action, the <a href="https://en.wikipedia.org/wiki/World_Health_Assembly" title="World Health Assembly">World Health Assembly</a>
adopted the resolution WHA68.15 in 2015 that stated, "Strengthening
emergency and essential surgical care and anesthesia as a component of
universal health coverage." This not only mandated the <a href="https://en.wikipedia.org/wiki/World_Health_Organization" title="World Health Organization">WHO</a>
to prioritize strengthening the surgical and anesthesia care globally,
but also led to governments of the member states recognizing the urgent
need for increasing capacity in surgery and anesthesia. Additionally,
the third edition of <a href="https://en.wikipedia.org/wiki/Disease_Control_Priorities_Project" title="Disease Control Priorities Project">Disease Control Priorities</a> (DCP3), published in 2015 by the <a href="https://en.wikipedia.org/wiki/World_Bank" title="World Bank">World Bank</a>, declared surgery as essential and featured an entire volume dedicated to building surgical capacity.
</p><p>Data from WHO and the World Bank indicate that scaling up
infrastructure to enable access to surgical care in regions where it is
currently limited or is non-existent is a low-cost measure relative to
the significant morbidity and mortality caused by lack of surgical
treatment. In fact, a systematic review found that the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cost-effectiveness" title="Cost-effectiveness">cost-effectiveness ratio</a>
– dollars spent per DALYs averted – for surgical interventions is on
par or exceeds those of major public health interventions such as <a href="https://en.wikipedia.org/wiki/Oral_rehydration_therapy" title="Oral rehydration therapy">oral rehydration therapy</a>, <a href="https://en.wikipedia.org/wiki/Breastfeeding_promotion" title="Breastfeeding promotion">breastfeeding promotion</a>, and even <a href="https://en.wikipedia.org/wiki/Management_of_HIV/AIDS" title="Management of HIV/AIDS">HIV/AIDS antiretroviral therapy</a>.
This finding challenged the common misconception that surgical care is
financially prohibitive endeavor not worth pursuing in LMICs.
</p><p>A key policy framework that arose from this renewed global
commitment towards surgical care worldwide is the National Surgical
Obstetric and Anesthesia Plan (NSOAP).
NSOAP focuses on policy-to-action capacity building for surgical care
with tangible steps as follows: (1) analysis of baseline indicators, (2)
partnership with local champions, (3) broad stakeholder engagement, (4)
consensus building and synthesis of ideas, (5) language refinement, (6)
costing, (7) dissemination, and (8) implementation. This approach has
been widely adopted and has served as guiding principles between
international collaborators and local institutions and governments.
Successful implementations have allowed for sustainability in terms of
longterm monitoring, quality improvement, and continued political and
financial support.
</p>
<h2><span class="mw-headline" id="Human_rights">Human rights</span></h2><p>Access
to surgical care is increasingly recognized as an integral aspect of
healthcare, and therefore is evolving into a normative derivation of
human <a href="https://en.wikipedia.org/wiki/Right_to_health" title="Right to health">right to health</a>. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ICESCR" title="ICESCR">ICESCR</a> Article 12.1 and 12.2 define the human <a href="https://en.wikipedia.org/wiki/Right_to_health" title="Right to health">right to health</a> as "the right of everyone to the enjoyment of the highest attainable standard of physical and mental health" In the August 2000, the UN <a href="https://en.wikipedia.org/wiki/Committee_on_Economic,_Social_and_Cultural_Rights" title="Committee on Economic, Social and Cultural Rights">Committee on Economic, Social and Cultural Rights</a>
(CESCR) interpreted this to mean "right to the enjoyment of a variety
of facilities, goods, services, and conditions necessary for the
realization of the highest attainable health". Surgical care can be thereby viewed as a positive right – an entitlement to protective healthcare.
</p><p>Woven through the International Human and Health Rights
literature is the right to be free from surgical disease. The 1966
ICESCR Article 12.2a described the need for "provision for the reduction
of the stillbirth-rate and of infant mortality and for the healthy
development of the child" which was subsequently interpreted to mean "requiring measures to improve… emergency obstetric services".
Article 12.2d of the ICESCR stipulates the need for "the creation of
conditions which would assure to all medical service and medical
attention in the event of sickness",
and is interpreted in the 2000 comment to include timely access to
"basic preventative, curative services… for appropriate treatment of <a href="https://en.wikipedia.org/wiki/Injury" title="Injury">injury</a> and <a href="https://en.wikipedia.org/wiki/Disability" title="Disability">disability</a>.". Obstetric care shares close ties with <a href="https://en.wikipedia.org/wiki/Reproductive_rights" title="Reproductive rights">reproductive rights</a>, which includes access to reproductive health.
</p><p>Surgeons and <a href="https://en.wikipedia.org/wiki/Public_health" title="Public health">public health</a> advocates, such as <a href="https://en.wikipedia.org/wiki/Kelly_McQueen" title="Kelly McQueen">Kelly McQueen</a>, have described surgery as "Integral to the <a href="https://en.wikipedia.org/wiki/Right_to_health" title="Right to health">right to health</a>". This is reflected in the establishment of the WHO <a href="https://en.wikipedia.org/wiki/Global_Initiative_for_Emergency_and_Essential_Surgical_Care" title="Global Initiative for Emergency and Essential Surgical Care">Global Initiative for Emergency and Essential Surgical Care</a> in 2005, the 2013 formation of the Lancet Commission for Global Surgery, the 2015 <a href="https://en.wikipedia.org/wiki/World_Bank" title="World Bank">World Bank</a> Publication of Volume 1 of its <a href="https://en.wikipedia.org/wiki/Disease_Control_Priorities_Project" title="Disease Control Priorities Project">Disease Control Priorities Project</a> "Essential Surgery", and the 2015 <a href="https://en.wikipedia.org/wiki/World_Health_Assembly" title="World Health Assembly">World Health Assembly</a> 68.15 passing of the Resolution for Strengthening Emergency and Essential Surgical Care and <a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">Anesthesia</a> as a Component of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Universal_Health_Coverage" title="Universal Health Coverage">Universal Health Coverage</a>.
The Lancet Commission for Global Surgery outlined the need for access
to "available, affordable, timely and safe" surgical and anesthesia
care; dimensions paralleled in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/ICESCR" title="ICESCR">ICESCR</a> General Comment No. 14, which similarly outlines need for available, accessible, affordable and timely healthcare.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><div class="hatnote navigation-not-searchable" role="note">Main articles: <a href="https://en.wikipedia.org/wiki/History_of_surgery" title="History of surgery">History of surgery</a>, <a href="https://en.wikipedia.org/wiki/Prehistoric_medicine" title="Prehistoric medicine">Prehistoric medicine</a>, and <a href="https://en.wikipedia.org/wiki/History_of_general_anesthesia" title="History of general anesthesia">History of general anesthesia</a></div>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Edwin_Smith_Papyrus_v2.jpg"><img class="mw-file-element" data-file-height="1954" data-file-width="2550" height="307" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b4/Edwin_Smith_Papyrus_v2.jpg/220px-Edwin_Smith_Papyrus_v2.jpg" width="400" /></a><figcaption>Plates vi & vii of the <a href="https://en.wikipedia.org/wiki/Edwin_Smith_Papyrus" title="Edwin Smith Papyrus">Edwin Smith Papyrus</a>, an Egyptian surgical treatise</figcaption></figure>
<h3><span class="mw-headline" id="Trepanation">Trepanation</span></h3><p>Surgical treatments date back to the prehistoric era. The oldest for which there is evidence is <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Trepanation" title="Trepanation">trepanation</a>, in which a hole is <a href="https://en.wikipedia.org/wiki/Drill" title="Drill">drilled</a> or scraped into the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_skull" title="Human skull">skull</a>, thus exposing the <a href="https://en.wikipedia.org/wiki/Dura_mater" title="Dura mater">dura mater</a> in order to treat health problems related to intracranial pressure and other diseases.
</p>
<h3><span class="mw-headline" id="Ancient_Egypt">Ancient Egypt</span></h3><p>Prehistoric surgical techniques are seen in <a href="https://en.wikipedia.org/wiki/Ancient_Egypt" title="Ancient Egypt">Ancient Egypt</a>, where a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_mandible" title="Human mandible">mandible</a> dated to approximately 2650 BC shows two perforations just below the root of the first <a href="https://en.wikipedia.org/wiki/Molar_(tooth)" title="Molar (tooth)">molar</a>, indicating the draining of an <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tooth_abscess" title="Tooth abscess">abscessed tooth</a>.
Surgical texts from ancient Egypt date back about 3500 years ago.
Surgical operations were performed by priests, specialized in medical
treatments similar to today, and used sutures to close wounds. Infections were treated with honey.
</p>
<h3><span class="mw-headline" id="India">India</span></h3><p>9,000-year-old skeletal remains of a prehistoric individual from the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Indus_River_Valley" title="Indus River Valley">Indus River valley</a> show evidence of teeth having been drilled. <i><a href="https://en.wikipedia.org/wiki/Sushruta_Samhita" title="Sushruta Samhita">Sushruta Samhita</a></i> is one of the oldest known surgical texts and its period is usually placed in the first millennium BCE.
It describes in detail the examination, diagnosis, treatment, and
prognosis of numerous ailments, as well as procedures for various forms
of cosmetic surgery, <a href="https://en.wikipedia.org/wiki/Plastic_surgery" title="Plastic surgery">plastic surgery</a> and <a href="https://en.wikipedia.org/wiki/Rhinoplasty" title="Rhinoplasty">rhinoplasty</a>.
</p>
<h3><span class="mw-headline" id="Sri_Lanka">Sri Lanka</span></h3><p>In
1982 archaeologists were able to find significant evidence when the
ancient land, called 'Alahana Pirivena' situated in Polonnaruwa, with
ruins, was excavated. In that place ruins of an ancient hospital
emerged. The hospital building was 147.5 feet in width and 109.2 feet in
length. The instruments which were used for complex surgeries were
there among the things discovered from the place, including forceps,
scissors, probes, lancets, and scalpels. The instruments discovered may
be dated to 11<sup>th</sup> century AD.
</p>
<h3><span class="mw-headline" id="Ancient_and_Medieval_Greece">Ancient and Medieval Greece</span></h3><figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Hippocrates_rubens.jpg"><img class="mw-file-element" data-file-height="3301" data-file-width="2365" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/32/Hippocrates_rubens.jpg/160px-Hippocrates_rubens.jpg" width="287" /></a><figcaption>Bust of <a href="https://en.wikipedia.org/wiki/Hippocrates" title="Hippocrates">Hippocrates</a>, who advocated for surgery to be performed by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Specialist_doctor" title="Specialist doctor">specialists</a>.</figcaption></figure>
<p>In <a href="https://en.wikipedia.org/wiki/Ancient_Greece" title="Ancient Greece">ancient Greece</a>, temples dedicated to the healer-god <a href="https://en.wikipedia.org/wiki/Asclepius" title="Asclepius">Asclepius</a>, known as <i>Asclepieia</i> (<a href="https://en.wikipedia.org/wiki/Greek_language" title="Greek language">Greek</a>: <span lang="el">Ασκληπιεία</span>, sing. <i>Asclepieion</i> <i>Ασκληπιείον</i>), functioned as centers of medical advice, prognosis, and healing. In the Asclepieion of <a href="https://en.wikipedia.org/wiki/Epidaurus" title="Epidaurus">Epidaurus</a>,
some of the surgical cures listed, such as the opening of an abdominal
abscess or the removal of traumatic foreign material, are realistic
enough to have taken place. The Greek <a href="https://en.wikipedia.org/wiki/Galen" title="Galen">Galen</a>
was one of the greatest surgeons of the ancient world and performed
many audacious operations – including brain and eye surgery – that were
not tried again for almost two millennia. <a href="https://en.wikipedia.org/wiki/Hippocrates" title="Hippocrates">Hippocrates</a> stated in the <a href="https://en.wikipedia.org/wiki/Hippocratic_Oath" title="Hippocratic Oath">oath</a> (<abbr title="circa">c.</abbr><span style="white-space: nowrap;"> 400 BCE</span>) that general physicians must never practice surgery and that surgical procedures are to be conducted by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Specialist_doctor" title="Specialist doctor">specialists. </a>
</p><p>Researchers from the <a href="https://en.wikipedia.org/wiki/Adelphi_University" title="Adelphi University">Adelphi University</a> discovered in the Paliokastro on <a href="https://en.wikipedia.org/wiki/Thasos" title="Thasos">Thasos</a>
ten skeletal remains, four women and six men, who were buried between
the fourth and seventh centuries A.D. Their bones illuminated their
physical activities, traumas, and even a complex form of brain surgery.
According to the researchers: "The very serious trauma cases sustained
by both males and females had been treated surgically or orthopedically
by a very experienced physician/surgeon with great training in trauma
care. We believe it to have been a military physician". The researchers
were impressed by the complexity of the brain surgical operation.
</p><p>In 1991 at the Polystylon fort in Greece, researchers discovered
the head of a Byzantine warrior of the 14th century. Analysis of the
lower jaw revealed that a surgery has been performed, when the warrior
was alive, to the jaw which had been badly fractured and it tied back
together until it healed.
</p>
<h3><span class="mw-headline" id="Islamic_world">Islamic world</span></h3><p>During the <a href="https://en.wikipedia.org/wiki/Islamic_Golden_Age" title="Islamic Golden Age">Islamic Golden Age</a>, largely based upon <a href="https://en.wikipedia.org/wiki/Paul_of_Aegina" title="Paul of Aegina">Paul of Aegina</a>'s <i>Pragmateia</i>, the writings of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Albucasis" title="Albucasis">Albucasis</a> (Abu al-Qasim Khalaf ibn al-Abbas Al-Zahrawi), an <a href="https://en.wikipedia.org/wiki/Al-Andalus" title="Al-Andalus">Andalusian-Arab</a> physician and scientist who practiced in the Zahra suburb of <a href="https://en.wikipedia.org/wiki/C%C3%B3rdoba,_Spain" title="Córdoba, Spain">Córdoba</a>, were influential. l-Zahrawi specialized in curing disease by <a href="https://en.wikipedia.org/wiki/Cauterization" title="Cauterization">cauterization</a>. He invented several <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Surgical_instruments" title="Surgical instruments">surgical instruments</a> for purposes such as inspection of the interior of the <a href="https://en.wikipedia.org/wiki/Urethra" title="Urethra">urethra</a>
and for removing foreign bodies from the throat, the ear, and other
body organs. He was also the first to illustrate the various <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cannulae" title="Cannulae">cannulae</a> and to treat <a href="https://en.wikipedia.org/wiki/Wart" title="Wart">warts</a> with an iron tube and caustic metal as a boring instrument. He describes what is thought to be the first attempt at reduction <a href="https://en.wikipedia.org/wiki/Mammaplasty" title="Mammaplasty">mammaplasty</a> for the management of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gynaecomastia" title="Gynaecomastia">gynaecomastia</a> and the first <a href="https://en.wikipedia.org/wiki/Mastectomy" title="Mastectomy">mastectomy</a> to treat <a href="https://en.wikipedia.org/wiki/Breast_cancer" title="Breast cancer">breast cancer</a>. He is credited with the performance of the first <a href="https://en.wikipedia.org/wiki/Thyroidectomy" title="Thyroidectomy">thyroidectomy</a>. Al-Zahrawi pioneered techniques of <a href="https://en.wikipedia.org/wiki/Neurosurgery" title="Neurosurgery">neurosurgery</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurological" title="Neurological">neurological</a> diagnosis, treating <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Head_injuries" title="Head injuries">head injuries</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Skull_fractures" title="Skull fractures">skull fractures</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_injuries" title="Spinal injuries">spinal injuries</a>, <a href="https://en.wikipedia.org/wiki/Hydrocephalus" title="Hydrocephalus">hydrocephalus</a>, <a href="https://en.wikipedia.org/wiki/Subdural_effusion" title="Subdural effusion">subdural effusions</a> and <a href="https://en.wikipedia.org/wiki/Headache" title="Headache">headache</a>. The first clinical description of an operative procedure for <a href="https://en.wikipedia.org/wiki/Hydrocephalus" title="Hydrocephalus">hydrocephalus</a> was given by Al-Zahrawi, who clearly describes the evacuation of superficial <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intracranial" title="Intracranial">intracranial</a> fluid in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hydrocephalic" title="Hydrocephalic">hydrocephalic</a> children.
</p>
<h3><span class="mw-headline" id="Early_modern_Europe">Early modern Europe</span></h3><figure class="mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Augenoperation_1195.jpg"><img class="mw-file-element" data-file-height="1534" data-file-width="1073" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/43/Augenoperation_1195.jpg/150px-Augenoperation_1195.jpg" width="280" /></a><figcaption><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Illuminated_miniature" title="Illuminated miniature">Illuminated miniature</a> of 12th-century eye surgery in Italy</figcaption></figure>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Ambroise_Par%C3%A9_1573.jpg"><img class="mw-file-element" data-file-height="571" data-file-width="400" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c7/Ambroise_Par%C3%A9_1573.jpg/160px-Ambroise_Par%C3%A9_1573.jpg" width="281" /></a><figcaption>Ambroise Paré (c. 1510–1590), father of modern military surgery.</figcaption></figure>
<p>In <a href="https://en.wikipedia.org/wiki/Europe" title="Europe">Europe</a>, the demand grew for surgeons to formally study for many years before practicing; universities such as <a href="https://en.wikipedia.org/wiki/University_of_Montpellier" title="University of Montpellier">Montpellier</a>, <a href="https://en.wikipedia.org/wiki/University_of_Padua" title="University of Padua">Padua</a> and <a href="https://en.wikipedia.org/wiki/University_of_Bologna" title="University of Bologna">Bologna</a> were particularly renowned. In the 12th century, <a href="https://en.wikipedia.org/wiki/Rogerius_(physician)" title="Rogerius (physician)">Rogerius Salernitanus</a> composed his <i>Chirurgia</i>, laying the foundation for modern Western surgical manuals. <a href="https://en.wikipedia.org/wiki/Barber_surgeon" title="Barber surgeon">Barber-surgeons</a>
generally had a bad reputation that was not to improve until the
development of academic surgery as a specialty of medicine, rather than
an accessory field. Basic surgical principles for asepsis etc., are known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Halsteads_principles" title="Halsteads principles">Halsteads principles</a>.
</p><p>There were some important advances to the art of surgery during this period. The professor of anatomy at the <a href="https://en.wikipedia.org/wiki/University_of_Padua" title="University of Padua">University of Padua</a>, <a href="https://en.wikipedia.org/wiki/Andreas_Vesalius" title="Andreas Vesalius">Andreas Vesalius</a>, was a pivotal figure in the <a href="https://en.wikipedia.org/wiki/Renaissance" title="Renaissance">Renaissance</a> transition from classical medicine and anatomy based on the works of <a href="https://en.wikipedia.org/wiki/Galen" title="Galen">Galen</a>, to an empirical approach of 'hands-on' dissection. In his anatomic treaties <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/De_humani_corporis_fabrica" title="De humani corporis fabrica">De humani corporis fabrica</a></i>,
he exposed the many anatomical errors in Galen and advocated that all
surgeons should train by engaging in practical dissections themselves.
</p><p>The second figure of importance in this era was <a href="https://en.wikipedia.org/wiki/Ambroise_Par%C3%A9" title="Ambroise Paré">Ambroise Paré</a> (sometimes spelled "Ambrose"),
a French army surgeon from the 1530s until his death in 1590. The
practice for cauterizing gunshot wounds on the battlefield had been to
use boiling oil; an extremely dangerous and painful procedure. Paré
began to employ a less irritating emollient, made of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Egg_yolk" title="Egg yolk">egg yolk</a>, <a href="https://en.wikipedia.org/wiki/Rose_oil" title="Rose oil">rose oil</a> and <a href="https://en.wikipedia.org/wiki/Turpentine" title="Turpentine">turpentine</a>. He also described more efficient techniques for the effective <a href="https://en.wikipedia.org/wiki/Ligature_(medicine)" title="Ligature (medicine)">ligation</a> of the <a href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a> during an <a href="https://en.wikipedia.org/wiki/Amputation" title="Amputation">amputation</a>.
</p>
<h3><span class="mw-headline" id="Modern_surgery">Modern surgery</span></h3><p>The discipline of surgery was put on a sound, scientific footing during the <a href="https://en.wikipedia.org/wiki/Age_of_Enlightenment" title="Age of Enlightenment">Age of Enlightenment</a> in Europe. An important figure in this regard was the Scottish surgical scientist, <a href="https://en.wikipedia.org/wiki/John_Hunter_(surgeon)" title="John Hunter (surgeon)">John Hunter</a>, generally regarded as the father of modern scientific surgery. He brought an <a href="https://en.wikipedia.org/wiki/Empiricism" title="Empiricism">empirical</a> and <a href="https://en.wikipedia.org/wiki/Experiment" title="Experiment">experimental</a>
approach to the science and was renowned around Europe for the quality
of his research and his written works. Hunter reconstructed surgical
knowledge from scratch; refusing to rely on the testimonies of others,
he conducted his own surgical experiments to determine the truth of the
matter. To aid comparative analysis, he built up a collection of over
13,000 specimens of separate organ systems, from the simplest plants and
animals to humans.
</p><p>He greatly advanced knowledge of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Venereal_disease" title="Venereal disease">venereal disease</a> and introduced many new techniques of surgery, including new methods for repairing damage to the <a href="https://en.wikipedia.org/wiki/Achilles_tendon" title="Achilles tendon">Achilles tendon</a> and a more effective method for applying ligature of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Arteries" title="Arteries">arteries</a> in case of an <a href="https://en.wikipedia.org/wiki/Aneurysm" title="Aneurysm">aneurysm</a>. He was also one of the first to understand the importance of <a href="https://en.wikipedia.org/wiki/Pathology" title="Pathology">pathology</a>, the danger of the spread of <a href="https://en.wikipedia.org/wiki/Infection" title="Infection">infection</a> and how the problem of <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a> of the wound, bone <a href="https://en.wikipedia.org/wiki/Lesion" title="Lesion">lesions</a> and even <a href="https://en.wikipedia.org/wiki/Tuberculosis" title="Tuberculosis">tuberculosis</a>
often undid any benefit that was gained from the intervention. He
consequently adopted the position that all surgical procedures should be
used only as a last resort.
</p><p>Other important 18th- and early 19th-century surgeons included <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Percival_Pott" title="Percival Pott">Percival Pott</a> (1713–1788) who described <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pott_disease" title="Pott disease">tuberculosis on the spine</a> and first demonstrated that a cancer may be caused by an environmental <a href="https://en.wikipedia.org/wiki/Carcinogen" title="Carcinogen">carcinogen</a> (he noticed a connection between <a href="https://en.wikipedia.org/wiki/Chimney_sweep" title="Chimney sweep">chimney sweep</a>'s exposure to soot and their high incidence of <a href="https://en.wikipedia.org/wiki/Chimney_sweeps%27_carcinoma" title="Chimney sweeps' carcinoma">scrotal cancer</a>). <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Astley_Paston_Cooper" title="Astley Paston Cooper">Astley Paston Cooper</a> (1768–1841) first performed a successful ligation of the abdominal aorta, and <a href="https://en.wikipedia.org/wiki/James_Syme" title="James Syme">James Syme</a> (1799–1870) pioneered the Symes Amputation for the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ankle_joint" title="Ankle joint">ankle joint</a> and successfully carried out the first <a href="https://en.wikipedia.org/wiki/Hemipelvectomy" title="Hemipelvectomy">hip disarticulation</a>.
</p><p>Modern <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a> control through <a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">anesthesia</a> was discovered in the mid-19th century. Before the advent of <a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">anesthesia</a>, surgery was a traumatically painful procedure and surgeons were encouraged to be as swift as possible to minimize patient <a href="https://en.wikipedia.org/wiki/Suffering" title="Suffering">suffering</a>. This also meant that operations were largely restricted to <a href="https://en.wikipedia.org/wiki/Amputation" title="Amputation">amputations</a>
and external growth removals. Beginning in the 1840s, surgery began to
change dramatically in character with the discovery of effective and
practical anaesthetic chemicals such as <a href="https://en.wikipedia.org/wiki/Diethyl_ether" title="Diethyl ether">ether</a>, first used by the American surgeon <a href="https://en.wikipedia.org/wiki/Crawford_Long" title="Crawford Long">Crawford Long</a>, and <a href="https://en.wikipedia.org/wiki/Chloroform" title="Chloroform">chloroform</a>, discovered by Scottish obstetrician <a href="https://en.wikipedia.org/wiki/James_Young_Simpson" title="James Young Simpson">James Young Simpson</a> and later pioneered by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/John_Snow_(physician)" title="John Snow (physician)">John Snow</a>, physician to <a href="https://en.wikipedia.org/wiki/Queen_Victoria" title="Queen Victoria">Queen Victoria</a>.
In addition to relieving patient suffering, anaesthesia allowed more
intricate operations in the internal regions of the human body. In
addition, the discovery of <a href="https://en.wikipedia.org/wiki/Muscle_relaxant" title="Muscle relaxant">muscle relaxants</a> such as <a href="https://en.wikipedia.org/wiki/Curare" title="Curare">curare</a> allowed for safer applications.
</p>
<h4><span class="mw-headline" id="Infection_and_antisepsis">Infection and antisepsis</span></h4><p>The
introduction of anesthetics encouraged more surgery, which
inadvertently caused more dangerous patient post-operative infections.
The concept of infection was unknown until relatively modern times. The
first progress in combating infection was made in 1847 by the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hungarian_people" title="Hungarian people">Hungarian</a> doctor <a href="https://en.wikipedia.org/wiki/Ignaz_Semmelweis" title="Ignaz Semmelweis">Ignaz Semmelweis</a>
who noticed that medical students fresh from the dissecting room were
causing excess maternal death compared to midwives. Semmelweis, despite
ridicule and opposition, introduced compulsory handwashing for everyone
entering the maternal wards and was rewarded with a plunge in maternal
and fetal deaths; however, the <a href="https://en.wikipedia.org/wiki/Royal_Society" title="Royal Society">Royal Society</a> dismissed his advice.
</p>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Joseph_Lister2.jpg"><img class="mw-file-element" data-file-height="980" data-file-width="709" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e9/Joseph_Lister2.jpg/170px-Joseph_Lister2.jpg" width="289" /></a><figcaption><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Joseph_Lister,_1st_Baron_Lister" title="Joseph Lister, 1st Baron Lister">Joseph Lister</a>, pioneer of <a href="https://en.wikipedia.org/wiki/Antiseptic#Usage_in_surgery" title="Antiseptic">antiseptic surgery</a></figcaption></figure>
<p>Until the pioneering work of British surgeon <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Joseph_Lister,_1st_Baron_Lister" title="Joseph Lister, 1st Baron Lister">Joseph Lister</a> in the 1860s, most medical men believed that chemical damage from exposures to bad air (see "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Miasma_theory_of_disease" title="Miasma theory of disease">miasma</a>") was responsible for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Infections" title="Infections">infections</a> in wounds, and facilities for washing hands or a patient's <a href="https://en.wikipedia.org/wiki/Wound" title="Wound">wounds</a> were not available. Lister became aware of the work of French <a href="https://en.wikipedia.org/wiki/Chemist" title="Chemist">chemist</a> <a href="https://en.wikipedia.org/wiki/Louis_Pasteur" title="Louis Pasteur">Louis Pasteur</a>, who showed that rotting and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fermentation_(food)" title="Fermentation (food)">fermentation</a> could occur under <a href="https://en.wikipedia.org/wiki/Anaerobic_infection" title="Anaerobic infection">anaerobic conditions</a> if <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Micro-organisms" title="Micro-organisms">micro-organisms</a> were present. Pasteur suggested three methods to eliminate the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Micro-organisms" title="Micro-organisms">micro-organisms</a> responsible for <a href="https://en.wikipedia.org/wiki/Gangrene" title="Gangrene">gangrene</a>: filtration, exposure to heat, or exposure to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chemical_solutions" title="Chemical solutions">chemical solutions</a>. Lister confirmed Pasteur's conclusions with his own experiments and decided to use his findings to develop <a href="https://en.wikipedia.org/wiki/Antiseptic" title="Antiseptic">antiseptic</a>
techniques for wounds. As the first two methods suggested by Pasteur
were inappropriate for the treatment of human tissue, Lister
experimented with the third, spraying <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Carbolic_acid" title="Carbolic acid">carbolic acid</a> on his instruments. He found that this remarkably reduced the incidence of gangrene and he published his results in <i><a href="https://en.wikipedia.org/wiki/The_Lancet" title="The Lancet">The Lancet</a></i>. Later, on 9 August 1867, he read a paper before the British Medical Association in Dublin, on the <i><a href="https://en.wikipedia.org/wiki/Antiseptic_Principle_of_the_Practice_of_Surgery" title="Antiseptic Principle of the Practice of Surgery">Antiseptic Principle of the Practice of Surgery</a></i>, which was reprinted in the <i>British Medical Journal</i>.
His work was groundbreaking and laid the foundations for a rapid
advance in infection control that saw modern antiseptic operating
theatres widely used within 50 years.
</p><p>Lister continued to develop improved methods of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antisepsis" title="Antisepsis">antisepsis</a> and <a href="https://en.wikipedia.org/wiki/Asepsis" title="Asepsis">asepsis</a>
when he realised that infection could be better avoided by preventing
bacteria from getting into wounds in the first place. This led to the
rise of sterile surgery. Lister introduced the Steam Steriliser to <a href="https://en.wikipedia.org/wiki/Sterilization_(microbiology)" title="Sterilization (microbiology)">sterilize</a>
equipment, instituted rigorous hand washing and later implemented the
wearing of rubber gloves. These three crucial advances – the adoption of
a scientific methodology toward surgical operations, the use of
anaesthetic and the introduction of sterilised equipment – laid the
groundwork for the modern invasive surgical techniques of today.
</p><p>The use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/X-rays" title="X-rays">X-rays</a> as an important medical diagnostic tool began with their discovery in 1895 by German <a href="https://en.wikipedia.org/wiki/Physicist" title="Physicist">physicist</a> <a href="https://en.wikipedia.org/wiki/Wilhelm_R%C3%B6ntgen" title="Wilhelm Röntgen">Wilhelm Röntgen</a>. He noticed that these rays could penetrate the skin, allowing the skeletal structure to be captured on a specially treated <a href="https://en.wikipedia.org/wiki/Photographic_plate" title="">photographic plate</a>.
</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-55340260172432675552024-03-27T21:08:00.000-04:002024-03-27T21:08:04.006-04:00Degenerative disc disease<div class="vector-column-end">
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<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Degenerative disc disease</th></tr><tr><th class="infobox-label" scope="row">Other names</th><td class="infobox-data">Degenerative disc disorder, intervertebral disc degeneration</td></tr><tr align="center"><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Cervical_Spine_MRI_showing_degenerative_changes_closeup.jpg"><img class="mw-file-element" data-file-height="554" data-file-width="434" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/91/Cervical_Spine_MRI_showing_degenerative_changes_closeup.jpg/220px-Cervical_Spine_MRI_showing_degenerative_changes_closeup.jpg" width="313" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2">Degenerated disc between C5 and C6 (vertebra at the top of the picture is C2), with <a href="https://en.wikipedia.org/wiki/Osteophyte" title="Osteophyte">osteophytes</a> anteriorly (to the left) on the lower portion of the C5 and upper portion of the C6 <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebral_body" title="Vertebral body">vertebral body</a>.</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Orthopedics" title="Orthopedics">Orthopedics</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Risk_factor" title="Risk factor">Risk factors</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Connective_tissue_disease" title="Connective tissue disease">Connective tissue disease</a></td></tr></tbody></table>
<p><b>Degenerative disc disease</b> (<b>DDD</b>) is a medical condition
typically brought on by the normal aging process in which there are
anatomic changes and possibly a loss of function of one or more <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">intervertebral discs</a> of the <a href="https://en.wikipedia.org/wiki/Vertebral_column" title="Vertebral column">spine</a>.
DDD can take place with or without symptoms, but is typically
identified once symptoms arise. The root cause is thought to be loss of
soluble <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">proteins</a> within the fluid contained in the disc with resultant reduction of the <a href="https://en.wikipedia.org/wiki/Oncotic_pressure" title="Oncotic pressure">oncotic pressure</a>,
which in turn causes loss of fluid volume. Normal downward forces cause
the affected disc to lose height, and the distance between vertebrae is
reduced. The <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">anulus fibrosus</a>, the tough outer layers of a disc, also weakens. This loss of height causes laxity of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Longitudinal_ligaments" title="Longitudinal ligaments">longitudinal ligaments</a>, which may allow anterior, posterior, or lateral shifting of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebral_bodies" title="Vertebral bodies">vertebral bodies</a>, causing <a href="https://en.wikipedia.org/wiki/Facet_joint" title="Facet joint">facet joint</a> malalignment and <a href="https://en.wikipedia.org/wiki/Arthritis" title="Arthritis">arthritis</a>; <a href="https://en.wikipedia.org/wiki/Scoliosis" title="Scoliosis">scoliosis</a>; <a href="https://en.wikipedia.org/wiki/Cervical_vertebrae" title="Cervical vertebrae">cervical</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hyperlordosis" title="Hyperlordosis">hyperlordosis</a>; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thoracic" title="Thoracic">thoracic</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hyperkyphosis" title="Hyperkyphosis">hyperkyphosis</a>; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lumbar_hyperlordosis" title="Lumbar hyperlordosis">lumbar hyperlordosis</a>; narrowing of the space available for the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_tract" title="Spinal tract">spinal tract</a> within the vertebra (<a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>); or narrowing of the space through which a <a href="https://en.wikipedia.org/wiki/Spinal_nerve" title="Spinal nerve">spinal nerve</a> exits (<a href="https://en.wikipedia.org/wiki/Vertebral_foramen" title="Vertebral foramen">vertebral foramen</a> stenosis) with resultant <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a> and impingement of a spinal nerve, causing a <a href="https://en.wikipedia.org/wiki/Radiculopathy" title="Radiculopathy">radiculopathy</a>.
</p><p>DDD can cause mild to severe <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>, either acute or chronic, near the involved disc, as well as <a href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">neuropathic pain</a> if an adjacent spinal <a href="https://en.wikipedia.org/wiki/Nerve_root" title="Nerve root">nerve root</a>
is involved. Diagnosis is suspected when typical symptoms and physical
findings are present; and confirmed by x-rays of the vertebral column.
Occasionally the radiologic diagnosis of <i>disc degeneration</i> is
made incidentally when a cervical x-ray, chest x-ray, or abdominal x-ray
is taken for other reasons, and the abnormalities of the vertebral
column are recognized. The diagnosis of DDD is not a radiologic
diagnosis, since the interpreting radiologist is not aware whether there
are symptoms present or not. Typical radiographic findings include disc
space narrowing, displacement of vertebral bodies, fusion of adjacent
vertebral bodies, and development of bone in adjacent soft tissue (<a href="https://en.wikipedia.org/wiki/Osteophyte" title="Osteophyte">osteophyte</a> formation). An MRI is typically reserved for those with symptoms, signs, and x-ray findings suggesting the need for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Surgical" title="Surgical">surgical</a> intervention.
</p><p>Treatment may include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physical_Therapy" title="Physical Therapy">Physical Therapy</a> for pain relief, ROM, and appropriate muscle/<a href="https://en.wikipedia.org/wiki/Strength_training" title="Strength training">strength training</a> with emphasis on correcting abnormal posture, assisting the paravertebral (paraspinous) muscles in stabilizing the spine, and <a href="https://en.wikipedia.org/wiki/Core_(anatomy)" title="Core (anatomy)">core</a> muscle strengthening; stretching exercises; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Massage_therapy" title="Massage therapy">massage therapy</a>; oral <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Analgesia" title="Analgesia">analgesia</a> with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_agents" title="Non-steroidal anti-inflammatory agents">non-steroidal anti-inflammatory agents</a> (NSAIDS); and topical analgesia with <a href="https://en.wikipedia.org/wiki/Lidocaine" title="Lidocaine">lidocaine</a>,
ice and heat. Immediate surgery may be indicated if the symptoms are
severe or sudden in onset, or there is a sudden worsening of symptoms.
Elective surgery may be indicated after six months of conservative
therapy with unsatisfactory relief of symptoms.
</p>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2></div></div></div><p>Degenerative
disc disease can result in lower back or upper neck pain. The amount of
degeneration does not correlate well with the amount of pain patients
experience. Many people experience no pain while others, with the same
amount of damage have severe, chronic pain.
Whether a patient experiences pain or not largely depends on the
location of the affected disc and the amount of pressure that is being
put on the spinal column and surrounding nerve roots.
</p><p>Degenerative disc disease is one of the most common sources of back pain and affects approximately 30 million people every year.
With symptomatic degenerative disc disease, the pain can vary depending
on the location of the affected disc. A degenerated disc in the lower
back can result in lower <a href="https://en.wikipedia.org/wiki/Back_pain" title="Back pain">back pain</a>, sometimes radiating to the <a href="https://en.wikipedia.org/wiki/Hip" title="Hip">hips</a>, and <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a> in the <a href="https://en.wikipedia.org/wiki/Buttocks" title="Buttocks">buttocks</a>, <a href="https://en.wikipedia.org/wiki/Thigh" title="Thigh">thighs</a>, or legs. If pressure is being placed on the nerves by exposed nucleus pulposus, sporadic <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">tingling</a> or <a href="https://en.wikipedia.org/wiki/Weakness" title="Weakness">weakness</a> through the knees and legs can occur.
</p><p>A degenerated disc in the upper neck will often result in pain to
the neck, arm, shoulders and hands; tingling in the fingers may also
result if nerve impingement is occurring. Pain is most commonly felt or
worsened by movements such as sitting, bending, lifting, and twisting.
</p><p>After an injury, some discs become painful because of
inflammation and the pain comes and goes. Some people have nerve endings
that penetrate more deeply into the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anulus_fibrosus_disci_intervertebralis" title="Anulus fibrosus disci intervertebralis">anulus fibrosus</a>
(outer layer of the disc) than others, making discs more likely to
generate pain. The healing of trauma to the outer anulus fibrosus may
also result in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Innervation" title="Innervation">innervation</a> of the scar tissue and pain impulses from the disc, as these nerves become inflamed by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nucleus_pulposus" title="Nucleus pulposus">nucleus pulposus</a>
material. Degenerative disc disease can lead to a chronic debilitating
condition and can reduce a person's quality of life. When pain from
degenerative disc disease is severe, traditional nonoperative treatment
may be ineffective.
</p>
<h2><span class="mw-headline" id="Cause">Cause</span></h2><p>There is a
disc between each of the vertebrae in the spine. A healthy,
well-hydrated disc will contain a great deal of water in its center,
known as the <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">nucleus pulposus</a>,
which provides cushioning and flexibility for the spine. Much of the
mechanical stress that is caused by everyday movements is transferred to
the discs within the spine and the water content within them allows
them to effectively absorb the shock. At birth, a typical human nucleus
pulposus will contain about 80% water. However natural daily stresses and minor injuries can cause these discs to gradually lose water as the <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">annulus fibrosus</a>, or the tough outer fibrous material of a disc, weakens.
Because degenerative disc disease is largely due to natural daily
stresses, the American Academy of Orthopaedic Manual Physical Therapists
have suggested it is not truly a "disease" process.
</p><p>This water loss makes the discs more flexible and results in the gradual collapse and narrowing of the gap in the <a href="https://en.wikipedia.org/wiki/Vertebral_column" title="Vertebral column">spinal column</a>.
As the space between vertebrae gets smaller, extra pressure can be
placed on the discs causing tiny cracks or tears to appear in the
annulus. If enough pressure is exerted, it is possible for the nucleus
pulposus material to seep out through the tears in the annulus and can
cause what is known as a <a href="https://en.wikipedia.org/wiki/Spinal_disc_herniation" title="Spinal disc herniation">herniated disc</a>.
</p><p>As the two vertebrae above and below the affected disc begin to collapse upon each other, the <a href="https://en.wikipedia.org/wiki/Facet_joint" title="Facet joint">facet joints</a> at the back of the spine are forced to shift which can affect their function.
</p><p>Additionally, the body can react to the closing gap between vertebrae by creating <a href="https://en.wikipedia.org/wiki/Osteophyte" title="Osteophyte">bone spurs</a> around the disc space in an attempt to stop excess motion.
This can cause issues if the bone spurs start to grow into the spinal
canal and put pressure on the spinal cord and surrounding nerve roots as
it can cause pain and affect nerve function. This condition is called <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>.
</p><p>For women, there is evidence that <a href="https://en.wikipedia.org/wiki/Menopause" title="Menopause">menopause</a> and related <a href="https://en.wikipedia.org/wiki/Estrogen" title="Estrogen">estrogen</a>-loss
are associated with lumbar disc degeneration, usually occurring during
the first 15 years of the climacteric. The potential role of sex
hormones in the etiology of degenerative skeletal disorders is being
discussed for both genders.
</p><p>Mutations in several genes have been implicated in intervertebral disc degeneration. Probable candidate genes include <a href="https://en.wikipedia.org/wiki/Type_I_collagen" title="Type I collagen">type I collagen</a> (sp1 site), <a href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">type IX collagen</a>, <a href="https://en.wikipedia.org/wiki/Vitamin_D_receptor" title="Vitamin D receptor">vitamin D receptor</a>, <a href="https://en.wikipedia.org/wiki/Aggrecan" title="Aggrecan">aggrecan</a>, <a href="https://en.wikipedia.org/wiki/Asporin" title="Asporin">asporin</a>, <a href="https://en.wikipedia.org/wiki/MMP3" title="MMP3">MMP3</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interleukin-1" title="Interleukin-1">interleukin-1</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interleukin-6" title="Interleukin-6">interleukin-6</a> <a href="https://en.wikipedia.org/wiki/Gene_polymorphism" title="Gene polymorphism">polymorphisms</a>. Mutation in genes – such as <a href="https://en.wikipedia.org/wiki/MMP2" title="MMP2">MMP2</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/THBS2" title="THBS2">THBS2</a>
– that encode for proteins and enzymes involved in the regulation of
the extracellular matrix has been shown to contribute to lumbar disc
herniation.
</p>
<h2><span class="mw-headline" id="Mechanisms">Mechanisms</span></h2><figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Degenerative_disc_disease_-_intermed_mag.jpg"><img class="mw-file-element" data-file-height="2848" data-file-width="4272" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/55/Degenerative_disc_disease_-_intermed_mag.jpg/220px-Degenerative_disc_disease_-_intermed_mag.jpg" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Micrograph" title="Micrograph">Micrograph</a> of a fragment of a resected degenerative vertebral disc, showing degenerative <a href="https://en.wikipedia.org/wiki/Fibrocartilage" title="Fibrocartilage">fibrocartilage</a> and clusters of chondrocytes. <a href="https://en.wikipedia.org/wiki/HPS_stain" title="HPS stain">HPS stain</a>.</figcaption></figure>
<p>Degenerative discs typically show degenerative <a href="https://en.wikipedia.org/wiki/Fibrocartilage" title="Fibrocartilage">fibrocartilage</a> and clusters of chondrocytes, suggestive of repair. Inflammation may or may not be present. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Histologic" title="Histologic">Histologic</a> examination of disc fragments resected for presumed DDD is routine to exclude <a href="https://en.wikipedia.org/wiki/Malignancy" title="Malignancy">malignancy</a>.
</p><p>Fibrocartilage replaces the gelatinous mucoid material of the
nucleus pulposus as the disc changes with age. There may be splits in
the anulus fibrosus, permitting herniation of elements of nucleus
pulposus. There may also be shrinkage of the nucleus pulposus that
produces prolapse or folding of the anulus fibrosus with secondary
osteophyte formation at the margins of the adjacent vertebral body. The
pathologic findings in DDD include protrusion, <a href="https://en.wikipedia.org/wiki/Spondylolysis" title="Spondylolysis">spondylolysis</a>, and subluxation of vertebrae (spondylolisthesis) and <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>. It has been hypothesized that <i>Cutibacterium acnes</i> may play a role.
</p>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><p>Diagnosis
of degenerative disc disease will usually consist of an analysis of a
patient's individual medical history and an MRI to confirm the diagnosis
and rule out other causes.
</p>
<h2><span class="mw-headline" id="Treatment">Treatment</span></h2><p>Often, the symptoms of degenerative disc disease can be treated without <a href="https://en.wikipedia.org/wiki/Surgery" title="Surgery">surgery</a>. One or a combination of treatments such as <a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">physical therapy</a>, anti-inflammatory medications such as <a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">nonsteroidal anti-inflammatory drugs</a>, <a href="https://en.wikipedia.org/wiki/Traction_(orthopedics)" title="Traction (orthopedics)">traction</a>, or <a href="https://en.wikipedia.org/wiki/Epidural_steroid_injection" title="Epidural steroid injection">epidural steroid injection</a> can provide adequate relief of troubling symptoms.
</p><p>Surgery may be recommended if the conservative treatment options
do not provide relief within two to three months for cervical or 6
months for lumbar symptoms. If leg or back pain limits normal activity,
if there is weakness or numbness in the legs, if it is difficult to walk
or stand, or if medication or physical therapy are ineffective, surgery
may be necessary, most often <a href="https://en.wikipedia.org/wiki/Spinal_fusion" title="Spinal fusion">spinal fusion</a>. There are many surgical options for the treatment of degenerative disc disease, including anterior and posterior approaches. The most common surgical treatments include:
</p>
<div class="div-col" style="column-width: 30em;">
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Microdiscectomy" title="Microdiscectomy">Microdiscectomy</a>: A <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Minimally_Invasive_Spine_Surgery" title="Minimally Invasive Spine Surgery">minimally invasive</a> surgical procedure in which a portion of a <a href="https://en.wikipedia.org/wiki/Spinal_disc_herniation" title="Spinal disc herniation">herniated nucleus pulposus</a> is removed by way of a surgical instrument or laser while using an operating microscope or loupe for magnification.</li><li>Anterior cervical <a href="https://en.wikipedia.org/wiki/Discectomy" title="Discectomy">discectomy</a>
and fusion: A procedure that reaches the cervical spine (neck) through a
small incision in the front of the neck. The intervertebral disc is
removed and replaced with a small plug of bone or other graft
substitute, along with a height restoration device to un-impinge nerves,
and in time, the vertebrae will fuse together.</li><li><a href="https://en.wikipedia.org/wiki/Intervertebral_disc_arthroplasty" title="Intervertebral disc arthroplasty">Intervertebral disc arthroplasty</a>: also called Artificial Disc Replacement (ADR), or Total Disc Replacement (TDR), is a type of <a href="https://en.wikipedia.org/wiki/Arthroplasty" title="Arthroplasty">arthroplasty</a>. It is a surgical procedure in which degenerated <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">intervertebral discs</a> in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_column" title="Spinal column">spinal column</a> are replaced with artificial ones in the lumbar (lower) or cervical (upper) spine.</li><li>Cervical <a href="https://en.wikipedia.org/wiki/Corpectomy" title="Corpectomy">corpectomy</a>:
A procedure that removes a portion of the vertebra and adjacent
intervertebral discs to allow for decompression of the cervical spinal
cord and spinal nerves. A <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bone_graft" title="Bone graft">bone graft</a>, and in some cases a metal plate and screws, is used to stabilize the spine.</li><li>Dynamic Stabilisation: Following a discectomy, a stabilisation
implant is implanted with a 'dynamic' component. This can be with the
use of Pedicle screws (such as Dynesys or a flexible rod) or an
interspinous spacer with bands (such as a Wallis ligament). These
devices off load pressure from the disc by rerouting pressure through
the posterior part of the spinal column. Like a fusion, these implants
allow and maintain mobility to the segment by allowing flexion and
extension.</li><li><a href="https://en.wikipedia.org/wiki/Facetectomy" title="Facetectomy">Facetectomy</a>: A procedure that removes a part of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Zygapophysial_joint" title="Zygapophysial joint">facet</a> to increase the space.</li><li><a href="https://en.wikipedia.org/wiki/Foraminotomy" title="Foraminotomy">Foraminotomy</a>: A procedure that enlarges the <a href="https://en.wikipedia.org/wiki/Vertebral_foramen" title="Vertebral foramen">vertebral foramen</a> to increase the size of the nerve pathway. This surgery can be done alone or with a laminotomy.</li><li><a href="https://en.wikipedia.org/wiki/Intervertebral_disc_annuloplasty" title="Intervertebral disc annuloplasty">Intervertebral disc annuloplasty</a>
(IDET): A procedure wherein the disc is heated to 90 °C for 15 minutes
in an effort to seal the disc and perhaps deaden nerves irritated by the
degeneration.</li><li><a href="https://en.wikipedia.org/wiki/Laminoplasty" title="Laminoplasty">Laminoplasty</a>:
A procedure that reaches the cervical spine from the back of the neck.
The spinal canal is then reconstructed to make more room for the spinal
cord.</li><li><a href="https://en.wikipedia.org/wiki/Laminotomy" title="Laminotomy">Laminotomy</a>: A procedure that removes only a small portion of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lamina_of_the_vertebral_arch" title="Lamina of the vertebral arch">lamina</a> to relieve pressure on the nerve roots.</li><li>Percutaneous disc decompression: A procedure that reduces or
eliminates a small portion of the bulging disc through a needle inserted
into the disc, minimally invasive.</li><li><a href="https://en.wikipedia.org/wiki/Spinal_decompression" title="Spinal decompression">Spinal decompression</a>: A non-invasive procedure that temporarily (a few hours) enlarges the <a href="https://en.wikipedia.org/wiki/Intervertebral_foramen" title="Intervertebral foramen">intervertebral foramen</a> (IVF) by aiding in the rehydration of the spinal discs.</li><li>Spinal <a href="https://en.wikipedia.org/wiki/Laminectomy" title="Laminectomy">laminectomy</a>: A procedure for treating <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>
by relieving pressure on the spinal cord. A part of the lamina is
removed or trimmed to widen the spinal canal and create more space for
the spinal nerves.</li></ul></div>
<p>Traditional approaches in treating patients with DDD-resultant
herniated discs oftentimes include discectomy—which, in essence, is a
spine-related surgical procedure involving the removal of damaged
intervertebral discs (either whole removal, or partially-based). The
former of these two discectomy techniques involved in open discectomy is
known as Subtotal Discectomy (SD; or, aggressive discectomy) and the
latter, Limited Discectomy (LD; or, conservative discectomy). However,
with either technique, the probability of post-operative reherniation
exists and at a considerably high maximum of 21%, prompting patients to
potentially undergo recurrent disk surgery.
</p><p>New treatments are emerging that are still in the beginning clinical trial phases. <a href="https://en.wikipedia.org/wiki/Glucosamine" title="Glucosamine">Glucosamine</a> injections may offer pain relief for some without precluding the use of more aggressive treatment options. <a href="https://en.wikipedia.org/wiki/Adult_stem_cell" title="Adult stem cell">Adult stem cell</a>
or cell transplantation therapies for disc regeneration are in their
infancy of development, but initial clinical trials have shown cell
transplantation to be safe and initial observations suggest some
beneficial effects for associated pain and disability.
An optimal cell type, transplantation method, cell density, carrier, or
patient indication remains to be determined. Investigation into <a href="https://en.wikipedia.org/wiki/Mesenchymal_stem_cell" title="Mesenchymal stem cell">mesenchymal stem cell</a> therapy knife-less fusion of vertebrae in the United States began in 2006 and a DiscGenics nucleus pulposus progenitor cell transplantation clinical trial has started as of 2018 in the United States and Japan.
</p><p>Researchers and surgeons have conducted clinical and basic
science studies to uncover the regenerative capacity possessed by the
large animal species involved (humans and quadrupeds) for potential
therapies to treat the disease.
Some therapies, carried out by research laboratories in New York,
include introduction of biologically engineered, injectable riboflavin
cross-linked high density collagen (HDC-laden) gels into disease spinal
segments to induce regeneration, ultimately restoring functionality and
structure to the two main inner and outer components of vertebral
discs—anulus fibrosus and the nucleus pulposus.
</p>
<h2><span class="mw-headline" id="Other_animals">Other animals</span></h2>Degenerative disc disease can occur in other mammals besides humans. It is a common problem in several dog breeds, such as the <a href="https://en.wikipedia.org/wiki/Dachshund" title="Dachshund">Dachshund</a>, and attempts to remove this disease from dog populations have led to several hybrid breeds, such as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chiweenie" title="Chiweenie">Chiweenie</a>.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-22235250502446273492024-03-27T20:55:00.007-04:002024-03-27T20:55:39.481-04:00Back pain
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From Wikipedia, the free encyclopedia</div><div class="vector-dropdown mw-portlet mw-portlet-lang" id="p-lang-btn"><a href="https://en.wikipedia.org/wiki/Back_pain">https://en.wikipedia.org/wiki/Back_pain</a> </div><div class="vector-dropdown mw-portlet mw-portlet-lang" id="p-lang-btn"> </div><div aria-labelledby="firstHeading" class="vector-body ve-init-mw-desktopArticleTarget-targetContainer" data-mw-ve-target-container="" id="bodyContent"><div class="vector-body-before-content">
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<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Back pain</th></tr><tr><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Spinal_column_curvature-en.svg"><img class="mw-file-element" data-file-height="846" data-file-width="512" height="640" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/35/Spinal_column_curvature-en.svg/220px-Spinal_column_curvature-en.svg.png" width="387" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2">Different regions (curvatures) of the vertebral column</td></tr></tbody></table><p><b>Back pain</b> (<a href="https://en.wikipedia.org/wiki/Latin" title="Latin">Latin</a>: <i>dorsalgia</i>) is <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a> felt in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Back" title="Back">back</a>. It may be classified as <a href="https://en.wikipedia.org/wiki/Neck_pain" title="Neck pain">neck pain</a> (cervical), <a href="https://en.wikipedia.org/wiki/Middle_back_pain" title="Middle back pain">middle back pain</a> (thoracic), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lower_back_pain" title="Lower back pain">lower back pain</a> (lumbar) or <a href="https://en.wikipedia.org/wiki/Coccydynia" title="Coccydynia">coccydynia</a> (tailbone or sacral pain) based on the segment affected. The lumbar area is the most common area affected. An episode of back pain may be <a href="https://en.wikipedia.org/wiki/Acute_(medicine)" title="Acute (medicine)">acute</a>, subacute or <a href="https://en.wikipedia.org/wiki/Chronic_condition" title="Chronic condition">chronic</a>
depending on the duration. The pain may be characterized as a dull
ache, shooting or piercing pain or a burning sensation. Discomfort can
radiate to the <a href="https://en.wikipedia.org/wiki/Arm" title="Arm">arms</a> and <a href="https://en.wikipedia.org/wiki/Hand" title="Hand">hands</a> as well as the <a href="https://en.wikipedia.org/wiki/Human_leg" title="Human leg">legs</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_foot" title="Human foot">feet</a>, and may include <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">numbness</a> or weakness in the legs and arms.
</p><p>The majority of back pain is nonspecific and <a href="https://en.wikipedia.org/wiki/Idiopathic_disease" title="Idiopathic disease">idiopathic</a><sup>.</sup> Common underlying mechanisms include degenerative or traumatic changes to the <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">discs</a> and <a href="https://en.wikipedia.org/wiki/Facet_joint" title="Facet joint">facet joints</a>, which can then cause secondary pain in the <a href="https://en.wikipedia.org/wiki/Muscle" title="Muscle">muscles</a> and <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerves</a> and <a href="https://en.wikipedia.org/wiki/Referred_pain" title="Referred pain">referred pain</a> to the <a href="https://en.wikipedia.org/wiki/Bone" title="Bone">bones</a>, <a href="https://en.wikipedia.org/wiki/Joint" title="Joint">joints</a> and extremities. Diseases and inflammation of the <a href="https://en.wikipedia.org/wiki/Gallbladder" title="Gallbladder">gallbladder</a>, <a href="https://en.wikipedia.org/wiki/Pancreas" title="Pancreas">pancreas</a>, <a href="https://en.wikipedia.org/wiki/Aorta" title="Aorta">aorta</a> and <a href="https://en.wikipedia.org/wiki/Kidney" title="Kidney">kidneys</a> may also cause referred pain in the back. Tumors of the <a href="https://en.wikipedia.org/wiki/Vertebra" title="Vertebra">vertebrae</a>, neural tissues and adjacent structures can also manifest as back pain.
</p><p>Back pain is common; approximately nine of ten adults experience
it at some point in their lives, and five of ten working adults
experience back pain each year. Some estimate that as many of 95% of people will experience back pain at some point in their lifetime. It is the most common cause of chronic pain and is a major contributor to missed work and disability.
For most individuals, back pain is self-limiting. Most people with back
pain do not experience chronic severe pain but rather persistent or
intermittent pain that is mild or moderate. In most cases of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Herniated_disk" title="Herniated disk">herniated disks</a> and <a href="https://en.wikipedia.org/wiki/Stenosis" title="Stenosis">stenosis</a>, rest, injections or surgery have similar general pain-resolution outcomes on average after one year. In the <a href="https://en.wikipedia.org/wiki/United_States" title="United States">United States</a>, acute low back pain is the fifth most common reason for physician visits and causes 40% of missed work days. It is the single leading cause of disability worldwide.
</p>
<div class="toclimit-3"></div>
<h2><span class="mw-headline" id="Classification">Classification</span></h2></div></div></div><p>Back pain is classified in terms of duration of symptoms.
</p>
<ol><li>Acute back pain lasts <6 weeks</li><li>Subacute back pain lasts between 6 and 12 weeks.</li><li>Chronic back pain lasts for greater than 12 weeks.</li></ol>
<h2><span class="mw-headline" id="Causes">Causes</span></h2><p>There are many causes of back pain, including blood vessels, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Internal_organs" title="Internal organs">internal organs</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Infections" title="Infections">infections</a>, mechanical and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autoimmune" title="Autoimmune">autoimmune</a> causes.
Approximately 90 percent of people with back pain are diagnosed with
nonspecific, idiopathic acute pain with no identifiable underlying
pathology. In approximately 10 percent of people, a cause can be identified through diagnostic imaging. Fewer than two percent of cases are attributed to secondary factors, with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Metastatic_cancer" title="Metastatic cancer">metastatic cancers</a> and serious infections, such as spinal <a href="https://en.wikipedia.org/wiki/Osteomyelitis" title="Osteomyelitis">osteomyelitis</a> and <a href="https://en.wikipedia.org/wiki/Epidural_abscess" title="Epidural abscess">epidural abscesses</a>, accounting for approximately one percent.
</p>
<table class="wikitable">
<caption>Common causes
</caption>
<tbody><tr>
<th><b>Cause</b>
</th>
<th><b>% of people with back pain</b>
</th></tr>
<tr>
<td>Nonspecific
</td>
<td>90%
</td></tr>
<tr>
<td>Vertebral compression fracture
</td>
<td>4%
</td></tr>
<tr>
<td>Metastatic cancer
</td>
<td>0.7%
</td></tr>
<tr>
<td>Infection
</td>
<td>0.01%
</td></tr>
<tr>
<td>Cauda equina
</td>
<td>0.04%
</td></tr></tbody></table>
<h3><span class="mw-headline" id="Nonspecific">Nonspecific</span></h3><p>In as many as 90 percent of cases, no physiological causes or abnormalities on diagnostic tests can be found. Nonspecific back pain can result from <a href="https://en.wikipedia.org/wiki/Back_strain" title="Back strain">back strain</a>
or sprains, which can cause peripheral injury to muscle or ligaments.
Many patients cannot identify the events or activities that may have
caused the strain. The pain can present acutely but in some cases can persist, leading to chronic pain.
</p><p>Chronic back pain in people with otherwise normal scans can result from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Central_sensitization" title="Central sensitization">central sensitization</a>,
in which an initial injury causes a longer-lasting state of heightened
sensitivity to pain. This persistent state maintains pain even after the
initial injury has healed. Treatment of sensitization may involve low doses of <a href="https://en.wikipedia.org/wiki/Antidepressant" title="Antidepressant">antidepressants</a> and directed rehabilitation such as <a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">physical therapy</a>.
</p>
<h3><span class="mw-headline" id="Spinal_disc_disease">Spinal disc disease</span></h3><p>
Spinal disc disease occurs when the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nucleus_pulposus" title="Nucleus pulposus">nucleus pulposus</a>, a gel-like material in the inner core of the vertebral disc, ruptures. Rupturing of the nucleus pulposus can lead to compression of nerve roots.
Symptoms may be unilateral or bilateral, and correlate to the region of
the spine affected. The most common region for spinal disk disease is
at L4–L5 or L5–S1.
The risk for lumbar disc disease is increased in overweight individuals
because of the increased compressive force on the nucleus pulposus, and
is twice as likely to occur in men. A 2002 study found that lifestyle factors such as night-shift work and
lack of physical activity can also increase the risk of lumbar disc
disease. </p><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Disc_herniation_--_Smart-Servier.png"><img class="mw-file-element" data-file-height="2810" data-file-width="2197" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Disc_herniation_--_Smart-Servier.png/220px-Disc_herniation_--_Smart-Servier.png" width="313" /></a><figcaption>Lumbar disc herniation</figcaption></figure>
<p>Severe spinal-cord compression is considered a surgical emergency and
requires decompression to preserve motor and sensory function. <a href="https://en.wikipedia.org/wiki/Cauda_equina_syndrome" title="Cauda equina syndrome">Cauda equina syndrome</a> involves severe compression of the <a href="https://en.wikipedia.org/wiki/Cauda_equina" title="Cauda equina">cauda equina</a> and presents initially with pain followed by motor and sensory. Bladder incontinence is seen in later stages of cauda equina syndrome.
</p>
<h3><span class="mw-headline" id="Degenerative_disease">Degenerative disease</span></h3><p><a href="https://en.wikipedia.org/wiki/Spondylosis" title="Spondylosis">Spondylosis</a>,
or degenerative arthritis of the spine, occurs when the intervertebral
disc undergoes degenerative changes, causing the disc to fail at
cushioning the vertebrae. There is an association between intervertebral
disc space narrowing and lumbar spine pain. The space between the vertebrae becomes more narrow, resulting in compression and irritation of the nerves.
</p><p><a href="https://en.wikipedia.org/wiki/Spondylolisthesis" title="Spondylolisthesis">Spondylolithesis</a>
is the anterior shift of one vertebra compared to the neighboring
vertebra. It is associated with age-related degenerative changes as well
as trauma and congenital anomalies.
</p><p><a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">Spinal stenosis</a>
can occur in cases of severe spondylosis, spondylotheisis and
age-associated thickening of the ligamentum flavum. Spinal stenosis
involves narrowing of the spinal canal and typically presents in
patients greater than 60 years of age. <a href="https://en.wikipedia.org/wiki/Neurogenic_claudication" title="Neurogenic claudication">Neurogenic claudication</a>
can occur in cases of severe lumbar spinal stenosis and presents with
symptoms of pain in the lower back, buttock or leg that is worsened by
standing and relieved by sitting.
</p><p><a href="https://en.wikipedia.org/wiki/Vertebral_compression_fracture" title="Vertebral compression fracture">Vertebral compression fractures</a> occur in four percent of patients presenting with lower back pain. Risk factors include age, female gender, history of osteoporosis, and chronic <a href="https://en.wikipedia.org/wiki/Glucocorticoid" title="Glucocorticoid">glucocorticoid</a> use. Fractures can occur as a result of trauma but in many cases can be asymptomatic.
</p>
<h3><span class="mw-headline" id="Infection">Infection</span></h3><p>Common infectious causes of back pain include <a href="https://en.wikipedia.org/wiki/Osteomyelitis" title="Osteomyelitis">osteomyelitis</a>, <a href="https://en.wikipedia.org/wiki/Discitis" title="Discitis">septic discitis</a>, paraspinal abscess and <a href="https://en.wikipedia.org/wiki/Epidural_abscess" title="Epidural abscess">epidural abscess</a>. Infectious causes that lead to back pain involve various structures surrounding the spine.
</p><p><a href="https://en.wikipedia.org/wiki/Osteomyelitis" title="Osteomyelitis">Osteomyelitis</a> is the bacterial infection of the bone. <a href="https://en.wikipedia.org/wiki/Vertebral_osteomyelitis" title="Vertebral osteomyelitis">Vertebral osteomyelitis</a> is most commonly caused by <a href="https://en.wikipedia.org/wiki/Staphylococcus" title="Staphylococcus">staphylococci</a>.
Risk factors include skin infection, urinary tract infection, IV
catheter use, IV drug use, previous endocarditis and lung disease.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_epidural_abscess" title="Spinal epidural abscess">Spinal epidural abscess</a> is commonly caused by severe infection with <a href="https://en.wikipedia.org/wiki/Bloodstream_infections" title="Bloodstream infections">bacteremia</a>. Risk factors include recent administration of epidurals, IV drug use or recent infection.
</p>
<h3><span class="mw-headline" id="Cancer">Cancer</span></h3><p>Spread of
cancer to the bone or spinal cord can lead to back pain. Bone is one of
the most common sites of metastatic lesions. Patients typically have a
history of malignancy. Common types of cancer that present with back
pain include <a href="https://en.wikipedia.org/wiki/Multiple_myeloma" title="Multiple myeloma">multiple myeloma</a>, <a href="https://en.wikipedia.org/wiki/Lymphoma" title="Lymphoma">lymphoma</a>, <a href="https://en.wikipedia.org/wiki/Leukemia" title="Leukemia">leukemia</a>, spinal cord tumors, primary vertebral tumors and <a href="https://en.wikipedia.org/wiki/Prostate_cancer" title="Prostate cancer">prostate cancer</a>. Back pain is present in 29% of patients with systemic cancer. Unlike other causes of back pain that commonly affect the lumbar spine, the thoracic spine is most commonly affected. The pain can be associated with systemic symptoms such as weight loss, chills, fever, nausea and vomiting. Unlike other causes of back pain, <a href="https://en.wikipedia.org/wiki/Neoplasm" title="Neoplasm">neoplasm</a>-associated back pain is constant, dull, poorly localized and worsens with rest. <a href="https://en.wikipedia.org/wiki/Metastasis" title="Metastasis">Metastasis</a> to the bone also increases the risk of <a href="https://en.wikipedia.org/wiki/Spinal_cord_compression" title="Spinal cord compression">spinal-cord compression</a> or vertebral fractures that require emergency surgical treatment.
</p>
<h3><span class="mw-headline" id="Autoimmune">Autoimmune</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Discogenic_Pain.png"><img class="mw-file-element" data-file-height="1024" data-file-width="768" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/27/Discogenic_Pain.png/220px-Discogenic_Pain.png" width="300" /></a><figcaption>Back pain can be caused by the vertebrae compressing the intervertebral discs.</figcaption></figure>
<p>Inflammatory arthritides such as <a href="https://en.wikipedia.org/wiki/Ankylosing_spondylitis" title="Ankylosing spondylitis">ankylosing spondylitis</a>, <a href="https://en.wikipedia.org/wiki/Psoriatic_arthritis" title="Psoriatic arthritis">psoriatic arthritis</a>, <a href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis">rheumatoid arthritis</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Systemic_lupus_erythematosus" title="Systemic lupus erythematosus">systemic lupus erythematosus</a>
can all cause varying levels of joint destruction. Among the
inflammatory arthritides, ankylosing spondylitis is most closely
associated with back pain because of the inflammatory destruction of the
bony components of the spine. Ankylosing spondylitis is common in young
men and presents with a range of possible symptoms such as <a href="https://en.wikipedia.org/wiki/Uveitis" title="Uveitis">uveitis</a>, <a href="https://en.wikipedia.org/wiki/Psoriasis" title="Psoriasis">psoriasis</a> and <a href="https://en.wikipedia.org/wiki/Inflammatory_bowel_disease" title="Inflammatory bowel disease">inflammatory bowel disease</a>.
</p>
<h3><span class="mw-headline" id="Referred_pain">Referred pain</span></h3><p>Back pain can also be <a href="https://en.wikipedia.org/wiki/Referred_pain" title="Referred pain">referred</a>
from another source. Referred pain occurs when pain is felt at a
location different than the source of the pain. Disease processes that
can present with back pain include <a href="https://en.wikipedia.org/wiki/Pancreatitis" title="Pancreatitis">pancreatitis</a>, <a href="https://en.wikipedia.org/wiki/Kidney_stone_disease" title="Kidney stone disease">kidney stones</a>, severe <a href="https://en.wikipedia.org/wiki/Urinary_tract_infection" title="Urinary tract infection">urinary tract infections</a> and <a href="https://en.wikipedia.org/wiki/Abdominal_aortic_aneurysm" title="Abdominal aortic aneurysm">abdominal aortic aneurysms</a>.
</p>
<h3><span class="mw-headline" id="Risk_factors">Risk factors</span></h3><p>Heavy lifting, obesity, sedentary lifestyle and lack of exercise can increase the risk of back pain. Cigarette smokers are more likely to experience back pain than are nonsmokers. Weight gain in pregnancy is also a risk factor for back pain. In general, fatigue can worsen pain.
</p><p>A few studies suggest that <a href="https://en.wikipedia.org/wiki/Psychosocial" title="Psychosocial">psychosocial</a> factors such as work-related stress and <a href="https://en.wikipedia.org/wiki/Dysfunctional_family" title="Dysfunctional family">dysfunctional family relationships</a> may correlate more closely with back pain than do structural abnormalities revealed in X-rays and other medical imaging scans.
</p><p>Back pain physical effects can range from muscle aching to a
shooting, burning, or stabbing sensation. Pain can radiate down the
legs and can be increased by bending, twisting, lifting, standing, or
walking. While the physical effects of back pain are always at the
forefront, back pain also can have psychological effects. Back pain has
been linked to depression, anxiety, stress, and avoidance behaviors due
to mentally not being able to cope with the physical pain. Both acute
and chronic back pain can be associated with psychological distress in
the form of anxiety (worries, stress) or depression (sadness,
discouragement). Psychological distress is a common reaction to the
suffering aspects of acute back pain, even when symptoms are short-term
and not medically serious.
</p>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Acutebackpainworkup.png"><img class="mw-file-element" data-file-height="1050" data-file-width="1413" height="297" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/66/Acutebackpainworkup.png/400px-Acutebackpainworkup.png" width="400" /></a><figcaption>Diagnostic work-up for acute back pain.</figcaption></figure>
<p>Initial assessment of back pain consists of a history and physical examination.
Important characterizing features of back pain include location,
duration, severity, history of prior back pain and possible trauma.
Other important components of the patient history include age, physical
trauma, prior history of cancer, fever, weight loss, urinary
incontinence, progressive weakness or expanding sensory changes, which
can indicate a medically urgent condition.
</p><p>Physical examination of the back should assess for posture and
deformities. Pain elicited by palpating certain structures may be
helpful in localizing the affected area. A neurologic exam is needed to
assess for changes in <a href="https://en.wikipedia.org/wiki/Gait" title="Gait">gait</a>, sensation and motor function.
</p><p>Determining if there are radicular symptoms, such as pain,
numbness or weakness that radiate down limbs, is important for
differentiating between central and peripheral causes of back pain. The <a href="https://en.wikipedia.org/wiki/Straight_leg_raise" title="Straight leg raise">straight leg test</a> is a maneuver used to determine the presence of lumbosacral <a href="https://en.wikipedia.org/wiki/Radiculopathy" title="Radiculopathy">radiculopathy</a>, which occurs when there is irritation in the <a href="https://en.wikipedia.org/wiki/Nerve_root" title="Nerve root">nerve root</a>
that causes neurologic symptoms such as numbness and tingling.
Non-radicular back pain is most commonly caused by injury to the spinal
muscles or ligaments, <a href="https://en.wikipedia.org/wiki/Degenerative_disc_disease" title="Degenerative disc disease">degenerative spinal disease</a> or a <a href="https://en.wikipedia.org/wiki/Spinal_disc_herniation" title="Spinal disc herniation">herniated disc</a>. Disc herniation and foraminal stenosis are the most common causes of radiculopathy.
</p><p>Imaging of the spine and laboratory tests is not recommended during the acute phase. This assumes that there is no reason to expect that the patient has an underlying problem. In most cases, the pain subsides naturally after several weeks.
People who seek diagnosis through imaging are typically less likely to
receive a better outcome than are those who wait for the condition to
resolve.
</p>
<h3><span class="mw-headline" id="Imaging">Imaging</span></h3><p><a href="https://en.wikipedia.org/wiki/Magnetic_resonance_imaging" title="Magnetic resonance imaging">Magnetic resonance imaging</a>
(MRI) is the preferred modality for the evaluation of back pain and
visualization of bone, soft tissue, nerves and ligaments. X-rays are a
less costly initial option offered to patients with a low clinical
suspicion of infection or malignancy, and they are combined with
laboratory studies for interpretation.
</p><p>Imaging is not warranted for most patients with acute back pain.
Without signs and symptoms indicating a serious underlying condition,
imaging does not improve clinical outcomes in these patients. Four to
six weeks of treatment is appropriate before consideration of imaging
studies. If a serious condition is suspected, MRI is usually most
appropriate. Computed tomography is an alternative if MRI is
contraindicated or unavailable.
In cases of acute back pain, MRI is recommended for those with major
risk factors or clinical suspicion of cancer, spinal infection or severe
progressive neurological deficits.
For patients with subacute to chronic back pain, MRI is recommended if
minor risk factors exist for cancer, ankylosing spondylitis or vertebral
compression fracture, or if significant trauma or symptomatic spinal
stenosis is present.
</p><p>Early imaging studies during the acute phase do not improve care or prognosis. Imaging findings are not correlated with severity or outcome.
</p>
<h3><span class="mw-headline" id="Laboratory_studies">Laboratory studies</span></h3><p>Laboratory studies are employed when there are suspicions of autoimmune causes, infection or malignancy. Laboratory testing may include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/White_blood_cell_count" title="White blood cell count">white blood cell (WBC) count</a>, <a href="https://en.wikipedia.org/wiki/Erythrocyte_sedimentation_rate" title="Erythrocyte sedimentation rate">erythrocyte sedimentation rate</a> (ESR), and <a href="https://en.wikipedia.org/wiki/C-reactive_protein" title="C-reactive protein">C-reactive protein</a> (CRP).
</p>
<ul><li>Elevated ESR could indicate infection, malignancy, chronic disease, inflammation, trauma or tissue <a href="https://en.wikipedia.org/wiki/Ischemia" title="Ischemia">ischemia</a>.</li><li>Elevated CRP levels are associated with infection.</li></ul>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Ossifikation_Ligamentum_longitudinale_posterius_BWS_-_CT_axial_und_sagittal.jpg"><img class="mw-file-element" data-file-height="456" data-file-width="738" height="247" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c7/Ossifikation_Ligamentum_longitudinale_posterius_BWS_-_CT_axial_und_sagittal.jpg/220px-Ossifikation_Ligamentum_longitudinale_posterius_BWS_-_CT_axial_und_sagittal.jpg" width="400" /></a><figcaption>CT scan of the spine, showing calcification of the longitudinal posterior ligament.</figcaption></figure>
<p>Because laboratory testing lacks specificity, MRI with and without
contrast media and often, biopsy are essential for accurate diagnosis
</p>
<h3><span class="mw-headline" id="Red_flags">Red flags</span></h3><p>Imaging
is not typically needed in the initial diagnosis or treatment of back
pain. However, if there are certain "red flag" symptoms present, <a href="https://en.wikipedia.org/wiki/Radiography" title="Radiography">plain radiographs</a> (X-ray), <a href="https://en.wikipedia.org/wiki/CT_scan" title="CT scan">CT scan</a> or magnetic resonance imaging may be recommended. These red flags include:
</p>
<ul><li>History of cancer</li><li>Unexplained weight loss</li><li><a href="https://en.wikipedia.org/wiki/Immunosuppression" title="Immunosuppression">Immunosuppression</a></li><li><a href="https://en.wikipedia.org/wiki/Urinary_tract_infection" title="Urinary tract infection">Urinary infection</a></li><li>Intravenous drug use</li><li>Prolonged use of corticosteroids</li><li>Back pain not improved with conservative management</li><li>History of significant trauma</li><li>Minor fall or heavy lift in a potentially osteoporotic or elderly individual</li><li>Acute onset of <a href="https://en.wikipedia.org/wiki/Urinary_retention" title="Urinary retention">urinary retention</a>, <a href="https://en.wikipedia.org/wiki/Overflow_incontinence" title="Overflow incontinence">overflow incontinence</a>, loss of anal sphincter tone, or fecal incontinence</li><li><a href="https://en.wikipedia.org/wiki/Saddle_anesthesia" title="Saddle anesthesia">Saddle anesthesia</a></li><li>Global or progressive motor weakness in the lower limbs</li></ul>
<h2><span class="mw-headline" id="Prevention">Prevention</span></h2><p>Moderate-quality
evidence exists that suggests that the combination of education and
exercise may reduce an individual's risk of developing an episode of low
back pain. Lesser-quality evidence points to exercise alone as a possible deterrent to the risk of the condition.
</p>
<h2><span class="mw-headline" id="Management">Management</span></h2><h3><span class="mw-headline" id="Nonspecific_pain">Nonspecific pain</span></h3><p>Patients with uncomplicated back pain should be encouraged to remain active and to return to normal activities.
</p><p>The <a href="https://en.wikipedia.org/wiki/Pain_management" title="Pain management">management</a>
goals when treating back pain are to achieve maximal reduction in pain
intensity as rapidly as possible, to restore the individual's ability to
function in everyday activities, to help the patient cope with residual
pain, to assess for side effects of therapy and to facilitate the
patient's passage through the legal and socioeconomic impediments to
recovery. For many, the goal is to keep the pain at a manageable level
to progress with rehabilitation, which then can lead to long-term pain
relief. Also, for some people the goal is to use nonsurgical therapies
to manage the pain and avoid major surgery, while for others surgery may
represent the quickest path to pain relief.
</p><p>Not all treatments work for all conditions or for all individuals
with the same condition, and many must try several treatment options to
determine what works best for them. The present stage of the condition
(acute or chronic) is also a determining factor in the choice of
treatment. Only a minority of people with back pain (most estimates are
1–10%) require surgery.
</p>
<h4><span class="mw-headline" id="Nonmedical">Nonmedical</span></h4><p>Back
pain is generally first treated with nonpharmacological therapy, as it
typically resolves without the use of medication. Superficial heat and
massage, acupuncture and spinal manipulation therapy may be recommended.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Heat_therapy" title="Heat therapy">Heat therapy</a> is useful for back <a href="https://en.wikipedia.org/wiki/Spasm" title="Spasm">spasms</a> or other conditions. A review concluded that heat therapy can reduce symptoms of acute and subacute low-back pain.</li><li>Regular activity and gentle stretching exercises is encouraged in
uncomplicated back pain and is associated with better long-term
outcomes. Physical therapy to strengthen the muscles in the abdomen and around the spine may also be recommended.
These exercises are associated with better patient satisfaction,
although they have not been shown to provide functional improvement. However, one review found that exercise is effective for chronic back pain but not for acute pain. Exercise should be performed under the supervision of a healthcare professional.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Massage_therapy" title="Massage therapy">Massage therapy</a> may provide short-term pain relief, but not functional improvement, for those with acute lower back pain.
It may also offer short-term pain relief and functional improvement for
those with long-term (chronic) and subacute lower pack pain, but this
benefit does not appear to be sustained after six months of treatment. There do not appear to be any serious adverse effects associated with massage.</li><li><a href="https://en.wikipedia.org/wiki/Acupuncture" title="Acupuncture">Acupuncture</a> may provide some relief for back pain. However, further research with stronger evidence is needed.</li><li><a href="https://en.wikipedia.org/wiki/Spinal_manipulation" title="Spinal manipulation">Spinal manipulation</a> appears to provide similar effects to other recommended treatments for chronic low back pain.
There is no evidence it is more effective than other therapies or sham,
or as an adjunct to other treatments, for acute low back pain</li><li>"Back school" is an intervention that consists of both education and physical exercises.There is no strong evidence supporting the use of back school for treating acute, subacute, or chronic non-specific back pain.</li><li><a href="https://en.wikipedia.org/wiki/Shoe_insert" title="Shoe insert">Insoles</a> appear to be an ineffective treatment intervention.</li><li>While <a href="https://en.wikipedia.org/wiki/Traction_(orthopedics)" title="Traction (orthopedics)">traction</a>
for back pain is often used in combination with other approaches, there
appears to be little or no impact on pain intensity, functional status,
global improvement or return to work.</li></ul>
<h4><span class="mw-headline" id="Medication">Medication</span></h4><p>If nonpharmacological measures are ineffective, medication may be administered.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">Non-steroidal anti-inflammatory drugs (NSAIDs)</a> are typically attempted first. NSAIDs have been proven more effective than placebo, and are usually more effective than <a href="https://en.wikipedia.org/wiki/Paracetamol" title="Paracetamol">paracetamol (acetaminophen)</a>.</li><li>Long-term use of <a href="https://en.wikipedia.org/wiki/Opioid" title="Opioid">opioids</a> has not been tested to determine whether it is effective or safe for treating chronic lower back pain. For severe back pain not relieved by NSAIDs or acetaminophen, opioids may be used. Opioids may not be better than NSAIDs or antidepressants for chronic back pain with regard to pain relief and gain of function.</li><li><a href="https://en.wikipedia.org/wiki/Muscle_relaxant" title="Muscle relaxant">Skeletal muscle relaxers</a> may also be used. Their short-term use has been proven effective in the relief of acute back pain. However, the evidence of this effect has been disputed, and these medications do have negative side effects.</li><li>For patients with nerve root pain and acute radiculopathy, there is evidence that a single dose of steroids, such as <a href="https://en.wikipedia.org/wiki/Dexamethasone" title="Dexamethasone">dexamethasone</a>, may provide pain relief.</li><li><a href="https://en.wikipedia.org/wiki/Epidural_steroid_injection" title="Epidural steroid injection">Epidural corticosteroid injection</a> (ESI) is a procedure in which steroid medications are injected into the <a href="https://en.wikipedia.org/wiki/Epidural_space" title="Epidural space">epidural space</a>. The steroid medications reduce inflammation and thus decrease pain and improve function.
ESI has long been used to both diagnose and treat back pain, although
recent studies have shown a lack of efficacy in treating low back pain.</li></ul>
<h3><span class="mw-headline" id="Surgery">Surgery</span></h3><p>Surgery for back pain is typically used as a last resort, when serious neurological deficit is evident.
A 2009 systematic review of back surgery studies found that, for
certain diagnoses, surgery is moderately better than other common
treatments, but the benefits of surgery often decline in the long term.
</p><p>Surgery may sometimes be appropriate for people with severe <a href="https://en.wikipedia.org/wiki/Myelopathy" title="Myelopathy">myelopathy</a> or <a href="https://en.wikipedia.org/wiki/Cauda_equina_syndrome" title="Cauda equina syndrome">cauda equina syndrome</a>. Causes of neurological deficits can include <a href="https://en.wikipedia.org/wiki/Spinal_disc_herniation" title="Spinal disc herniation">spinal disc herniation</a>, <a href="https://en.wikipedia.org/wiki/Spinal_stenosis" title="Spinal stenosis">spinal stenosis</a>, <a href="https://en.wikipedia.org/wiki/Degenerative_disc_disease" title="Degenerative disc disease">degenerative disc disease</a>, <a href="https://en.wikipedia.org/wiki/Neoplasm" title="Neoplasm">tumor</a>, infection, and spinal <a href="https://en.wikipedia.org/wiki/Hematoma" title="Hematoma">hematomas</a>, all of which can impinge on the nerve roots around the spinal cord. There are multiple surgical options to treat back pain, and these options vary depending on the cause of the pain.
</p><p>When a herniated disc is compressing the nerve roots, hemi- or partial-<a href="https://en.wikipedia.org/wiki/Laminectomy" title="Laminectomy">laminectomy</a> or <a href="https://en.wikipedia.org/wiki/Discectomy" title="Discectomy">discectomy</a> may be performed, in which the material compressing on the nerve is removed. A mutli-level laminectomy can be done to widen the spinal canal in the case of spinal stenosis. A <a href="https://en.wikipedia.org/wiki/Foraminotomy" title="Foraminotomy">foraminotomy</a> or foraminectomy may also be necessary, if the vertebrae are causing significant nerve root compression.
A discectomy is performed when the intervertebral disc has herniated or
torn. It involves removing the protruding disc, either a portion of it
or all of it, that is placing <a href="https://en.wikipedia.org/wiki/Pressure" title="Pressure">pressure</a> on the <a href="https://en.wikipedia.org/wiki/Nerve_root" title="Nerve root">nerve root</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Total_Disc_Replacement" title="Total Disc Replacement">Total disc replacement</a>
can also be performed, in which the source of the pain (the damaged
disc) is removed and replaced, while maintaining spinal mobility. When an entire disc is removed (as in discectomy), or when the vertebrae are unstable, spinal fusion surgery may be performed. <a href="https://en.wikipedia.org/wiki/Spinal_fusion" title="Spinal fusion">Spinal fusion</a> is a procedure in which <a href="https://en.wikipedia.org/wiki/Bone_grafting" title="Bone grafting">bone grafts</a>
and metal hardware is used to fix together two or more vertebrae, thus
preventing the bones of the spinal column from compressing on the spinal
cord or nerve roots.
</p><p>If infection, such as a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_epidural_abscess" title="Spinal epidural abscess">spinal epidural abscess</a>, is the source of the back pain, surgery may be indicated when a trial of antibiotics is ineffective. Surgical evacuation of spinal <a href="https://en.wikipedia.org/wiki/Hematoma" title="Hematoma">hematoma</a> can also be attempted, if the blood products fail to break down on their own.
</p>
<h2><span class="mw-headline" id="Pregnancy">Pregnancy</span></h2><p>About 50% of women experience low back pain during pregnancy.
Some studies have suggested that women who have experienced back pain
before pregnancy are at a higher risk of experiencing back pain during
pregnancy. It may be severe enough to cause significant pain and disability in as many as one third of pregnant women. Back pain typically begins at approximately 18 weeks of <a href="https://en.wikipedia.org/wiki/Gestation" title="Gestation">gestation</a> and peaks between 24 and 36 weeks.
Approximately 16% of women who experience back pain during pregnancy
report continued back pain years after pregnancy, indicating that those
with significant back pain are at greater risk of back pain following
pregnancy.
</p><p>Biomechanical factors of pregnancy shown to be associated with back pain include increased curvature of the lower back, or <a href="https://en.wikipedia.org/wiki/Lordosis" title="Lordosis">lumbar lordosis</a>, to support the added weight on the abdomen. Also, the hormone <a href="https://en.wikipedia.org/wiki/Relaxin" title="Relaxin">relaxin</a> is released during pregnancy, which softens the structural tissues in the pelvis and lower back to prepare for <a href="https://en.wikipedia.org/wiki/Vaginal_delivery" title="Vaginal delivery">vaginal delivery</a>. This softening and increased flexibility of the ligaments and joints in the lower back can result in pain. Back pain in pregnancy is often accompanied by <a href="https://en.wikipedia.org/wiki/Radiculopathy" title="Radiculopathy">radicular symptoms</a>, suggested to be caused by the baby pressing on the <a href="https://en.wikipedia.org/wiki/Sacral_plexus" title="Sacral plexus">sacral plexus</a> and <a href="https://en.wikipedia.org/wiki/Lumbar_plexus" title="Lumbar plexus">lumbar plexus</a> in the pelvis.
</p><p>Typical factors aggravating the back pain of pregnancy include
standing, sitting, forward bending, lifting and walking. Back pain in
pregnancy may also be characterized by pain radiating into the thigh and
buttocks, nighttime pain severe enough to wake the patient, pain that
is increased at night or pain that is increased during the daytime.
</p><p>Local heat, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acetaminophen" title="Acetaminophen">acetaminophen</a> (paracetamol) and massage can be used to help relieve pain. Avoiding standing for prolonged periods of time is also suggested.
</p>
<h2><span class="mw-headline" id="Economics">Economics</span></h2>Although
back pain does not typically cause permanent disability, it is a
significant contributor to physician visits and missed work days in the
United States, and is the single leading cause of disability worldwide.
The American Academy of Orthopaedic Surgeons report approximately 12
million visits to doctor's offices each year are due to back pain. Missed work and disability related to low back pain costs over $50 billion each year in the United States. In the United Kingdom in 1998, approximately £1.6 billion per year was spent on expenses related to disability from back pain.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-61167828064763545532024-03-27T20:33:00.003-04:002024-03-27T20:33:20.309-04:00Chronic pain<div class="vector-column-end">
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<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Chronic Pain</th></tr><tr><th class="infobox-label" scope="row">Other names</th><td class="infobox-data">Burning pain, dull pain, throbbing pain</td></tr><tr><td class="infobox-full-data" colspan="2"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Runners-knee_SAG.jpg"><img alt="Chronic pain can be caused by joint or bone damage during heavy and irregular sports." class="mw-file-element" data-file-height="1080" data-file-width="1920" height="225" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Runners-knee_SAG.jpg/295px-Runners-knee_SAG.jpg" width="400" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2">Heavy and irregular sports, in a long term, can be the basis of <a href="https://en.wikipedia.org/wiki/Joint" title="Joint">joint</a> or bone injuries and as a result chronic pain.</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data">Specialist in pain, <a href="https://en.wikipedia.org/wiki/Neurology" title="Neurology">neurology</a> and <a href="https://en.wikipedia.org/wiki/Psychology" title="Psychology">psychology</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Signs_and_symptoms" title="Signs and symptoms">Symptoms</a></th><td class="infobox-data">Pain lasts longer than the expected period of recovery.</td></tr><tr><th class="infobox-label" scope="row">Usual onset</th><td class="infobox-data">All age groups</td></tr><tr><th class="infobox-label" scope="row">Duration</th><td class="infobox-data">From three months to several years</td></tr><tr><th class="infobox-label" scope="row">Causes</th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Blood_sugar" title="Blood sugar">high blood sugar</a>, cancer, genetic disorder in neural differentiation, tissue damage, <a href="https://en.wikipedia.org/wiki/Neurological_disorder" title="Neurological disorder">neurological disorder</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Viral_diseases" title="Viral diseases">viral diseases</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Risk_factor" title="Risk factor">Risk factors</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a>, <a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a> and <a href="https://en.wikipedia.org/wiki/Cardiovascular_disease" title="Cardiovascular disease">heart diseases</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_diagnosis" title="Medical diagnosis">Diagnostic method</a></th><td class="infobox-data">Based on <a href="https://en.wikipedia.org/wiki/Medical_history" title="Medical history">medical history</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Clinical_examination" title="Clinical examination">clinical examination</a>, questionnaire and <a href="https://en.wikipedia.org/wiki/Neuroimaging" title="Neuroimaging">neuroimaging</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">Differential diagnosis</a></th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gastric_ulcer" title="Gastric ulcer">gastric ulcer</a>, <a href="https://en.wikipedia.org/wiki/Bone_fracture" title="Bone fracture">bone fracture</a>, <a href="https://en.wikipedia.org/wiki/Hernia" title="Hernia">hernia</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neoplasia" title="Neoplasia">neoplasia</a> of the spinal cord</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medication" title="Medication">Medication</a></th><td class="infobox-data">Non-opioid: <a href="https://en.wikipedia.org/wiki/Ibuprofen" title="Ibuprofen">ibuprofen</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acetaminophen" title="Acetaminophen">acetaminophen</a>, <a href="https://en.wikipedia.org/wiki/Naproxen" title="Naproxen">naproxen</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug" title="Non-steroidal anti-inflammatory drug">NSAIDs</a> and <a href="https://en.wikipedia.org/wiki/Olanzapine" title="Olanzapine">olanzapine</a> <br /> Opioid: <a href="https://en.wikipedia.org/wiki/Morphine" title="Morphine">morphine</a>, <a href="https://en.wikipedia.org/wiki/Codeine" title="Codeine">codeine</a>, <a href="https://en.wikipedia.org/wiki/Endorphins" title="Endorphins">endorphins</a> and <a href="https://en.wikipedia.org/wiki/Buprenorphine" title="Buprenorphine">buprenorphine</a></td></tr><tr><th class="infobox-label" scope="row">Frequency</th><td class="infobox-data">8% to 55.2% in different countries</td></tr></tbody></table><p><b>Chronic pain</b> or <b>chronic pain syndrome</b> is a type of <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>
that is also known by other titles such as gradual burning pain,
electrical pain, throbbing pain, and nauseating pain. This type of pain
is sometimes confused with acute pain and can last from three months to several years; Various diagnostic manuals such as <a href="https://en.wikipedia.org/wiki/DSM-5" title="DSM-5">DSM-5</a> and <a href="https://en.wikipedia.org/wiki/ICD-11" title="ICD-11">ICD-11</a>
have proposed several definitions of chronic pain, but the accepted
definition is that it is "pain that lasts longer than the expected <a href="https://en.wikipedia.org/wiki/Post-anesthesia_care_unit" title="Post-anesthesia care unit">period of recovery</a>."
</p><p>Creating a pain mechanism prevents possible damage to the body,
but chronic pain is a pain without biological value (doesn't have a
positive effect). This pain has different divisions; <a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">Cancer</a>, post-<a href="https://en.wikipedia.org/wiki/Major_trauma" title="Major trauma">traumatic</a> or <a href="https://en.wikipedia.org/wiki/Surgery" title="Surgery">surgery</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Musculoskeletal" title="Musculoskeletal">musculoskeletal</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Visceral" title="Visceral">visceral</a> are the most important of these divisions. Various factors cause the formation of chronic pain, which can be <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurogenic" title="Neurogenic">neurogenic</a> (gene-dependent), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nociceptive" title="Nociceptive">nociceptive</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neuropathic" title="Neuropathic">neuropathic</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Psychological" title="Psychological">psychological</a> or unknown. Some diseases such as <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a> (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/High_blood_sugar" title="High blood sugar">high blood sugar</a>), <a href="https://en.wikipedia.org/wiki/Shingles" title="Shingles">shingles</a> (some <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Viral_diseases" title="Viral diseases">viral diseases</a>), <a href="https://en.wikipedia.org/wiki/Phantom_limb" title="Phantom limb">phantom limb</a> pain, <a href="https://en.wikipedia.org/wiki/Hypertension" title="Hypertension">hypertension</a> and <a href="https://en.wikipedia.org/wiki/Stroke" title="Stroke">stroke</a> also play a role in the formation of chronic pain. The most common types of chronic pain are <a href="https://en.wikipedia.org/wiki/Back_pain" title="Back pain">back pain</a>, severe <a href="https://en.wikipedia.org/wiki/Headache" title="Headache">headache</a>, <a href="https://en.wikipedia.org/wiki/Migraine" title="Migraine">migraine</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Facial_pain" title="Facial pain">facial pain</a>.
</p><p>Chronic pain can cause very severe psychological and physical
effects that sometimes continue until the end of life. Analysis of the <a href="https://en.wikipedia.org/wiki/Grey_matter" title="Grey matter">grey matter</a> (damage to <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> neurons), <a href="https://en.wikipedia.org/wiki/Insomnia" title="Insomnia">insomnia</a> and <a href="https://en.wikipedia.org/wiki/Sleep_deprivation" title="Sleep deprivation">sleep deprivation</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Metabolic" title="Metabolic">metabolic</a> problems, <a href="https://en.wikipedia.org/wiki/Chronic_stress" title="Chronic stress">chronic stress</a>, <a href="https://en.wikipedia.org/wiki/Obesity" title="Obesity">obesity</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_attack" title="Heart attack">heart attack</a> are examples of physical disorder; And <a href="https://en.wikipedia.org/wiki/Depression_(mood)" title="Depression (mood)">depression</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cognitive_disorders" title="Cognitive disorders">cognitive disorders</a>, <a class="new" href="https://en.wikipedia.org/w/index.php?title=Perceived_injustice&action=edit&redlink=1" title="Perceived injustice (page does not exist)">perceived injustice</a> (PI) and <a href="https://en.wikipedia.org/wiki/Neurosis" title="Neurosis">neurosis</a> are examples of <a href="https://en.wikipedia.org/wiki/Mental_disorder" title="Mental disorder">mental disorder</a>.
</p><p>A wide range of treatments are performed for this disease; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Drug_therapy" title="Drug therapy">Drug therapy</a> (types of <a href="https://en.wikipedia.org/wiki/Opioid" title="Opioid">opioid</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nonopiod_analgesics" title="Nonopiod analgesics">non-opioid</a> drugs), <a href="https://en.wikipedia.org/wiki/Cognitive_behavioral_therapy" title="Cognitive behavioral therapy">cognitive behavioral therapy</a> and <a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">physical therapy</a> are the most significant of them. Medicines are usually associated with <a href="https://en.wikipedia.org/wiki/Side_effect" title="Side effect">side effects</a> and are prescribed when the effects of pain become severe. Medicines such as <a href="https://en.wikipedia.org/wiki/Aspirin" title="Aspirin">aspirin</a> and <a href="https://en.wikipedia.org/wiki/Ibuprofen" title="Ibuprofen">ibuprofen</a> are used for milder pain and <a href="https://en.wikipedia.org/wiki/Morphine" title="Morphine">morphine</a> and <a href="https://en.wikipedia.org/wiki/Codeine" title="Codeine">codeine</a>
for severe pain. Other treatment methods, such as behavioral therapy
and physiotherapy, are often used as a supplement along with drugs due
to their low effectiveness. There is currently no definitive cure for
any of these methods, and research continues into a wide variety of new
management and therapeutic interventions, such as <a href="https://en.wikipedia.org/wiki/Nerve_block" title="Nerve block">nerve block</a> and <a href="https://en.wikipedia.org/wiki/Radiation_therapy" title="Radiation therapy">radiation therapy</a>.
</p><p>Chronic pain is considered a kind of <a href="https://en.wikipedia.org/wiki/Disease" title="Disease">disease</a>, this type of pain has affected the people of the world more than diabetes, cancer and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_diseases" title="Heart diseases">heart diseases</a>. During several <a href="https://en.wikipedia.org/wiki/Epidemiology" title="Epidemiology">epidemiological</a> studies conducted in different countries, wide differences in the <a href="https://en.wikipedia.org/wiki/Prevalence" title="Prevalence">prevalence</a> rate of chronic pain have been reported from 8% to 55.2% in countries; For example, studies evaluate the incidence in <a href="https://en.wikipedia.org/wiki/Iran" title="Iran">Iran</a> and <a href="https://en.wikipedia.org/wiki/Canada" title="Canada">Canada</a> between 10% and 20% and in the <a href="https://en.wikipedia.org/wiki/United_States" title="United States">United States</a>
between 30% and 40%. The results show that an average of 8% to 11.2% of
people in different countries have severe chronic pain, and its
epidemic is higher in industrialized countries than in other countries.
According to the estimates of the <a href="https://en.wikipedia.org/wiki/American_Medical_Association" title="American Medical Association">American Medical Association</a>, the costs related to this disease in this country are about 560 to 635 billion dollars.
</p>
<h2><span class="mw-headline" id="Classification">Classification</span></h2></div></div></div><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Pain#Classification" title="Pain">Pain § Classification</a></div>
<p>The <a href="https://en.wikipedia.org/wiki/International_Association_for_the_Study_of_Pain" title="International Association for the Study of Pain">International Association for the Study of Pain</a> (IASP) defines chronic pain as a general <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a> without <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Biological" title="Biological">biological</a> value that sometimes continues even after the healing of the affected area; A type of pain that cannot be classified as acute pain
and lasts longer than expected to heal, or typically, pain that has
been experienced on most days or daily for the past six months, is
considered chronic pain. According to the <a href="https://en.wikipedia.org/wiki/DSM-5" title="DSM-5">DSM-5</a> index, a complication is "<i>chronic</i>"
when the resulting complication (pain, disorder, and illness) lasts for
a period of more than six months (this type of classification does not
have any prerequisites such as physical or mental injury).
The classification of chronic pain is not only limited to pains that
arise in the presence of real tissue damage (secondary pains resulting
from a primary event); The title "nociplastic pain" or primary pain is
related to the pains that occur in the absence of a health-threatening
factor, such as disease or damage to the body's <a href="https://en.wikipedia.org/wiki/Somatosensory_system" title="Somatosensory system">somatosensory system</a>, and as a result of permanent <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerve</a> stimulation.
</p><p>The <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/International_Statistical_Classification_of_Diseases" title="International Statistical Classification of Diseases">International Statistical Classification of Diseases</a></i>, in its 11th edition (<a href="https://en.wikipedia.org/wiki/ICD-11" title="ICD-11">ICD-11</a>), proposed a seven-category classification for chronic pain:
</p>
<ol><li>Primary chronic pain: Defined by 3 months of continuous pain in one or more areas of the <a href="https://en.wikipedia.org/wiki/Human_body" title="Human body">body</a>, the origin of which is not understood.</li><li>Chronic cancer pain: pain in one of the body's organs caused by <a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a> damage (in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Internal_organs" title="Internal organs">internal organs</a>, <a href="https://en.wikipedia.org/wiki/Bone" title="Bone">bone</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Skeletal_muscular" title="Skeletal muscular">skeletal muscular</a>) is formed.</li><li>Chronic pain post-<a href="https://en.wikipedia.org/wiki/Major_trauma" title="Major trauma">traumatic</a> or <a href="https://en.wikipedia.org/wiki/Surgery" title="Surgery">surgery</a>: Pain that occurs 3 months after an injury or surgery, without taking into account <a href="https://en.wikipedia.org/wiki/Infection" title="Infection">infectious</a> conditions and the severity of tissue damage; Also, the person's past pain is not important in this classification.</li><li>Chronic <a href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">neuropathic pain</a>: pain caused by damage to the <a href="https://en.wikipedia.org/wiki/Somatosensory_system" title="Somatosensory system">somatosensory nervous system</a>.</li><li>Chronic <a href="https://en.wikipedia.org/wiki/Headache" title="Headache">headache</a> and <a href="https://en.wikipedia.org/wiki/Orofacial_pain" title="Orofacial pain">orofacial pain</a>: pain that originates in the head or <a href="https://en.wikipedia.org/wiki/Face" title="Face">face</a>, and occurs for 50% or more days over a 3 months period.</li><li>Chronic visceral pain: pain originating in an internal organ.</li><li>Chronic musculoskeletal pain: pain originating in the bones, muscles, <a href="https://en.wikipedia.org/wiki/Joint" title="Joint">joints</a> or <a href="https://en.wikipedia.org/wiki/Connective_tissue" title="Connective tissue">connective tissue</a>.</li></ol>
<p>Also, the <a href="https://en.wikipedia.org/wiki/World_Health_Organization" title="World Health Organization">World Health Organization</a>
(WHO) states that optional criteria or codes can be used in the
classification of chronic pain for each of the seven categories of
chronic pain (for example, "<i>diabetic</i> neuropathic" pain).
</p><p>Another classification for chronic pain is "nociceptive" (caused by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Inflamed" title="Inflamed">inflamed</a> or damaged tissue that activates special pain sensors called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nociceptors" title="Nociceptors">nociceptors</a>) and "neuropathic" (caused by damage or malfunction of the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a>).
The type of "nociceptive" itself is divided into two parts:
"superficial" and "deep"; also, deep pains are divided into two parts:
"deep physical" and "deep visceral" pain. "neuropathic" pains are also divided into "peripheral" (source The <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a>) and "central" (<a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">Central nervous system</a> from the brain or <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>) are divided. <a href="https://en.wikipedia.org/wiki/Peripheral_neuropathy" title="Peripheral neuropathy">Peripheral neuropathic pain</a> is often described as "burning", "tingling", "electrical", "stabbing", or "pins and needles".
</p><p>"Superficial pain" is the result of the activation of pain receptors in the <a href="https://en.wikipedia.org/wiki/Skin" title="Skin">skin</a> or superficial tissues; "Deep somatic pain" is caused by stimulation of pain receptors in <a href="https://en.wikipedia.org/wiki/Ligament" title="Ligament">ligaments</a>, <a href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">tendons</a>, bones, <a href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a>, <a href="https://en.wikipedia.org/wiki/Fascia" title="Fascia">fascia</a>, and muscles. (this type of pain is constant but weak)
and "deep visceral pain" is pain that originates from one of the body's
organs. Deep pain is often very difficult to localize and occurs in
multiple areas of the body when injured or inflamed. In the "deep
visceral" type, the feeling of pain exists in a place far from the
injury, for this reason it is also called vague pain.
</p>
<h2><span class="mw-headline" id="Etiology">Etiology</span></h2><p>Chronic
pain has many pathophysiological and environmental causes and can occur
in cases such as neuropathy of the central nervous system, after
cerebral hemorrhage, tissue damage such as extensive burns,
inflammation, autoimmune disorders such as rheumatoid arthritis,
psychological stress such as headache, migraine or abdominal pain
(caused by emotional, psychological or behavioral) and mechanical pain
caused by tissue wear and tear such as arthritis.
In some cases, chronic pain can be caused by genetic factors which
interfere with neuronal differentiation, leading to a permanently
lowered threshold for pain.
</p><p>The <a href="https://en.wikipedia.org/wiki/Pathophysiology" title="Pathophysiology">pathophysiology</a> of chronic pain remains unclear. Many theories of chronic pain
fail to clearly explain why the same pathological conditions do not
invariably result in chronic pain. Patients' anatomical predisposition
to proximal neural compression (in particular of peripheral nerves) may
be the answer to this conundrum. Difficulties in diagnosing proximal
neural lesion may account for the theoretical perplexity of chronic pain.
</p>
<h3><span class="mw-headline" id="Pathophysiology">Pathophysiology</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Discogenic_Pain.png"><img class="mw-file-element" data-file-height="1024" data-file-width="768" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/27/Discogenic_Pain.png/220px-Discogenic_Pain.png" width="300" /></a><figcaption>Continuous pressure on the spine can destroy the <a href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">intervertebral disc</a> and cause the <a href="https://en.wikipedia.org/wiki/Sciatic_nerve" title="Sciatic nerve">sciatic nerve</a> to actively produce pain.</figcaption></figure>
<p>The mechanism of continuous activation and transmission of pain messages, leads the body to an activity to relieve pain (a <a href="https://en.wikipedia.org/wiki/Mechanism_(biology)" title="Mechanism (biology)">mechanism</a> to prevent damage in the body), this action causes the release of <a href="https://en.wikipedia.org/wiki/Prostaglandin" title="Prostaglandin">prostaglandin</a> and increase the sensitivity of that part to <a href="https://en.wikipedia.org/wiki/Stimulation" title="Stimulation">stimulation</a>; Prostaglandin secretion causes unbearable and chronic pain. Under persistent activation, the transmission of pain signals to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Posterior_horn_of_spinal_cord" title="Posterior horn of spinal cord">dorsal horn</a> may produce a <a href="https://en.wikipedia.org/wiki/Pain_wind-up" title="Pain wind-up">pain wind-up</a>
phenomenon. This triggers changes that lower the threshold for pain
signals to be transmitted. In addition, it may cause non-nociceptive
nerve fibers to respond to, generate, and transmit pain signals. Researchers believe that the nerve fibers that cause this type of pain are <a href="https://en.wikipedia.org/wiki/Group_C_nerve_fiber" title="Group C nerve fiber">group C nerve fibers</a>; These fibers are not <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myelinated" title="Myelinated">myelinated</a> (have low transmission speed) and cause long-term pain.
</p><p>These changes in neural structure can be explained by <a href="https://en.wikipedia.org/wiki/Neuroplasticity" title="Neuroplasticity">neuroplasticity</a>. When there is chronic pain, the <a href="https://en.wikipedia.org/wiki/Somatotopic_arrangement" title="Somatotopic arrangement">somatotopic arrangement</a> of the body (the distribution view of nerve cells) is abnormally changed due to continuous stimulation and can cause <a href="https://en.wikipedia.org/wiki/Allodynia" title="Allodynia">allodynia</a> or <a href="https://en.wikipedia.org/wiki/Hyperalgesia" title="Hyperalgesia">hyperalgesia</a>. In chronic pain, this process is difficult to reverse or stop once established. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/EEG" title="EEG">EEG</a> of people with chronic pain showed that brain activity and <a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" title="Synaptic plasticity">synaptic plasticity</a> change as a result of pain, and specifically, the relative activity of <a href="https://en.wikipedia.org/wiki/Beta_wave" title="Beta wave">beta wave</a> increases and <a href="https://en.wikipedia.org/wiki/Alpha_wave" title="Alpha wave">alpha</a> and <a href="https://en.wikipedia.org/wiki/Theta_wave" title="Theta wave">theta waves</a> decrease.
</p><p>Inefficient management of <a href="https://en.wikipedia.org/wiki/Dopamine" title="Dopamine">dopamine</a> secretion in the brain can act as a common mechanism between chronic pain, <a href="https://en.wikipedia.org/wiki/Insomnia" title="Insomnia">insomnia</a> and <a href="https://en.wikipedia.org/wiki/Major_depressive_disorder" title="Major depressive disorder">major depressive disorder</a> and cause its unpleasant side effects. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Astrocytes" title="Astrocytes">Astrocytes</a>, <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">microglia</a> and <a href="https://en.wikipedia.org/wiki/Satellite_glial_cell" title="Satellite glial cell">satellite glial cells</a>
also lose their effective function in chronic pain. Increasing the
activity of microglia, changing microglia networks, and increasing the
production of <a href="https://en.wikipedia.org/wiki/Chemokine" title="Chemokine">chemokines</a> and <a href="https://en.wikipedia.org/wiki/Cytokine" title="Cytokine">cytokines</a> by microglia may exacerbate chronic pain. It has also been observed that astrocytes lose their ability to regulate the <a href="https://en.wikipedia.org/wiki/Electron_mobility" title="Electron mobility">excitability of neurons</a> and increase the spontaneous activity of neurons in pain circuits.
</p>
<h2><span class="mw-headline" id="Management">Management</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Pain_management" title="Pain management">Pain management</a></div>
<p><a href="https://en.wikipedia.org/wiki/Pain_management" title="Pain management">Pain management</a> is a branch of medicine that uses an interdisciplinary approach. The combined knowledge of various medical professions and <a href="https://en.wikipedia.org/wiki/Allied_health_professions" title="Allied health professions">allied health professions</a> is used to ease <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a> and improve the <a href="https://en.wikipedia.org/wiki/Quality_of_life" title="Quality of life">quality of life</a> of those living with pain. The typical pain management team includes <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medical_practitioner" title="Medical practitioner">medical practitioners</a> (particularly anesthesiologists), <a href="https://en.wikipedia.org/wiki/Rehabilitation_psychology" title="Rehabilitation psychology">rehabilitation psychologists</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physiotherapist" title="Physiotherapist">physiotherapists</a>, <a href="https://en.wikipedia.org/wiki/Occupational_therapist" title="Occupational therapist">occupational therapists</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physician_assistants" title="Physician assistants">physician assistants</a>, and <a href="https://en.wikipedia.org/wiki/Nurse_practitioner" title="Nurse practitioner">nurse practitioners</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acute_pain" title="Acute pain">Acute pain</a>
usually resolves with the efforts of one practitioner; however, the
management of chronic pain frequently requires the coordinated efforts
of a treatment team. Complete, longterm <a href="https://en.wikipedia.org/wiki/Remission_(medicine)" title="Remission (medicine)">remission</a> of many types of chronic pain is rare.
</p><p>Chronic pain may originate in the body, or in the brain or spinal
cord. It is often difficult to treat. Epidemiological studies have
found that 8–11.2% of people in various countries have chronic
widespread pain. Various <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nonopiod_analgesics" title="Nonopiod analgesics">non-opioid</a> medicines are initially recommended to treat chronic pain, depending on whether the pain is due to tissue damage or is <a href="https://en.wikipedia.org/wiki/Peripheral_neuropathy" title="Peripheral neuropathy">neuropathic</a>. Psychological treatments including <a href="https://en.wikipedia.org/wiki/Cognitive_behavioral_therapy" title="Cognitive behavioral therapy">cognitive behavioral therapy</a> and <a href="https://en.wikipedia.org/wiki/Acceptance_and_commitment_therapy" title="Acceptance and commitment therapy">acceptance and commitment therapy</a> may be effective for improving quality of life in those with chronic pain. Some people with chronic pain may benefit from <a href="https://en.wikipedia.org/wiki/Opioid" title="Opioid">opioid</a> treatment while others can be harmed by it.
People with non-cancer pain who have not been helped by non-opioid
medicines might be recommended to try opioids if there is no history of <a href="https://en.wikipedia.org/wiki/Substance_use_disorder" title="Substance use disorder">substance use disorder</a> and no current <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mental_illness" title="Mental illness">mental illness</a>.
</p>
<h3><span class="mw-headline" id="Nonopioids">Nonopioids</span></h3><p>Initially recommended efforts are <a href="https://en.wikipedia.org/wiki/Analgesic" title="Analgesic">non-opioid</a> based therapies. Non-opioid treatment of chronic pain with pharmaceutical medicines might include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acetaminophen" title="Acetaminophen">acetaminophen (paracetamol)</a> or <a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">NSAIDs</a>.
</p><p>Various other nonopioid medicines can be used, depending on whether the pain is a result of tissue damage or is <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neuropathic" title="Neuropathic">neuropathic</a> (pain caused by a damaged or dysfunctional nervous system). There is limited evidence that <a href="https://en.wikipedia.org/wiki/Cancer_pain" title="Cancer pain">cancer pain</a> or chronic pain from tissue damage as a result of a conditions (e.g. <a href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis">rheumatoid arthritis</a>) is best treated with opioids. For <a href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">neuropathic pain</a> other drugs may be more effective than opioids, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tricyclic_antidepressants" title="Tricyclic antidepressants">tricyclic antidepressants</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Serotonin-norepinephrine_reuptake_inhibitors" title="Serotonin-norepinephrine reuptake inhibitors">serotonin-norepinephrine reuptake inhibitors</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anticonvulsants" title="Anticonvulsants">anticonvulsants</a>. Some atypical antipsychotics, such as <a href="https://en.wikipedia.org/wiki/Olanzapine" title="Olanzapine">olanzapine</a>, may also be effective, but the evidence to support this is in very early stages. In women with chronic pain, hormonal medications such as oral contraceptive pills ("the pill") might be helpful. When there is no evidence of a single best fit, doctors may need to look for a treatment that works for the individual person.
It is difficult for doctors to predict who will use opioids just for
pain management and who will go on to develop an addiction. It is also
challenging for doctors to know which patients ask for opioids because
they are living with an opioid addiction. Withholding, interrupting or
withdrawing opioid treatment in people who benefit from it can cause
harm.
</p><p><a href="https://en.wikipedia.org/wiki/Interventional_pain_management" title="Interventional pain management">Interventional pain management</a> may be appropriate, including techniques such as <a href="https://en.wikipedia.org/wiki/Myofascial_trigger_point#Trigger_point_injection" title="Myofascial trigger point">trigger point injections</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurolytic_block" title="Neurolytic block">neurolytic blocks</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Radiotherapy" title="Radiotherapy">radiotherapy</a>. While there is no high quality evidence to support <a href="https://en.wikipedia.org/wiki/Therapeutic_ultrasound" title="Therapeutic ultrasound">ultrasound</a>, it has been found to have a small effect on improving function in non-specific chronic low back pain.
</p><p>Psychological treatments, including <a href="https://en.wikipedia.org/wiki/Cognitive_behavioral_therapy" title="Cognitive behavioral therapy">cognitive behavioral therapy</a> and <a href="https://en.wikipedia.org/wiki/Acceptance_and_commitment_therapy" title="Acceptance and commitment therapy">acceptance and commitment therapy</a>
can be helpful for improving quality of life and reducing pain
interference. Brief mindfulness-based treatment approaches have been
used, but they are not yet recommended as a first-line treatment. The effectiveness of <a href="https://en.wikipedia.org/wiki/Mindfulness-based_pain_management" title="Mindfulness-based pain management">mindfulness-based pain management</a> (MBPM) has been supported by a range of studies.
</p><p>Among older adults psychological interventions can help reduce pain and improve <a href="https://en.wikipedia.org/wiki/Self-efficacy" title="Self-efficacy">self-efficacy</a> for pain management.
Psychological treatments have also been shown to be effective in
children and teens with chronic headache or mixed chronic pain
conditions.
</p><p>While exercise has been offered as a method to lessen chronic
pain and there is some evidence of benefit, this evidence is tentative. For people living with chronic pain, exercise results in few side effects.
</p>
<h3><span class="mw-headline" id="Opioids">Opioids</span></h3><p>In those who have not benefited from other measures and have no history of either <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mental_illness" title="Mental illness">mental illness</a> or <a href="https://en.wikipedia.org/wiki/Substance_use_disorder" title="Substance use disorder">substance use disorder</a> treatment with opioids may be tried. If significant benefit does not occur it is recommended that they be stopped. In those on opioids, stopping or decreasing their use may improve outcomes including pain.
</p><p>Some people with chronic pain benefit from <a href="https://en.wikipedia.org/wiki/Opioid" title="Opioid">opioid</a> treatment and others do not; some are harmed by the treatment. Possible harms include reduced sex hormone production, <a href="https://en.wikipedia.org/wiki/Hypogonadism" title="Hypogonadism">hypogonadism</a>, infertility, impaired immune system, falls and fractures in older adults, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neonatal_abstinence_syndrome" title="Neonatal abstinence syndrome">neonatal abstinence syndrome</a>, heart problems, sleep-disordered breathing, <a href="https://en.wikipedia.org/wiki/Opioid-induced_hyperalgesia" title="Opioid-induced hyperalgesia">opioid-induced hyperalgesia</a>, <a href="https://en.wikipedia.org/wiki/Physical_dependence" title="Physical dependence">physical dependence</a>, addiction, abuse, and overdose.
</p>
<h3><span class="mw-headline" id="Alternative_medicine">Alternative medicine</span></h3><p>Alternative
medicine refers to health practices or products that are used to treat
pain or illness that are not necessarily considered a part of
conventional medicine.
When dealing with chronic pain, these practices generally fall into the
following four categories: biological, mind-body, manipulative body,
and energy medicine.
</p><p>Implementing dietary changes, which is considered a
biological-based alternative medicine practice, has been shown to help
improve symptoms of chronic pain over time.
Adding supplements to one's diet is a common dietary change when trying
to relieve chronic pain, with some of the most studied supplements
being: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Acetyl_L_Carnitine" title="Acetyl L Carnitine">acetyl-<small>L</small>-carnitine</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alpha-lipoic_acid" title="Alpha-lipoic acid">alpha-lipoic acid</a>, and <a href="https://en.wikipedia.org/wiki/Vitamin_E" title="Vitamin E">vitamin E</a>. Vitamin E is perhaps the most studied out of the three, with strong evidence that it helps lower <a href="https://en.wikipedia.org/wiki/Neurotoxicity" title="Neurotoxicity">neurotoxicity</a> in those with cancer, multiple sclerosis, and cardiovascular diseases.
</p><p><a href="https://en.wikipedia.org/wiki/Hypnosis" title="Hypnosis">Hypnosis</a>, including <a href="https://en.wikipedia.org/wiki/Self-hypnosis" title="Self-hypnosis">self-hypnosis</a>, has tentative evidence. Hypnosis, specifically, can offer pain relief for most people and may be a safe alternative to pharmaceutical medication. Evidence does not support hypnosis for chronic pain due to a spinal cord injury.
</p><p>Preliminary studies have found <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medical_marijuana" title="Medical marijuana">medical marijuana</a> to be beneficial in treating neuropathic pain, but not other kinds of long term pain. As of 2018,
the evidence for its efficacy in treating neuropathic pain or pain
associated with rheumatic diseases is not strong for any benefit and
further research is needed. For chronic non-cancer pain, a recent study concluded that it is unlikely that <a href="https://en.wikipedia.org/wiki/Cannabinoid" title="Cannabinoid">cannabinoids</a> are highly effective. However, more rigorous research into cannabis or cannabis-based medicines is needed.
</p><p><a href="https://en.wikipedia.org/wiki/Tai_chi" title="Tai chi">Tai chi</a>
has been shown to improve pain, stiffness, and quality of life in
chronic conditions such as osteoarthritis, low back pain, and
osteoporosis. <a href="https://en.wikipedia.org/wiki/Acupuncture" title="Acupuncture">Acupuncture</a>
has also been found to be an effective and safe treatment in reducing
pain and improving quality of life in chronic pain including <a href="https://en.wikipedia.org/wiki/Chronic_prostatitis/chronic_pelvic_pain_syndrome" title="Chronic prostatitis/chronic pelvic pain syndrome">chronic pelvic pain syndrome</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Transcranial_magnetic_stimulation" title="Transcranial magnetic stimulation">Transcranial magnetic stimulation</a> for reduction of chronic pain is not supported by high quality evidence, and the demonstrated effects are small and short-term.
</p><p>Spa therapy could potentially improve pain in patients with
chronic lower back pain, but more studies are needed to provide stronger
evidence of this.
</p><p>While some studies have investigated the efficacy of St John's
Wort or nutmeg for treating neuropathic (nerve) pain, their findings
have raised serious concerns about the accuracy of their results.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/KT_tape" title="KT tape">Kinesio tape</a> has not been shown to be effective in managing chronic non-specific low-back pain.
</p><p><a href="https://en.wikipedia.org/wiki/Myofascial_release" title="Myofascial release">Myofascial release</a> has been used in some cases of <a href="https://en.wikipedia.org/wiki/Fibromyalgia" title="Fibromyalgia">fibromyalgia</a>, chronic <a href="https://en.wikipedia.org/wiki/Low_back_pain" title="Low back pain">low back pain</a>, and <a href="https://en.wikipedia.org/wiki/Tennis_elbow" title="Tennis elbow">tennis elbow</a> but there is not enough evidence to support this as method of treatment.
</p>
<h2><span class="mw-headline" id="Epidemiology">Epidemiology</span></h2><p>Chronic
pain varies in different countries affecting anywhere from 8% to 55% of
the population. It affects women at a higher rate than men, and chronic
pain uses a large amount of healthcare resources around the globe.
</p><p>A large-scale telephone survey of 15 European countries and
Israel found that 19% of respondents over 18 years of age had suffered
pain for more than 6 months, including the last month, and more than
twice in the last week, with pain intensity of 5 or more for the last
episode, on a scale of 1 (no pain) to 10 (worst imaginable). 4839 of
these respondents with chronic pain were interviewed in-depth. Sixty-six
percent scored their pain intensity at moderate (5–7), and 34% at
severe (8–10); 46% had constant pain, 56% intermittent; 49% had suffered
pain for 2–15 years; and 21% had been diagnosed with depression due to
the pain. Sixty-one percent were unable or less able to work outside the
home, 19% had lost a job, and 13% had changed jobs due to their pain.
Forty percent had inadequate pain management and less than 2% were
seeing a pain management specialist.
</p><p>In the United States, chronic pain has been estimated to occur in
approximately 35% of the population, with approximately 50 million
Americans experiencing partial or total disability as a consequence.<sup class="reference" id="cite_ref-94"><a href="https://en.wikipedia.org/wiki/Chronic_pain#cite_note-94">[91]</a></sup> According to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Institute_of_Medicine" title="Institute of Medicine">Institute of Medicine</a>,
there are about 116 million Americans living with chronic pain, which
suggests that approximately half of American adults have some chronic
pain condition.<sup class="reference" id="cite_ref-painreview_95-0"><a href="https://en.wikipedia.org/wiki/Chronic_pain#cite_note-painreview-95">[92]</a></sup><sup class="reference" id="cite_ref-96"><a href="https://en.wikipedia.org/wiki/Chronic_pain#cite_note-96">[93]</a></sup> The Mayday Fund estimate of 70 million Americans with chronic pain is slightly more conservative.<sup class="reference" id="cite_ref-97"><a href="https://en.wikipedia.org/wiki/Chronic_pain#cite_note-97">[94]</a></sup>
In an internet study, the prevalence of chronic pain in the United
States was calculated to be 30.7% of the population: 34.3% for women and
26.7% for men.
</p><p>In Canada it is estimated that approximately 1 in 5 Canadians
live with chronic pain and half of those people have lived with chronic
pain for 10 years or longer. Chronic pain in Canada also occurs more and is more severe in women and Canada's <a href="https://en.wikipedia.org/wiki/Indigenous_peoples_in_Canada" title="Indigenous peoples in Canada">Indigenous communities</a>.
</p>
<h2><span class="mw-headline" id="Outcomes">Outcomes</span></h2><p>Sleep disturbance, and <a href="https://en.wikipedia.org/wiki/Insomnia" title="Insomnia">insomnia</a> due to medication and illness symptoms are often experienced by those with chronic pain.
These conditions can be difficult to treat due to the high potential of
medication interactions, especially when the conditions are treated by
different doctors.
</p><p>Severe chronic pain is associated with increased risk of death
over a ten-year period, particularly from heart disease and respiratory
disease. Several mechanisms have been proposed for this increase, such as an abnormal <a href="https://en.wikipedia.org/wiki/Fight-or-flight_response" title="Fight-or-flight response">stress response</a> in the body's <a href="https://en.wikipedia.org/wiki/Endocrine_system" title="Endocrine system">endocrine system</a>. Additionally, chronic stress seems to affect risks to heart and lung (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular" title="Cardiovascular">cardiovascular</a>) health by increasing how quickly plaque can build up on artery walls (<a href="https://en.wikipedia.org/wiki/Arteriosclerosis" title="Arteriosclerosis">arteriosclerosis</a>).
However, further research is needed to clarify the relationship between
severe chronic pain, stress and cardiovascular health.
</p><p>People with chronic pain tend to have higher rates of depression
and although the exact connection between the comorbidities is unclear,
a 2017 study on neuroplasticity found that "injury sensory pathways of
body pains have been shown to share the same brain regions involved in
mood management."
Chronic pain can contribute to decreased physical activity due to fear
of making the pain worse. Pain intensity, pain control, and resilience
to pain can be influenced by different levels and types of <a href="https://en.wikipedia.org/wiki/Social_support" title="Social support">social support</a> that a person with chronic pain receives, and are also influenced by the person's <a href="https://en.wikipedia.org/wiki/Socioeconomic_status" title="Socioeconomic status">socioeconomic status</a>.
</p><p>Chronic pain of different causes has been characterized as a disease that affects brain structure and function. <a href="https://en.wikipedia.org/wiki/Magnetic_resonance_imaging" title="Magnetic resonance imaging">MRI</a> studies have shown abnormal anatomical and functional connectivity, even during rest<sup> </sup>involving areas related to the processing of pain. Also, persistent pain has been shown to cause <a href="https://en.wikipedia.org/wiki/Grey_matter" title="Grey matter">grey matter</a> loss, which is reversible once the pain has resolved.
</p><p>One approach to predicting a person's experience of chronic pain is the <a href="https://en.wikipedia.org/wiki/Biopsychosocial_model" title="Biopsychosocial model">biopsychosocial model</a>,
according to which an individual's experience of chronic pain may be
affected by a complex mixture of their biology, psychology, and their
social environment.
</p>
<h2><span class="mw-headline" id="Psychology">Psychology</span></h2><h3><span class="mw-headline" id="Personality">Personality</span></h3><p>Two of the most frequent personality profiles found in people with chronic pain by the <a href="https://en.wikipedia.org/wiki/Minnesota_Multiphasic_Personality_Inventory" title="Minnesota Multiphasic Personality Inventory">Minnesota Multiphasic Personality Inventory</a> (MMPI) are the <i>conversion V</i> and the <i>neurotic triad</i>.
The conversion V personality expresses exaggerated concern over body
feelings, develops bodily symptoms in response to stress, and often
fails to recognize their own emotional state, including depression. The
neurotic triad personality also expresses exaggerated concern over body
feelings and develops bodily symptoms in response to stress, but is
demanding and complaining.
</p><p>Some investigators have argued that it is this <a href="https://en.wikipedia.org/wiki/Neuroticism" title="Neuroticism">neuroticism</a>
that causes acute pain to turn chronic, but clinical evidence points
the other way, to chronic pain causing neuroticism. When long term pain
is relieved by therapeutic intervention, scores on the neurotic triad
and <a href="https://en.wikipedia.org/wiki/Anxiety" title="Anxiety">anxiety</a> fall, often to normal levels. Self-esteem, often low in people with chronic pain, also shows improvement once pain has resolved.
</p><p>It has been suggested that <a href="https://en.wikipedia.org/wiki/Pain_catastrophizing" title="Pain catastrophizing">catastrophizing</a> might play a role in the experience of pain. <i>Pain catastrophizing</i>
is the tendency to describe a pain experience in more exaggerated terms
than the average person, to think a great deal more about the pain when
it occurs, or to feel more helpless about the experience.
People who score highly on measures of catastrophization are likely to
rate a pain experience as more intense than those who score low on such
measures. It is often reasoned that the tendency to catastrophize <i>causes</i>
the person to experience the pain as more intense. One suggestion is
that catastrophizing influences pain perception through altering
attention and anticipation, and heightening emotional responses to pain. However, at least some aspects of catastrophization may be the <i>product</i>
of an intense pain experience, rather than its cause. That is, the more
intense the pain feels to the person, the more likely they are to have
thoughts about it that fit the definition of catastrophization.
</p>
<h3><span class="mw-headline" id="Comorbidity_with_trauma">Comorbidity with trauma</span></h3><p>Individuals with post-traumatic stress disorder (PTSD) have a high comorbidity with chronic pain. Patients with both PTSD and chronic pain report higher severity of pain than those who do not have a PTSD comorbidity.
</p>
<h3><span class="mw-headline" id="Comorbidity_with_depression">Comorbidity with depression</span></h3><p>People with chronic pain may also have symptoms of depression. In 2017, the British Medical Association found that 49% of people with chronic pain had depression.
</p>
<h3><span class="mw-headline" id="Effect_on_cognition">Effect on cognition</span></h3><p>Chronic
pain's impact on cognition is an under-researched area, but several
tentative conclusions have been published. Most people with chronic pain
complain of <a href="https://en.wikipedia.org/wiki/Cognitive_impairment" title="Cognitive impairment">cognitive impairment</a>,
such as forgetfulness, difficulty with attention, and difficulty
completing tasks. Objective testing has found that people in chronic
pain tend to experience impairment in attention, memory, mental
flexibility, verbal ability, speed of response in a cognitive task, and
speed in executing structured tasks.
A review of studies in 2018 reports a relationship between people in
chronic pain and abnormal results in test of memory, attention, and
processing speed.
</p>
<h2><span class="mw-headline" id="Prognosis">Prognosis</span></h2><p>Chronic
pain leads to a significant decrease in quality of life, decreased
productivity, decreased wages, worsening of other chronic diseases, and
mental disorders such as depression, anxiety, and <a href="https://en.wikipedia.org/wiki/Substance_use_disorder" title="Substance use disorder">substance use disorder</a>.
Many drugs that are often used to treat chronic pain have risks and
potential side effects and possible complications associated with their
use, and the constant use of opioids is associated with decreased life
expectancy and increased mortality of patients. Acetaminophen, a standard drug treatment for chronic pain, can cause <a href="https://en.wikipedia.org/wiki/Hepatotoxicity" title="Hepatotoxicity">hepatotoxicity</a> when taken in excess of four grams per day. In addition, therapeutic doses for patients with chronic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Liver_diseases" title="Liver diseases">liver diseases</a> may also cause hepatotoxicity. Long-term risks and side effects of opioids include <a href="https://en.wikipedia.org/wiki/Constipation" title="Constipation">constipation</a>, drug <a href="https://en.wikipedia.org/wiki/Drug_tolerance" title="Drug tolerance">tolerance</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Drug_dependence" title="Drug dependence">dependence</a>, <a href="https://en.wikipedia.org/wiki/Nausea" title="Nausea">nausea</a>, <a href="https://en.wikipedia.org/wiki/Indigestion" title="Indigestion">indigestion</a>, <a href="https://en.wikipedia.org/wiki/Arrhythmia" title="Arrhythmia">arrhythmia</a> (QT prolongation of <a href="https://en.wikipedia.org/wiki/Electrocardiography" title="Electrocardiography">electrocardiography</a> in <a href="https://en.wikipedia.org/wiki/Methadone" title="Methadone">methadone</a> treatment), and <a href="https://en.wikipedia.org/wiki/Endocrine_gland" title="Endocrine gland">endocrine gland</a> that can lead to <a href="https://en.wikipedia.org/wiki/Amenorrhea" title="Amenorrhea">amenorrhea</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Impotence" title="Impotence">impotence</a>, <a href="https://en.wikipedia.org/wiki/Gynecomastia" title="Gynecomastia">gynecomastia</a>, and decreased become energy. Also there is a risk of opioid <a href="https://en.wikipedia.org/wiki/Drug_overdose" title="Drug overdose">overdose</a> depending on the dose taken by the patient.
</p><p>Current treatments for chronic pain can reduce pain by 30%.
This reduction in pain can significantly improve patients' performance
and quality of life. However, the general and long-term prognosis of
chronic pain shows decreased function and quality of life.
Also, this disease causes many complications and increases the
possibility of death of patients and suffering from other chronic
diseases and <a href="https://en.wikipedia.org/wiki/Obesity" title="Obesity">obesity</a>.
Similarly, patients with chronic pain who require opioids often develop
drug tolerance over time, and this increase in the amount of the dose
taken to be effective increases the risk of side effects and death.
</p><p>Mental disorders can amplify pain signals and make symptoms more severe.
In addition, comorbid psychiatric disorders, such as major depressive
disorder, can significantly delay the diagnosis of pain disorders.
Major depressive disorder and generalized anxiety disorder are the most
common comorbidities associated with chronic pain. Patients with
underlying pain and comorbid mental disorders receive twice as much
medication from doctors annually as compared to patients who do not have
such co-morbidities.
Studies have shown that when coexisting diseases exist along with
chronic pain, the treatment and improvement of one of these disorders
can be effective in the improvement of the other. Patients with chronic pain are at higher risk for <a href="https://en.wikipedia.org/wiki/Suicide" title="Suicide">suicide</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Suicidal_thought" title="Suicidal thought">suicidal thoughts</a>.
Research has shown approximately 20% of people with suicidal thoughts
and between 5 and 14% of patients with chronic pain who commit suicide. Of patients who attempted suicide, 53.6% died of gunshot wounds and 16.2% died of opioid overdose.<sup> </sup>A multimodal treatment approach is important for better pain
control and outcomes, as well as minimizing the need for high-risk
treatments such as opioid medications. Managing comorbid depression and
anxiety is critical in reducing chronic pain.<sup> </sup>Also, patients with chronic pain should be carefully monitored for severe depression and any suicidal thoughts and plans.
Periodic referral of the patient to the doctor for physical examination
and to check the effectiveness of treatment 2 is necessary, and the
rapid and correct treatment and management of chronic pain can prevent
the occurrence of potential negative consequences on the patient's life
and increase in healthcare costs.
</p>
<h2><span class="mw-headline" id="Social_and_personal_impacts">Social and personal impacts</span></h2><h3><span class="mw-headline" id="Social_support">Social support</span></h3><p><a href="https://en.wikipedia.org/wiki/Social_support" title="Social support">Social support</a>
has important consequences for individuals with chronic pain. In
particular, pain intensity, pain control, and resiliency to pain have
been implicated as outcomes influenced by different levels and types of
social support. Much of this research has focused on emotional,
instrumental, tangible and informational social support. People with
persistent pain conditions tend to rely on their social support as a
coping mechanism and therefore have better outcomes when they are a part
of larger more supportive social networks. Across a majority of studies
investigated, there was a direct significant association between social
activities or social support and pain. Higher levels of pain were
associated with a decrease in social activities, lower levels of social
support, and reduced social functioning.
</p>
<h3><span class="mw-headline" id="Racial_disparities">Racial disparities</span></h3><p>Evidence exists for unconscious biases and negative stereotyping against <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Racial_minority" title="Racial minority">racial minorities</a> requesting pain treatment, although clinical decision making was not affected, according to one 2017 review. Minorities may be denied diagnoses for pain and pain medications, and are more likely to go through <a href="https://en.wikipedia.org/wiki/Substance_abuse" title="Substance abuse">substance abuse</a> assessment, and are less likely to transfer for pain specialist referral.
A 2010 University of Michigan Health study found that black patients in
pain clinics received 50% of the amount of drugs that patients who were
white received.
Preliminary research showed that health providers might have less
empathy for black patients and underestimated their pain levels,
resulting in treatment delays. Minorities may experience a <a href="https://en.wikipedia.org/wiki/Language_barrier" title="Language barrier">language barrier</a>, limiting the high level of engagement between the person with pain and health providers for treatment.
</p>
<h3><span class="mw-headline" id="Perceptions_of_injustice">Perceptions of injustice</span></h3><p>Similar
to the damaging effects seen with catastrophizing, perceived injustice
is thought to contribute to the severity and duration of chronic pain.
Pain-related injustice perception has been conceptualized as a
cognitive appraisal reflecting the severity and irreparability of pain-
or injury-related loss (e.g., "I just want my life back"), and
externalizing blame and unfairness ("I am suffering because of someone
else's negligence.").
It has been suggested that understanding problems with top down
processing/cognitive appraisals can be used to better understand and
treat this problem.
</p>
<h3><span class="mw-headline" id="Chronic_pain_and_COVID-19">Chronic pain and COVID-19</span></h3><p><a href="https://en.wikipedia.org/wiki/COVID-19" title="COVID-19">COVID-19</a> has disrupted the lives of many, leading to major physical, psychological and socioeconomic impacts in the general population.
Social distancing practices defining the response to the pandemic alter
familiar patterns of social interaction, creating the conditions for
what some psychologists are describing as a period of collective grief.
Individuals with chronic pain tend to embody an ambiguous status, at
times expressing that their type of suffering places them between and
outside of conventional medicine.
With a large proportion of the global population enduring prolonged
periods of social isolation and distress, one study found that people
with chronic pain from COVID-19 experienced more empathy towards their
suffering during the pandemic.
</p>
<h3><span class="mw-headline" id="Effect_of_chronic_pain_in_the_workplace">Effect of chronic pain in the workplace</span></h3>In
the workplace, chronic pain conditions are a significant problem for
both the person with the condition and the organization; a problem only
expected to increase in many countries due to an aging workforce.
In light of this, it may be helpful for organizations to consider the
social environment of their workplace, and how it may be working to ease
or worsen chronic pain issues for employees.
As an example of how the social environment can affect chronic pain,
some research has found that high levels of socially prescribed
perfectionism (perfectionism induced by external pressure from others,
such as a supervisor) can interact with the guilt felt by a person with
chronic pain, thereby increasing job tension, and decreasing job
satisfaction.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-73453264041539957212024-03-27T20:00:00.004-04:002024-03-27T20:00:33.970-04:00Postural orthostatic tachycardia syndrome<div class="vector-column-end">
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<div class="hatnote navigation-not-searchable" role="note"><a href="https://en.wikipedia.org/wiki/Postural_orthostatic_tachycardia_syndrome">https://en.wikipedia.org/wiki/Postural_orthostatic_tachycardia_syndrome</a></div><div class="hatnote navigation-not-searchable" role="note"> <br /></div>
<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Postural orthostatic tachycardia syndrome</th></tr><tr><th class="infobox-label" scope="row"><br /></th><td class="infobox-data"><br /></td></tr><tr><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Dependent_Acrocyanosis_in_a_Norwegian_33-year_old_male_POTS_patient.jpg"><img alt="Acrocyanosis in a male Norwegian POTS patient. The patient's legs appear red and purple due to the condition." class="mw-file-element" data-file-height="2361" data-file-width="3330" height="284" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/8f/Dependent_Acrocyanosis_in_a_Norwegian_33-year_old_male_POTS_patient.jpg/220px-Dependent_Acrocyanosis_in_a_Norwegian_33-year_old_male_POTS_patient.jpg" width="400" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2">Acrocyanosis in a male Norwegian POTS patient</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Cardiology" title="Cardiology">Cardiology</a>, <a href="https://en.wikipedia.org/wiki/Neurology" title="Neurology">neurology</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Signs_and_symptoms" title="Signs and symptoms">Symptoms</a></th><td class="infobox-data">More often with standing: <a href="https://en.wikipedia.org/wiki/Lightheadedness" title="Lightheadedness">lightheadedness</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Brain_fog" title="Brain fog">trouble thinking</a>, <a href="https://en.wikipedia.org/wiki/Tachycardia" title="Tachycardia">tachycardia</a>, weakness, <a href="https://en.wikipedia.org/wiki/Palpitations" title="Palpitations">palpitations</a>, <a href="https://en.wikipedia.org/wiki/Heat_intolerance" title="Heat intolerance">heat intolerance</a>, <a href="https://en.wikipedia.org/wiki/Acrocyanosis" title="Acrocyanosis">acrocyanosis</a></td></tr><tr><th class="infobox-label" scope="row">Usual onset</th><td class="infobox-data">Most common (modal) age of onset is 14 years</td></tr><tr><th class="infobox-label" scope="row">Types</th><td class="infobox-data">Neuropathic POTS, Hyperadrenergic POTS, Secondary POTS.</td></tr><tr><th class="infobox-label" scope="row">Causes</th><td class="infobox-data">Antibodies against the Alpha 1 adrenergic receptor and muscarinic acetylcholine M4 receptor</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Risk_factor" title="Risk factor">Risk factors</a></th><td class="infobox-data">Family history, Ehlers Danlos Syndrome</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_diagnosis" title="Medical diagnosis">Diagnostic method</a></th><td class="infobox-data">An increase in heart rate by 30 beats/min with standing</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">Differential diagnosis</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Dehydration" title="Dehydration">Dehydration</a>, heart problems, <a href="https://en.wikipedia.org/wiki/Adrenal_insufficiency" title="Adrenal insufficiency">adrenal insufficiency</a>, <a href="https://en.wikipedia.org/wiki/Epilepsy" title="Epilepsy">epilepsy</a>, <a href="https://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease">Parkinson's disease</a>, <a href="https://en.wikipedia.org/wiki/Anemia" title="Anemia">anemia</a></td></tr><tr><th class="infobox-label" scope="row">Treatment</th><td class="infobox-data">Avoiding factors that bring on symptoms, increasing dietary salt and water, <a href="https://en.wikipedia.org/wiki/Compression_stockings" title="Compression stockings">compression stockings</a>, exercise, medications</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medication" title="Medication">Medication</a></th><td class="infobox-data">Off label Medications: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beta_blockers" title="Beta blockers">Beta blockers</a>, <a href="https://en.wikipedia.org/wiki/Ivabradine" title="Ivabradine">Ivabradine</a>, <a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">midodrine</a>, and <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a>.</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Prognosis" title="Prognosis">Prognosis</a></th><td class="infobox-data">c. 90% improve with treatment, 25% of patients unable to work</td></tr><tr><th class="infobox-label" scope="row">Frequency</th><td class="infobox-data">~ 1,000,000 ~ 3,000,000 (US)</td></tr></tbody></table>
<p><b>Postural orthostatic tachycardia syndrome</b> (<b>POTS</b>) is a condition characterized by an abnormally large <a href="https://en.wikipedia.org/wiki/Tachycardia" title="Tachycardia">increase in heart rate</a> upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead the individual to experience a variety of symptoms. Symptoms may include <a href="https://en.wikipedia.org/wiki/Lightheadedness" title="Lightheadedness">lightheadedness</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Brain_Fog" title="Brain Fog">brain fog</a>, <a href="https://en.wikipedia.org/wiki/Blurred_vision" title="Blurred vision">blurred vision</a>, weakness, <a href="https://en.wikipedia.org/wiki/Fatigue" title="Fatigue">fatigue</a>, <a href="https://en.wikipedia.org/wiki/Headache" title="Headache">headaches</a>, <a href="https://en.wikipedia.org/wiki/Palpitations" title="Palpitations">heart palpitations</a>, <a href="https://en.wikipedia.org/wiki/Exercise_intolerance" title="Exercise intolerance">exercise intolerance</a>, <a href="https://en.wikipedia.org/wiki/Nausea" title="Nausea">nausea</a>, diminished concentration, <a href="https://en.wikipedia.org/wiki/Tremor" title="Tremor">tremulousness</a> (shaking), <a href="https://en.wikipedia.org/wiki/Syncope_(medicine)" title="Syncope (medicine)">syncope</a> (fainting), coldness or pain in the extremities, chest pain and shortness of breath. Other conditions associated with POTS include <a href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">migraine headaches</a>, <a href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">Ehlers–Danlos syndrome</a>, <a href="https://en.wikipedia.org/wiki/Asthma" title="Asthma">asthma</a>, <a href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">autoimmune disease</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vasovagal_syncope" title="Vasovagal syncope">vasovagal syncope</a> and <a href="https://en.wikipedia.org/wiki/Mast_cell_activation_syndrome" title="Mast cell activation syndrome">mast cell activation syndrome</a>. POTS symptoms may be treated with lifestyle changes such as increasing fluid and salt intake, wearing <a href="https://en.wikipedia.org/wiki/Compression_stockings" title="Compression stockings">compression stockings</a>, gentler and slow postural changes, avoiding prolonged bedrest, <a href="https://en.wikipedia.org/wiki/Medication" title="Medication">medication</a>, increasing electrolyte intake, and <a href="https://en.wikipedia.org/wiki/Physical_therapy" title="Physical therapy">physical therapy</a>.
</p><p>The causes of POTS are varied. POTS may develop after a viral infection, surgery, trauma, or pregnancy. It has been shown to emerge in previously healthy patients after <a href="https://en.wikipedia.org/wiki/Long_COVID" title="Long COVID">COVID-19</a>, or in rare cases after <a href="https://en.wikipedia.org/wiki/COVID-19_vaccine" title="COVID-19 vaccine">COVID-19 vaccination</a>. POTS is more common among people who got infected with SARS-CoV-2 than among those who got vaccinated against COVID-19. Risk factors include a family history of the condition.
POTS in adults is characterized by a heart rate increase of 30 beats
per minute within ten minutes of standing up, accompanied by other
symptoms. This increased heart rate should occur in the absence of orthostatic hypotension (>20 mm Hg drop in systolic blood pressure)<sup> </sup>to be considered POTS. A spinal fluid leak (called spontaneous
intracranial hypotension) may have the same signs and symptoms as POTS
and should be excluded. Prolonged bedrest may lead to multiple symptoms, including blood volume loss and postural tachycardia. Other conditions which can cause similar symptoms, such as <a href="https://en.wikipedia.org/wiki/Dehydration" title="Dehydration">dehydration</a>, <a href="https://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">orthostatic hypotension</a>, heart problems, <a href="https://en.wikipedia.org/wiki/Adrenal_insufficiency" title="Adrenal insufficiency">adrenal insufficiency</a>, <a href="https://en.wikipedia.org/wiki/Epilepsy" title="Epilepsy">epilepsy</a>, and <a href="https://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease">Parkinson's disease</a>, must not be present. Treatment may include avoiding factors that bring on symptoms, increasing dietary salt and water, small and frequent meals, avoidance of immobilization, wearing <a href="https://en.wikipedia.org/wiki/Compression_stockings" title="Compression stockings">compression stockings</a>, and taking medications. Medications used may include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beta_blockers" title="Beta blockers">beta blockers</a>, <a href="https://en.wikipedia.org/wiki/Pyridostigmine" title="Pyridostigmine">pyridostigmine</a>, <a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">midodrine</a> or <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a>. More than 50% of patients whose condition was triggered by a viral infection get better within five years.
About 80% of patients have symptomatic improvement with treatment,
while 25 percent of patients are so disabled they are unable to work.<sup> </sup>A retrospective study on patients with adolescent-onset has shown that
five years after diagnosis, 19% of patients had a full resolution of
symptoms.
</p><p>It is estimated that 1–3 million people in the United States have POTS. The average age for POTS onset is 20 years, and it occurs about five times more frequently in females than in males.
</p>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2></div></div></div><figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Tachycardia_while_standing_with_a_pulse_oximeter.jpg"><img class="mw-file-element" data-file-height="4472" data-file-width="3358" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4e/Tachycardia_while_standing_with_a_pulse_oximeter.jpg/182px-Tachycardia_while_standing_with_a_pulse_oximeter.jpg" width="301" /></a><figcaption>Person standing and measuring heart rate with a <a href="https://en.wikipedia.org/wiki/Pulse_oximetry" title="Pulse oximetry">pulse oximeter</a> which shows tachycardia of 108 bpm</figcaption></figure>
<p>In adults, the primary manifestation is an increase in heart rate of
more than 30 beats per minute within ten minutes of standing up. The resulting heart rate is typically more than 120 beats per minute. For people between ages 12 and 19, the minimum increase for a POTS diagnosis is 40 beats per minute. POTS is often accompanied by common features of <a href="https://en.wikipedia.org/wiki/Orthostatic_intolerance" title="Orthostatic intolerance">orthostatic intolerance</a>—in which symptoms that develop while upright are relieved by reclining. These orthostatic symptoms include <a href="https://en.wikipedia.org/wiki/Palpitations" title="Palpitations">palpitations</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Light-headedness" title="Light-headedness">light-headedness</a>, chest discomfort, <a href="https://en.wikipedia.org/wiki/Shortness_of_breath" title="Shortness of breath">shortness of breath</a>, nausea, weakness or "heaviness" in the lower legs, <a href="https://en.wikipedia.org/wiki/Blurred_vision" title="Blurred vision">blurred vision</a>, and cognitive difficulties. Symptoms may be exacerbated with prolonged sitting, prolonged standing, alcohol, heat, exercise, or eating a large meal.
</p><p>Up to one-third of POTS patients experience <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fainting" title="Fainting">fainting</a> for many reasons, including but not limited to standing, physical exertion, or heat exposure. POTS patients may also experience <a href="https://en.wikipedia.org/wiki/Orthostatic_headache" title="Orthostatic headache">orthostatic headaches</a>.
Some POTS patients may develop blood pooling in the extremities,
characterized by a reddish-purple color of the legs and/or hands upon
standing. 48% of people with POTS report chronic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatigue_(medical)" title="Fatigue (medical)">fatigue</a> and 32% report <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sleep_disturbance" title="Sleep disturbance">sleep disturbances</a>. Other POTS patients only exhibit the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardinal_sign_(pathology)" title="Cardinal sign (pathology)">cardinal symptom</a> of orthostatic tachycardia.
Additional signs and symptoms are varied, and may include excessive
sweating, lack of sweating, heat intolerance, digestive issues such as
nausea, indigestion, constipation or diarrhea, <a href="https://en.wikipedia.org/wiki/Post-exertional_malaise" title="Post-exertional malaise">post-exertional malaise</a>, coat-hanger pain, brain fog, and <a href="https://en.wikipedia.org/wiki/Syncope_(medicine)" title="Syncope (medicine)">syncope</a> or <a href="https://en.wikipedia.org/wiki/Lightheadedness" title="Lightheadedness">presyncope</a>.
</p><p>Whereas POTS is primarily characterized by its profound impact on
the autonomic and cardiovascular systems, it can lead to substantial
functional impairment. This impairment, often manifesting as symptoms
such as fatigue, cognitive dysfunction, and sleep disturbances, can
significantly diminish the patient's quality of life.
</p>
<h3><span class="mw-headline" id="Brain_fog">Brain fog</span></h3><p>One of the most disabling and prevalent symptoms in POTS is "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Brain_Fog" title="Brain Fog">brain fog</a>",
a term used by patients to describe the cognitive difficulties they
experience. In one survey of 138 POTS patients, brain fog was defined as
"forgetful" (91%), "difficulty thinking" (89%), and "difficulty
focusing" (88%). Other common descriptions were "difficulty processing
what others say" (80%), "<a href="https://en.wikipedia.org/wiki/Confusion" title="Confusion">confusion</a>" (71%), "getting lost" (64%), and "thoughts moving too quickly" (40%). The same survey described the most common triggers of brain fog to be fatigue (91%), <a href="https://en.wikipedia.org/wiki/Sleep_deprivation" title="Sleep deprivation">lack of sleep</a> (90%), prolonged standing (87%), and <a href="https://en.wikipedia.org/wiki/Dehydration" title="Dehydration">dehydration</a> (86%).
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neuropsychological_testing" title="Neuropsychological testing">Neuropsychological testing</a> has shown that a POTS patient has reduced attention (Ruff 2&7 speed and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/WAIS-III" title="WAIS-III">WAIS-III</a> digits forward), short-term memory (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/WAIS-III" title="WAIS-III">WAIS-III</a> digits back), cognitive processing speed (<a href="https://en.wikipedia.org/wiki/Digit_symbol_substitution_test" title="Digit symbol substitution test">Symbol digits modalities test</a>), and executive function (<a href="https://en.wikipedia.org/wiki/Stroop_effect" title="Stroop effect">Stroop word color</a> and <a href="https://en.wikipedia.org/wiki/Trail_Making_Test" title="Trail Making Test">trails B</a>).
</p><p>A potential cause for brain fog is a decrease in cerebral blood flow (CBF), especially in upright position.
</p><p>There may be a loss of neurovascular coupling and reduced
functional hyperemia in response to cognitive challenge under
orthostatic stress – perhaps related to a loss of autoregulatory
buffering of beat-by-beat fluctuations in arterial blood flow.
</p>
<h2><span class="mw-headline" id="Causes">Causes</span></h2><p>The symptoms of POTS can be caused by several distinct <a href="https://en.wikipedia.org/wiki/Pathophysiology" title="Pathophysiology">pathophysiological</a> mechanisms. These mechanisms are poorly understood, and can overlap, with many patients showing features of multiple POTS types. Many people with POTS exhibit low blood volume (<a href="https://en.wikipedia.org/wiki/Hypovolemia" title="Hypovolemia">hypovolemia</a>), which can decrease the rate of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Venous_return_curve" title="Venous return curve">blood flow to the heart</a>. To compensate for low blood volume, the heart increases its <a href="https://en.wikipedia.org/wiki/Cardiac_output" title="Cardiac output">cardiac output</a> by beating faster (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Reflex_tachycardia" title="Reflex tachycardia">reflex tachycardia</a>), leading to the symptoms of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Presyncope" title="Presyncope">presyncope</a>.
</p><p>In the 30% to 60% of cases classified as <i>hyperadrenergic POTS</i>, <a href="https://en.wikipedia.org/wiki/Norepinephrine" title="Norepinephrine">norepinephrine</a> levels are elevated on standing, often due to hypovolemia or partial <a href="https://en.wikipedia.org/wiki/Autonomic_neuropathy" title="Autonomic neuropathy">autonomic neuropathy</a>.
A smaller minority of people with POTS have (typically very high)
standing norepinephrine levels that are elevated even in the absence of
hypovolemia and autonomic neuropathy; this is classified as <i>central hyperadrenergic POTS</i>. The high norepinephrine levels contribute to symptoms of tachycardia. Another subtype, <i>neuropathic POTS</i>, is associated with <a href="https://en.wikipedia.org/wiki/Denervation" title="Denervation">denervation</a> of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sympathetic_nerve" title="Sympathetic nerve">sympathetic nerves</a> in the lower limbs. In this subtype, it is thought that impaired <a href="https://en.wikipedia.org/wiki/Vasoconstriction" title="Vasoconstriction">constriction of the blood vessels</a> causes blood <a href="https://en.wikipedia.org/wiki/Peripheral_edema" title="Peripheral edema">to pool in the veins of the lower limbs</a>. Heart rate increases to compensate for this blood pooling.
</p><p>In up to 50% of cases, there was an onset of symptoms following a viral illness. It may also be linked to physical trauma, concussion, pregnancy, surgery or psychosocial stress. It is believed that these events could act as a trigger for an autoimmune response that result in POTS. It has been shown to emerge in previously healthy patients after <a href="https://en.wikipedia.org/wiki/Long_COVID" title="Long COVID">COVID-19</a> or after <a href="https://en.wikipedia.org/wiki/COVID-19_vaccine" title="COVID-19 vaccine">COVID-19 vaccination</a>. A 2023 review found that the chances of being diagnosed with POTS within 90 days after <a href="https://en.wikipedia.org/wiki/MRNA_vaccine" title="MRNA vaccine">mRNA vaccination</a>
were 1.33 times higher compared to 90 days before vaccination, still,
the results are inconclusive due to a small sample size; only 12 cases
of newly diagnosed POTS after mRNA vaccination were reported, all these
12 patients having <a href="https://en.wikipedia.org/wiki/Autoimmunity" title="Autoimmunity">autoimmune antibodies</a>. However, the risk of POTS-related diagnoses was 5.35 times higher after getting infected with <a href="https://en.wikipedia.org/wiki/SARS-CoV-2" title="SARS-CoV-2">SARS-CoV-2</a> compared to after mRNA vaccination.
Possible mechanisms for COVID-induced POTS are hypovolemia,
autoimmunity/inflammation from antibody production against autonomic
nerve fibers, and direct toxic effects of COVID-19, or secondary
sympathetic nervous system stimulation.
</p><p>POTS is more common in <a href="https://en.wikipedia.org/wiki/Female" title="Female">females</a> than <a href="https://en.wikipedia.org/wiki/Male" title="Male">males</a>. POTS also has been linked to patients with a history of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autoimmune_diseases" title="Autoimmune diseases">autoimmune diseases</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Long_Covid" title="Long Covid">Long Covid</a>, <a href="https://en.wikipedia.org/wiki/Irritable_bowel_syndrome" title="Irritable bowel syndrome">irritable bowel syndrome</a>, <a href="https://en.wikipedia.org/wiki/Anemia" title="Anemia">anemia</a>, <a href="https://en.wikipedia.org/wiki/Hyperthyroidism" title="Hyperthyroidism">hyperthyroidism</a>, <a href="https://en.wikipedia.org/wiki/Fibromyalgia" title="Fibromyalgia">fibromyalgia</a>, <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a>, <a href="https://en.wikipedia.org/wiki/Amyloidosis" title="Amyloidosis">amyloidosis</a>, <a href="https://en.wikipedia.org/wiki/Sarcoidosis" title="Sarcoidosis">sarcoidosis</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Systemic_lupus_erythematosus" title="Systemic lupus erythematosus">systemic lupus erythematosus</a>, and <a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a>.
Genetics likely plays a role, with one study finding that one in eight
POTS patients reported a history of orthostatic intolerance in their
family.
</p>
<h3><span class="mw-headline" id="Autoimmunity">Autoimmunity</span></h3><p>There is an increasing number of studies indicating that POTS is an autoimmune disease. A high number of patients has elevated levels of autoantibodies against the <a href="https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor" title="Alpha-1 adrenergic receptor">adrenergic alpha 1 receptor</a> and against the <a href="https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4" title="Muscarinic acetylcholine receptor M4">muscarinic acetylcholine M4 receptor</a>.
</p><p>Elevations of autoantibodies targeting adrenergic α1 receptor has been associated with symptoms severity in patients with POTS.
</p><p>More recently, autoantibodies against other targets have been identified in small cohorts of POTS patients.
Signs of innate immune system activation with elaboration of
pro-inflammatory cytokines has also been reported in a cohort of POTS
patients.
</p>
<h3><span class="mw-headline" id="Secondary_POTS">Secondary POTS</span></h3><p>If POTS is caused by another condition, it may be classified as <i>secondary POTS</i>. Chronic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a> is one common cause.
POTS can also be secondary to gastrointestinal disorders that are
associated with low fluid intake due to nausea or fluid loss through
diarrhea, leading to hypovolemia. Systemic lupus erythematosus and other autoimmune diseases have also been linked to POTS.
</p><p>There is a subset of patients who present with both POTS and <a href="https://en.wikipedia.org/wiki/Mast_cell_activation_syndrome" title="Mast cell activation syndrome">mast cell activation syndrome</a>
(MCAS), and it is not yet clear whether MCAS is a secondary cause of
POTS or simply comorbid, however, treating MCAS for these patients can
significantly improve POTS symptoms.
</p><p>POTS can also co-occur in all types of <a href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">Ehlers–Danlos syndrome</a> (EDS), a hereditary connective tissue disorder marked by loose hypermobile joints prone to subluxations and <a href="https://en.wikipedia.org/wiki/Joint_dislocation" title="Joint dislocation">dislocations</a>, skin that exhibits moderate or greater laxity, easy bruising, and many other symptoms. A trifecta of POTS, EDS, and <a href="https://en.wikipedia.org/wiki/Mast_cell_activation_syndrome" title="Mast cell activation syndrome">mast cell activation syndrome</a> (MCAS) is becoming increasingly more common, with a genetic marker common among all three conditions. POTS is also often accompanied by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vasovagal_syncope" title="Vasovagal syncope">vasovagal syncope</a>, with a 25% overlap being reported. There are some overlaps between POTS and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chronic_fatigue_syndrome" title="Chronic fatigue syndrome">chronic fatigue syndrome</a>, with evidence of POTS in 10–20% of CFS cases. Fatigue and reduced exercise tolerance are prominent symptoms of both conditions, and <a href="https://en.wikipedia.org/wiki/Dysautonomia" title="Dysautonomia">dysautonomia</a> may underlie both conditions.
</p><p>POTS can sometimes be a <a href="https://en.wikipedia.org/wiki/Paraneoplastic_syndrome" title="Paraneoplastic syndrome">paraneoplastic syndrome</a> associated with cancer.
</p><p>There are case reports of people developing POTS and other forms of <a href="https://en.wikipedia.org/wiki/Dysautonomia" title="Dysautonomia">dysautonomia</a> <a href="https://en.wikipedia.org/wiki/Long_COVID" title="Long COVID">post-COVID</a>. There is no good large-scale empirical evidence yet to prove a connection, so for now the evidence is preliminary.
</p>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Tilt_table_test_showing_POTS.webp"><img class="mw-file-element" data-file-height="507" data-file-width="604" height="336" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/63/Tilt_table_test_showing_POTS.webp/220px-Tilt_table_test_showing_POTS.webp.png" width="400" /></a><figcaption>Results of a tilt table test positive for POTS</figcaption></figure>
<p>POTS is most commonly diagnosed by a cardiologist (41%), cardiac electrophysiologist (15%), or neurologist (19%). The average number of physicians seen before receiving diagnosis is seven, and the average delay before diagnosis is 4.7 years.
</p>
<h3><span class="mw-headline" id="Diagnostic_criteria">Diagnostic criteria</span></h3><p>A POTS diagnosis requires the following characteristics:
</p>
<ul><li>For patients age 20 or older, a sustained increase in heart rate ≥30 bpm within ten minutes of upright posture (<a href="https://en.wikipedia.org/wiki/Tilt_table_test" title="Tilt table test">tilt table test</a> or standing) from a supine position.
<ul><li>For patients age 12–19, heart rate increase must be >40 bpm.</li></ul></li><li>Associated with frequent symptoms of lightheadedness, palpitations,
tremulousness, generalized weakness, blurred vision, or fatigue that are
worse with upright posture and that improve with recumbence.</li><li>An absence of orthostatic hypotension (i.e. no sustained systolic blood pressure drop of 20 mmHg or more).</li><li>Chronic symptoms that have lasted for longer than three months.</li><li>In the absence of other disorders, medications, or functional states that are known to predispose to orthostatic tachycardia.</li></ul>
<p>Alternative tests to the tilt table test are also used, such as the NASA Lean Test and the adapted Autonomic Profile (aAP) which require less equipment to complete.
</p>
<h3><span class="mw-headline" id="Orthostatic_intolerance">Orthostatic intolerance</span></h3><p>An increase in heart rate upon moving to an upright posture is known as orthostatic (upright) <a href="https://en.wikipedia.org/wiki/Tachycardia" title="Tachycardia">tachycardia</a> (fast heart rate). It occurs without any coinciding drop in blood pressure, as that would indicate <a href="https://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">orthostatic hypotension</a>. Certain medications to treat POTS may cause orthostatic hypotension. It is accompanied by other features of <a href="https://en.wikipedia.org/wiki/Orthostatic_intolerance" title="Orthostatic intolerance">orthostatic intolerance</a>—symptoms that develop in an upright position and are relieved by reclining. These orthostatic symptoms include <a href="https://en.wikipedia.org/wiki/Palpitations" title="Palpitations">palpitations</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Light-headedness" title="Light-headedness">light-headedness</a>, chest discomfort, <a href="https://en.wikipedia.org/wiki/Shortness_of_breath" title="Shortness of breath">shortness of breath</a>, nausea, weakness or "heaviness" in the lower legs, <a href="https://en.wikipedia.org/wiki/Blurred_vision" title="Blurred vision">blurred vision</a>, and cognitive difficulties.
</p>
<h3><span class="mw-headline" id="Differential_diagnoses">Differential diagnoses</span></h3><p>A variety of autonomic tests are employed to <a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">exclude</a> <a href="https://en.wikipedia.org/wiki/Dysautonomia" title="Dysautonomia">autonomic disorders</a> that could underlie symptoms, while <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Endocrine" title="Endocrine">endocrine</a> testing is used to exclude <a href="https://en.wikipedia.org/wiki/Hyperthyroidism" title="Hyperthyroidism">hyperthyroidism</a> and rarer endocrine conditions. <a href="https://en.wikipedia.org/wiki/Electrocardiography" title="Electrocardiography">Electrocardiography</a> is normally performed on all patients to exclude other possible causes of tachycardia. In cases where a particular associated condition or <a href="https://en.wikipedia.org/wiki/Complication_(medicine)" title="Complication (medicine)">complicating</a> factor are suspected, other non-autonomic tests may be used: <a href="https://en.wikipedia.org/wiki/Echocardiography" title="Echocardiography">echocardiography</a> to exclude <a href="https://en.wikipedia.org/wiki/Mitral_valve_prolapse" title="Mitral valve prolapse">mitral valve prolapse</a>, and thermal threshold tests for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Small-fiber_neuropathy" title="Small-fiber neuropathy">small-fiber neuropathy</a>.
</p><p>Testing the cardiovascular response to prolonged head-up tilting,
exercise, eating, and heat stress may help determine the best strategy
for managing symptoms. POTS has also been divided into several types (see <a href="https://en.wikipedia.org/wiki/Postural_orthostatic_tachycardia_syndrome#Causes">§ Causes</a>), which may benefit from distinct treatments. People with neuropathic POTS show a loss of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sweating" title="Sweating">sweating</a> in the feet during sweat tests, as well as impaired <a href="https://en.wikipedia.org/wiki/Norepinephrine" title="Norepinephrine">norepinephrine</a> release in the leg, but not arm. This is believed to reflect peripheral sympathetic <a href="https://en.wikipedia.org/wiki/Denervation" title="Denervation">denervation</a> in the lower limbs.<sup> </sup>People with hyperadrenergic POTS show a marked increase of blood
pressure and norepinephrine levels when standing, and are more likely to
have from prominent palpitations, anxiety, and tachycardia. People with POTS can be misdiagnosed with <a href="https://en.wikipedia.org/wiki/Inappropriate_sinus_tachycardia" title="Inappropriate sinus tachycardia">inappropriate sinus tachycardia</a>
(IST) as they present similarly. One distinguishing feature is those
with POTS rarely exhibit >100 bpm while in a supine position, while
patients with IST often have a resting heart rate >100 bpm.
Additionally patients with POTS display a more pronounced change in
heart rate in response to postural change.
</p>
<h2><span class="mw-headline" id="Treatment">Treatment</span></h2><p>POTS
treatment involves using multiple methods in combination to counteract
cardiovascular dysfunction, address symptoms, and simultaneously address
any associated disorders. For most patients, water intake should be increased, especially after waking, in order to expand blood volume (reducing <a href="https://en.wikipedia.org/wiki/Hypovolemia" title="Hypovolemia">hypovolemia</a>). Eight to ten cups of water daily are recommended. Increasing <a href="https://en.wikipedia.org/wiki/Salt" title="Salt">salt</a> intake, by adding salt to food, taking salt tablets, or drinking sports drinks and other <a href="https://en.wikipedia.org/wiki/Electrolyte" title="Electrolyte">electrolyte</a>
solutions is an effective way to raise blood pressure by helping the
body retain water. Different physicians recommend different amounts of
sodium to their patients. Combining these techniques with gradual physical training enhances their effect. In some cases, when increasing oral fluids and salt intake is not enough, intravenous <a href="https://en.wikipedia.org/wiki/Saline_(medicine)" title="Saline (medicine)">saline</a> or the drug <a href="https://en.wikipedia.org/wiki/Desmopressin" title="Desmopressin">desmopressin</a> is used to help increase fluid retention.
</p><p>Large meals worsen symptoms for some people. These people may
benefit from eating small meals frequently throughout the day instead. <a href="https://en.wikipedia.org/wiki/Alcoholic_beverage" title="Alcoholic beverage">Alcohol</a> and food high in <a href="https://en.wikipedia.org/wiki/Carbohydrate" title="Carbohydrate">carbohydrates</a> can also exacerbate symptoms of orthostatic hypotension. Excessive consumption of <a href="https://en.wikipedia.org/wiki/Caffeine" title="Caffeine">caffeine</a> beverages should be avoided, because they can promote urine production (leading to fluid loss) and consequently hypovolemia. Exposure to extreme heat may also aggravate symptoms.
</p><p>Prolonged physical inactivity can worsen the symptoms of POTS. Techniques that increase a person's capacity for exercise, such as <a href="https://en.wikipedia.org/wiki/Endurance_training" title="Endurance training">endurance training</a> or <a href="https://en.wikipedia.org/wiki/Graded_exercise_therapy" title="Graded exercise therapy">graded exercise therapy</a>, can relieve symptoms for some patients. <a href="https://en.wikipedia.org/wiki/Aerobic_exercise" title="Aerobic exercise">Aerobic exercise</a> performed for 20 minutes a day, three times a week, is sometimes recommended for patients who can tolerate it. Exercise may have the immediate effect of worsening tachycardia, especially after a meal or on a hot day. In these cases, it may be easier to exercise in a semi-reclined position, such as riding a <a href="https://en.wikipedia.org/wiki/Recumbent_bicycle" title="Recumbent bicycle">recumbent bicycle</a>, <a href="https://en.wikipedia.org/wiki/Rowing" title="Rowing">rowing</a>, or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Human_swimming" title="Human swimming">swimming</a>.
</p><p>When changing to an upright posture, finishing a meal, or
concluding exercise, a sustained hand grip can briefly raise the blood
pressure, possibly reducing symptoms. <a href="https://en.wikipedia.org/wiki/Compression_garment" title="Compression garment">Compression garments</a> can also be of benefit by constricting blood pressures with external body pressure.
</p><p>Aggravating factors include exertion (81%), continued standing (80%), heat (79%), and after meals (42%).
</p>
<h3><span class="mw-headline" id="Medication">Medication</span></h3><p>If nonpharmacological methods are ineffective, medication may be necessary. Medications used may include <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beta_blockers" title="Beta blockers">beta blockers</a>, <a href="https://en.wikipedia.org/wiki/Pyridostigmine" title="Pyridostigmine">pyridostigmine</a>, <a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">midodrine</a>, or <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a>. As of 2013, no medication has been approved by the U.S. <a href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> to treat POTS, but a variety are used <a href="https://en.wikipedia.org/wiki/Off-label_use" title="Off-label use">off-label</a>. Their efficacy has not yet been examined in long-term <a href="https://en.wikipedia.org/wiki/Randomized_controlled_trial" title="Randomized controlled trial">randomized controlled trials</a>.
</p><p>Fludrocortisone may be used to enhance sodium retention and blood
volume, which may be beneficial not only by augmenting sympathetically
mediated vasoconstriction, but also because a large subset of POTS
patients appear to have low absolute blood volume. However, fludrocortisone may cause hypokalemia.
</p><p>While people with POTS typically have normal or even elevated
arterial blood pressure, the neuropathic form of POTS is presumed to
constitute a selective sympathetic venous denervation. In these patients the selective <a href="https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor" title="Alpha-1 adrenergic receptor">Alpha-1 adrenergic receptor</a> agonist midodrine may increase venous return, enhance stroke volume, and improve symptoms. Midodrine should only be taken during the daylight hours as it may promote supine hypertension.
</p><p>Sinus node blocker <a href="https://en.wikipedia.org/wiki/Ivabradine" title="Ivabradine">Ivabradine</a>
can successfully restrain heart rate in POTS without affecting blood
pressure, demonstrated in approximately 60% of people with POTS treated
in an open-label trial of ivabradine experienced symptom improvement.
</p><p>Pyridostigmine has been reported to restrain heart rate and
improve chronic symptoms in approximately half of people. However, it
may cause GI side effects that limit its use in around 20% of its
patient population.
</p><p>The selective alpha-1 agonist <a href="https://en.wikipedia.org/wiki/Phenylephrine" title="Phenylephrine">phenylephrine</a> has been used successfully to enhance venous return and stroke volume in some people with POTS. However, this medication may be hampered by poor oral bioavailability.
</p>
<table class="wikitable">
<caption>Pharmacologic treatments for postural tachycardia syndrome
</caption>
<tbody><tr>
<th>POTS subtypes
</th>
<th>Therapeutic action
</th>
<th>Goal
</th>
<th>Drug(s)
</th></tr>
<tr>
<td rowspan="2">Neuropathic POTS
</td>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alpha-1_agonist" title="Alpha-1 agonist">Alpha-1 adrenergic receptor agonist</a>
</td>
<td>Constrict the peripheral blood vessels aiding venous return.
</td>
<td><a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">Midodrine</a>
</td></tr>
<tr>
<td>Splanchnic–mesenteric vasoconstriction
</td>
<td>Splanchnic vasoconstriction
</td>
<td><a href="https://en.wikipedia.org/wiki/Octreotide" title="Octreotide">Octreotide</a>
</td></tr>
<tr>
<td rowspan="2">Hypovolemic POTS
</td>
<td>Synthetic mineralocorticoid
</td>
<td>Forces the body to retain salt. Increase blood volume
</td>
<td><a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">Fludrocortisone</a> (Florinef)
</td></tr>
<tr>
<td>Vasopressin receptor agonist
</td>
<td>Helps retain water, Increase blood volume
</td>
<td><a href="https://en.wikipedia.org/wiki/Desmopressin" title="Desmopressin">Desmopressin</a> (DDAVP)
</td></tr>
<tr>
<td rowspan="5">Hyperadrenergic POTS
</td>
<td>Beta-blockers (non-selective)
</td>
<td rowspan="2">Decrease sympathetic tone and heart rate.
</td>
<td><a href="https://en.wikipedia.org/wiki/Propranolol" title="Propranolol">Propranolol</a> (Inderal)
</td></tr>
<tr>
<td>Beta-blockers (selective)
</td>
<td><a href="https://en.wikipedia.org/wiki/Metoprolol" title="Metoprolol">Metoprolol</a> (Toprol), <a href="https://en.wikipedia.org/wiki/Bisoprolol" title="Bisoprolol">Bisoprolol</a>
</td></tr>
<tr>
<td>Selective sinus node blockade
</td>
<td>Directly reducing tachycardia.
</td>
<td><a href="https://en.wikipedia.org/wiki/Ivabradine" title="Ivabradine">Ivabradine</a>
</td></tr>
<tr>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alpha-2_adrenergic_receptor_agonist" title="Alpha-2 adrenergic receptor agonist">Alpha-2 adrenergic receptor agonist</a>
</td>
<td>Decreases blood pressure and sympathetic nerve traffic.
</td>
<td><a href="https://en.wikipedia.org/wiki/Clonidine" title="Clonidine">Clonidine</a>, <a href="https://en.wikipedia.org/wiki/Methyldopa" title="Methyldopa">Methyldopa</a>
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor" title="Acetylcholinesterase inhibitor">Anticholinesterase inhibitors</a>
</td>
<td>Splanchnic vasoconstriction. Increase blood pressure.
</td>
<td><a href="https://en.wikipedia.org/wiki/Pyridostigmine" title="Pyridostigmine">Pyridostigmine</a>
</td></tr>
<tr>
<td rowspan="5">Other (refractory POTS)
</td>
<td>Psychostimulant
</td>
<td>Improve cognitive symptoms (brain fog)
</td>
<td><a href="https://en.wikipedia.org/wiki/Modafinil" title="Modafinil">Modafinil</a>
</td></tr>
<tr>
<td>Central nervous system stimulant
</td>
<td>Tighten blood vessels. Increases alertness and improves brain fog.
</td>
<td><a href="https://en.wikipedia.org/wiki/Methylphenidate" title="Methylphenidate">Methylphenidate</a> (Ritalin, Concerta)
</td></tr>
<tr>
<td>Direct and indirect α1-adrenoreceptor agonist.
</td>
<td>Increased blood flows
</td>
<td><a href="https://en.wikipedia.org/wiki/Ephedrine" title="Ephedrine">Ephedrine</a> and <a href="https://en.wikipedia.org/wiki/Pseudoephedrine" title="Pseudoephedrine">Pseudoephedrine</a>
</td></tr>
<tr>
<td>Norepinephrine precursor
</td>
<td>Improve blood vessel contraction
</td>
<td><a href="https://en.wikipedia.org/wiki/Droxidopa" title="Droxidopa">Droxidopa</a> (Northera)
</td></tr>
<tr>
<td>Alpha-2 adrenergic antagonist
</td>
<td>Increase blood pressure
</td>
<td><a href="https://en.wikipedia.org/wiki/Yohimbine" title="Yohimbine">Yohimbine</a>
</td></tr></tbody></table>
<h2><span class="mw-headline" id="Prognosis">Prognosis</span></h2><p>POTS has a favorable <a href="https://en.wikipedia.org/wiki/Prognosis" title="Prognosis">prognosis</a> when managed appropriately. Symptoms improve within five years of diagnosis for many patients, and 60% return to their original level of functioning. Approximately 90% of people with POTS respond to a combination of pharmacological and physical treatments.
Those who develop POTS in their early to mid teens will likely respond
well to a combination of physical methods as well as pharmacotherapy. Outcomes are more guarded for adults newly diagnosed with POTS. Some people do not recover, and a few even worsen with time. The hyperadrenergic type of POTS typically requires continuous therapy. If POTS is caused by another condition, outcomes depend on the prognosis of the underlying disorder.
</p>
<h2><span class="mw-headline" id="Epidemiology">Epidemiology</span></h2><p>The <a href="https://en.wikipedia.org/wiki/Prevalence" title="Prevalence">prevalence</a> of POTS is unknown.
One study estimated a minimal rate of 170 POTS cases per 100,000
individuals, but the true prevalence is likely higher due to
underdiagnosis. Another study estimated that there are at least 500,000 cases in the United States. POTS is more common in women than men, with a female-to-male ratio of 4:1. Most people with POTS are aged between 20 and 40, with an average onset of 21. Diagnoses of POTS beyond age 40 are rare, perhaps because symptoms improve with age.
</p><p>As recently stated,
up to one-third of POTS patients also present with Vasovagal Syncope
(VVS). This ratio is probably higher if pre-Syncope patients, patients
that report the symptoms of Syncope without overt fainting, were
included. Given the difficulty with current autonomic measurements in
quantitatively isolating and differentiating Parasympathetic (Vagal)
activity from Sympathetic activity without assumption or approximation,
the current direction of research and clinical assessment is
understandable: perpetuating uncertainty regarding underlying cause,
prescribing beta-blockers and proper daily hydration as the only
therapy, not addressing the orthostatic dysfunction as the underlying
cause, and recommending acceptance and associated lifestyle changes to
cope.
</p><p>Direct measures of Parasympathetic (Vagal) activity obviates the
uncertainty and lack of true relief of POTS as well as VVS. For
example, the hypothesis that POTS is an auto-immune disorder may be an
indication that a significant number of POTS cases are indeed co-morbid
with VVS. Remember the Parasympathetic Nervous System is the memory
for, and controls and coordinates, the immune system. If
Parasympathetic (Vagal) over-, or prolonged-, activation is chronic then
portions of the immune system may remain active beyond the limits of
the infection. Given that portions of the immune system are not of
self, these portions remain active and continue to “feed.” Once the
only source of “feed” is self, the immune system begins to attack the
host. This is the definition of autoimmune. This is a
counter-hypothesis that may provide a simpler explanation with a more
immediate plan for therapy and relief. For it may be that relieving the
Vagal over-activation, will retires the self-attacking portion of the
immune system, thereby relieving the autoimmunity.
</p><p>Another example may be “Hyperadrenergic POTS.” A counter
hypothesis and perhaps a simpler explanation that leads to more direct
therapy and improved outcomes is again the fact that POTS and VVS may be
co-morbid. It is well known that Parasympathetic (Vagal)
over-activation may cause secondary Sympathetic over-activation.
Without direct Parasympathetic (Vagal) measures, the resulting
assumption is that the secondary Sympathetic over-activation (the
definition of “hyperadrenergic”) is actually the primary autonomic
dysfunction. Simply treating the (secondary) Sympathetic
over-activation may be just treating a symptom in these cases, which may
work for a while but then the body compensates and more medication is
needed or the patient become unresponsive and the permanent degraded
lifestyles are considered the only option. Again, this is unfortunate.
Given that cases of POTS with VVS involves different portions of the
nervous system (Parasympathetic and Sympathetic), and that both branches
may be treated simultaneously, albeit differently, true relief of both
conditions, as needed, is quite possible, and the cases of these newer
hypothesized causes may be relieved with current, less expensive, and
shorter-term therapy modalities.
</p>
<h3><span class="mw-headline" id="Co-morbidities">Co-morbidities</span></h3><p>Conditions that are commonly reported with POTS include:
</p>
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Migraine_headaches" title="Migraine headaches">Migraine headaches</a> (40%)</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndromes" title="Ehlers–Danlos syndromes">Ehlers–Danlos syndrome</a> (18–25%)</li><li><a href="https://en.wikipedia.org/wiki/Asthma" title="Asthma">Asthma</a> (20%)</li><li><a href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">Autoimmune disease</a> (16%)</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vasovagal_syncope" title="Vasovagal syncope">Vasovagal syncope</a> (13%)</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mast_cell_activation_disorder" title="Mast cell activation disorder">Mast cell activation disorder</a> (9%)</li></ul>
<h2><span class="mw-headline" id="History">History</span></h2><p>In 1871, physician <a href="https://en.wikipedia.org/wiki/Jacob_Mendes_Da_Costa" title="Jacob Mendes Da Costa">Jacob Mendes Da Costa</a> described a condition that resembled the modern concept of POTS. He named it <i>irritable heart syndrome</i>. Cardiologist <a href="https://en.wikipedia.org/wiki/Thomas_Lewis_(cardiologist)" title="Thomas Lewis (cardiologist)">Thomas Lewis</a> expanded on the description, coining the term <i>soldier's heart</i> because it was often found among military personnel. The condition came to be known as <a href="https://en.wikipedia.org/wiki/Da_Costa%27s_syndrome" title="Da Costa's syndrome">Da Costa's syndrome</a>, which is now recognized as several distinct disorders, including POTS.<i> Postural tachycardia syndrome</i> was coined in 1982 in a description of a patient who had postural tachycardia, but not orthostatic hypotension. Ronald Schondorf and Phillip A. Low of the <a href="https://en.wikipedia.org/wiki/Mayo_Clinic" title="Mayo Clinic">Mayo Clinic</a> first used the name <i>postural orthostatic tachycardia syndrome</i>, POTS, in 1993.
</p>
<h2><span class="mw-headline" id="Notable_cases">Notable cases</span></h2>British politician <a href="https://en.wikipedia.org/wiki/Nicola_Blackwood" title="Nicola Blackwood">Nicola Blackwood</a> revealed in March 2015 that she had been diagnosed with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndromes" title="Ehlers–Danlos syndromes">Ehlers–Danlos syndrome</a> in 2013 and that she had later been diagnosed with POTS. She was appointed Parliamentary Under-Secretary of State for Life Science by Prime Minister <a href="https://en.wikipedia.org/wiki/Theresa_May" title="Theresa May">Theresa May</a> in 2019 and given a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Life_peerage" title="Life peerage">life peerage</a>
that enabled her to take a seat in Parliament. As a junior minister, it
is her responsibility to answer questions in parliament on the subjects
of Health and departmental business. When answering these questions, it
is customary for ministers to sit when listening to the question and
then to rise to give an answer from the <a href="https://en.wikipedia.org/wiki/Despatch_box" title="Despatch box">despatch box</a>,
thus standing up and sitting down numerous times in quick succession
throughout a series of questions. On 17 June 2019, she fainted during
one of these questioning sessions after standing up from a sitting
position four times in the space of twelve minutes,
and it was suggested that her POTS was a factor in her fainting. Asked
about the incident, she stated: "I was frustrated and embarrassed my
body gave up on me at work ... But I am grateful it gives me a chance to
shine a light on a condition many others are also living with."David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-66649226758786310852024-03-27T17:31:00.000-04:002024-03-27T17:31:38.277-04:00Trigeminal nerve<div class="vector-column-end">
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<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background-color: lemonchiffon;">Trigeminal nerve</th></tr><tr><td class="infobox-image" colspan="2"><div style="text-align: center;"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Grant_1962_654.png"><img class="mw-file-element" data-file-height="1844" data-file-width="1720" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/59/Grant_1962_654.png/300px-Grant_1962_654.png" width="373" /></a></span></div><div class="infobox-caption">Schematic illustration of the trigeminal nerve and the organs (or structures) it supplies</div></td></tr></tbody></table><p>In <a href="https://en.wikipedia.org/wiki/Neuroanatomy" title="Neuroanatomy">neuroanatomy</a>, the <b>trigeminal nerve</b> (<a href="https://en.wikipedia.org/wiki/Literal_translation" title="Literal translation">lit.</a> <i>triplet</i> nerve), also known as the <b>fifth cranial nerve</b>, <b>cranial nerve V</b>, or simply <b>CN V</b>, is a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cranial_nerve" title="Cranial nerve">cranial nerve</a> responsible for <a href="https://en.wikipedia.org/wiki/Sense" title="Sense">sensation</a> in the <a href="https://en.wikipedia.org/wiki/Face" title="Face">face</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Motor_functions" title="Motor functions">motor functions</a> such as <a href="https://en.wikipedia.org/wiki/Biting" title="Biting">biting</a> and <a href="https://en.wikipedia.org/wiki/Chewing" title="Chewing">chewing</a>; it is the most complex of the <a href="https://en.wikipedia.org/wiki/Cranial_nerves" title="Cranial nerves">cranial nerves</a>. Its name (<i>trigeminal</i>, from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Latin_language" title="Latin language">Latin</a> <i> tri-</i> 'three', and <i> -geminus</i> 'twin') derives from each of the two nerves (one on each side of the <a href="https://en.wikipedia.org/wiki/Pons" title="Pons">pons</a>) having three major branches: the <a href="https://en.wikipedia.org/wiki/Ophthalmic_nerve" title="Ophthalmic nerve">ophthalmic nerve</a> (V<sub>1</sub>), the <a href="https://en.wikipedia.org/wiki/Maxillary_nerve" title="Maxillary nerve">maxillary nerve</a> (V<sub>2</sub>), and the <a href="https://en.wikipedia.org/wiki/Mandibular_nerve" title="Mandibular nerve">mandibular nerve</a> (V<sub>3</sub>). The ophthalmic and maxillary nerves are purely sensory, whereas the mandibular nerve supplies motor as well as sensory (or "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cutaneous" title="Cutaneous">cutaneous</a>") functions. Adding to the complexity of this nerve is that <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nerve fibers</a> as well as special <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sensory_fibers" title="Sensory fibers">sensory fibers</a> (<a href="https://en.wikipedia.org/wiki/Taste" title="Taste">taste</a>) are contained within it.
</p><p>The motor division of the trigeminal nerve derives from the <a href="https://en.wikipedia.org/wiki/Basal_plate_(neural_tube)" title="Basal plate (neural tube)">basal plate</a> of the <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryonic</a> <a href="https://en.wikipedia.org/wiki/Pons" title="Pons">pons</a>, and the sensory division originates in the <a href="https://en.wikipedia.org/wiki/Cranial_neural_crest" title="Cranial neural crest">cranial neural crest</a>. Sensory information from the face and body is processed by parallel pathways in the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>.
</p>
<h2><span class="mw-headline" id="Structure">Structure</span></h2></div></div></div><h3><span class="mw-headline" id="Origin">Origin</span></h3><p>From the trigeminal ganglion, a single, large sensory root (radix sensoria s. portio major) enters the <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a> at the level of the <a href="https://en.wikipedia.org/wiki/Pons" title="Pons">pons</a>. Immediately adjacent to the sensory root, a smaller motor root (radix motoria s. portio minor) emerges from the pons slightly rostrally and medially to the sensory root.
</p><p>Motor fibers pass through the trigeminal ganglion without
synapsing on their way to peripheral muscles, their cell bodies being
located in the nucleus of the fifth nerve, deep within the pons.
</p>
<h3><span class="mw-headline" id="Trigeminal_ganglion">Trigeminal ganglion</span></h3><p>
The three major branches of the trigeminal nerve—the <a href="https://en.wikipedia.org/wiki/Ophthalmic_nerve" title="Ophthalmic nerve">ophthalmic nerve</a> (V<sub>1</sub>), the <a href="https://en.wikipedia.org/wiki/Maxillary_nerve" title="Maxillary nerve">maxillary nerve</a> (V<sub>2</sub>) and the <a href="https://en.wikipedia.org/wiki/Mandibular_nerve" title="Mandibular nerve">mandibular nerve</a> (V<sub>3</sub>)—converge on the <a href="https://en.wikipedia.org/wiki/Trigeminal_ganglion" title="Trigeminal ganglion">trigeminal ganglion</a> (also called the semilunar ganglion or gasserian ganglion), located within <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Meckel%27s_cave" title="Meckel's cave">Meckel's cave</a> and containing the cell bodies of incoming sensory-nerve fibers. The trigeminal ganglion is analogous to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_root" title="Dorsal root">dorsal root</a> ganglia of the spinal cord, which contain the cell bodies of incoming sensory fibers from the rest of the body.</p><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gray784.png"><img alt="Drawing of the head, with areas served by specific nerves color-coded" class="mw-file-element" data-file-height="423" data-file-width="600" height="282" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/20/Gray784.png/220px-Gray784.png" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Dermatome_(anatomy)" title="Dermatome (anatomy)">Dermatome</a> distribution of the trigeminal nerve</figcaption></figure>
<h3><span class="mw-headline" id="Sensory_branches">Sensory branches</span></h3><figure class="mw-default-size mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Trig_innervation.svg"><img alt="Profile of the head, with the three sub-nerves color-coded" class="mw-file-element" data-file-height="366" data-file-width="290" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/2f/Trig_innervation.svg/220px-Trig_innervation.svg.png" width="317" /></a><figcaption>Dermatome distribution of the trigeminal nerve</figcaption></figure>
<p>The ophthalmic, maxillary and mandibular branches leave the skull through three separate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Foramina_of_the_skull" title="Foramina of the skull">foramina</a>: the <a href="https://en.wikipedia.org/wiki/Superior_orbital_fissure" title="Superior orbital fissure">superior orbital fissure</a>, the <a href="https://en.wikipedia.org/wiki/Foramen_rotundum" title="Foramen rotundum">foramen rotundum</a> and the <a href="https://en.wikipedia.org/wiki/Foramen_ovale_(skull)" title="Foramen ovale (skull)">foramen ovale</a>, respectively. The ophthalmic nerve (V<sub>1</sub>)
carries sensory information from the scalp and forehead, the upper
eyelid, the conjunctiva and cornea of the eye, the nose (including the
tip of the nose, except alae nasi), the nasal mucosa, the frontal
sinuses and parts of the <a href="https://en.wikipedia.org/wiki/Meninges" title="Meninges">meninges</a> (the <a href="https://en.wikipedia.org/wiki/Dura_mater" title="Dura mater">dura</a> and blood vessels). The maxillary nerve (V<sub>2</sub>) carries sensory information from the lower eyelid and cheek, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nares" title="Nares">nares</a>
and upper lip, the upper teeth and gums, the nasal mucosa, the palate
and roof of the pharynx, the maxillary, ethmoid and sphenoid sinuses and
parts of the meninges. The mandibular nerve (V<sub>3</sub>) carries
sensory information from the lower lip, the lower teeth and gums, the
chin and jaw (except the angle of the jaw, which is supplied by C2-C3),
parts of the external ear and parts of the meninges. The mandibular
nerve carries touch-position and pain-temperature sensations from the
mouth. Although it does not carry taste sensation (the <a href="https://en.wikipedia.org/wiki/Chorda_tympani" title="Chorda tympani">chorda tympani</a> is responsible for taste), one of its branches—the <a href="https://en.wikipedia.org/wiki/Lingual_nerve" title="Lingual nerve">lingual nerve</a>—carries sensation from the tongue.
</p><p>The peripheral processes of mesencephalic nucleus of V neurons
run in the motor root of the trigeminal nerve and terminate in the
muscle spindles in the muscles of mastication. They are proprioceptive
fibers, conveying information regarding the location of the masticatory
muscles. The central processes of mesencephalic V neurons synapse in the
motor nucleus V.
</p>
<h3><span class="mw-headline" id="Dermatomes">Dermatomes</span></h3><p>The
areas of cutaneous distribution (dermatomes) of the three sensory
branches of the trigeminal nerve have sharp borders with relatively
little overlap (unlike dermatomes in the rest of the body, which have
considerable overlap). The injection of a <a href="https://en.wikipedia.org/wiki/Local_anesthetic" title="Local anesthetic">local anesthetic</a>, such as <a href="https://en.wikipedia.org/wiki/Lidocaine" title="Lidocaine">lidocaine</a>,
results in the complete loss of sensation from well-defined areas of
the face and mouth. For example, teeth on one side of the jaw can be
numbed by injecting the mandibular nerve. Occasionally, injury or
disease processes may affect two (or all three) branches of the
trigeminal nerve; in these cases, the involved branches may be termed:
</p>
<ul><li><b>V1/V2 distribution</b> – Referring to the ophthalmic and maxillary branches</li><li><b>V2/V3 distribution</b> – Referring to the maxillary and mandibular branches</li><li><b>V1-V3 distribution</b> – Referring to all three branches</li></ul>
<p>Nerves on the left side of the jaw slightly outnumber the nerves on the right side of the jaw.
</p>
<h2><span class="mw-headline" id="Function">Function</span></h2><p>The sensory function of the trigeminal nerve is to provide tactile, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proprioceptive" title="Proprioceptive">proprioceptive</a>, and <a href="https://en.wikipedia.org/wiki/Nociception" title="Nociception">nociceptive</a> afference to the face and mouth. Its motor function activates the <a href="https://en.wikipedia.org/wiki/Muscles_of_mastication" title="Muscles of mastication">muscles of mastication</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tensor_tympani" title="Tensor tympani">tensor tympani</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tensor_veli_palatini" title="Tensor veli palatini">tensor veli palatini</a>, <a href="https://en.wikipedia.org/wiki/Mylohyoid_muscle" title="Mylohyoid muscle">mylohyoid</a> and the <a href="https://en.wikipedia.org/wiki/Digastric_muscle#Anterior_belly" title="Digastric muscle">anterior belly of the digastric</a>.
</p><p>The trigeminal nerve carries <a class="mw-redirect" href="https://en.wikipedia.org/wiki/General_somatic_afferent_fibers" title="General somatic afferent fibers">general somatic afferent fibers</a>
(GSA), which innervate the skin of the face via ophthalmic (V1),
maxillary (V2) and mandibular (V3) divisions. The trigeminal nerve also
carries <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Special_visceral_efferent" title="Special visceral efferent">special visceral efferent</a> (SVE) <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a>, which innervate the muscles of mastication via the mandibular (V3) division.
</p>
<h3><span class="mw-headline" id="Muscles">Muscles</span></h3><p>The
motor component of the mandibular division (V3) of the trigeminal nerve
controls the movement of eight muscles, including the four <a href="https://en.wikipedia.org/wiki/Muscles_of_mastication" title="Muscles of mastication">muscles of mastication</a>: the <a href="https://en.wikipedia.org/wiki/Masseter_muscle" title="Masseter muscle">masseter</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Temporal_muscle" title="Temporal muscle">temporal muscle</a>, and the <a href="https://en.wikipedia.org/wiki/Medial_pterygoid_muscle" title="Medial pterygoid muscle">medial</a> and <a href="https://en.wikipedia.org/wiki/Lateral_pterygoid_muscle" title="Lateral pterygoid muscle">lateral pterygoids</a>. The other four muscles are the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tensor_veli_palatini" title="Tensor veli palatini">tensor veli palatini</a>, the <a href="https://en.wikipedia.org/wiki/Mylohyoid_muscle" title="Mylohyoid muscle">mylohyoid</a>, the anterior belly of the <a href="https://en.wikipedia.org/wiki/Digastric_muscle" title="Digastric muscle">digastric</a> and the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tensor_tympani" title="Tensor tympani">tensor tympani</a>.
</p><p>With the exception of the tensor tympani, all these muscles are
involved in biting, chewing and swallowing and all have bilateral <a href="https://en.wikipedia.org/wiki/Cortex_(anatomy)" title="Cortex (anatomy)">cortical</a> representation. A unilateral central lesion (for example, a <a href="https://en.wikipedia.org/wiki/Stroke" title="Stroke">stroke</a>),
no matter how large, is unlikely to produce an observable deficit.
Injury to a peripheral nerve can cause paralysis of muscles on one side
of the jaw, with the jaw deviating towards the paralyzed side when it
opens. This direction of the mandible is due to the action of the
functioning pterygoids on the opposite side.
</p>
<h3><span class="mw-headline" id="Sensation">Sensation</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Somatosensory_system" title="Somatosensory system">Somatosensory system</a></div>
<p>The two basic types of sensation are touch-position and
pain-temperature. Touch-position input comes to attention immediately,
but pain-temperature input reaches the level of consciousness after a
delay; when a person steps on a pin, the awareness of stepping on
something is immediate but the pain associated with it is delayed.
</p><p>Touch-position information is generally carried by myelinated
(fast-conducting) nerve fibers, and pain-temperature information by
unmyelinated (slow-conducting) fibers. The primary sensory receptors for
touch-position (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Meissner%E2%80%99s_corpuscles" title="Meissner’s corpuscles">Meissner's corpuscles</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Merkel%27s_receptors" title="Merkel's receptors">Merkel's receptors</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pacinian_corpuscles" title="Pacinian corpuscles">Pacinian corpuscles</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ruffini%E2%80%99s_corpuscles" title="Ruffini’s corpuscles">Ruffini's corpuscles</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hair_receptors" title="Hair receptors">hair receptors</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Muscle_spindle_organs" title="Muscle spindle organs">muscle spindle organs</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Golgi_tendon_organs" title="Golgi tendon organs">Golgi tendon organs</a>) are structurally more complex than those for pain-temperature, which are nerve endings.
</p><p>Sensation in this context refers to the conscious perception of
touch-position and pain-temperature information, rather than the <a href="https://en.wikipedia.org/wiki/Special_senses" title="Special senses">special senses</a>
(smell, sight, taste, hearing and balance) processed by different
cranial nerves and sent to the cerebral cortex through different
pathways. The perception of magnetic fields, electrical fields,
low-frequency vibrations and infrared radiation by some nonhuman
vertebrates is processed by their equivalent of the fifth cranial nerve.
</p><p>Touch in this context refers to the perception of detailed, localized tactile information, such as <a href="https://en.wikipedia.org/wiki/Two-point_discrimination" title="Two-point discrimination">two-point discrimination</a>
(the difference between touching one point and two closely spaced
points) or the difference between coarse, medium or fine sandpaper.
People without touch-position perception can feel the surface of their
bodies and perceive touch in a broad sense, but they lack perceptual
detail.
</p><p>Position, in this context, refers to conscious <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">proprioception</a>.
Proprioceptors (muscle spindle and Golgi tendon organs) provide
information about joint position and muscle movement. Although much of
this information is processed at an unconscious level (primarily by the <a href="https://en.wikipedia.org/wiki/Cerebellum" title="Cerebellum">cerebellum</a> and the <a href="https://en.wikipedia.org/wiki/Vestibular_system" title="Vestibular system">vestibular</a> nuclei), some is available at a conscious level.
</p><p>Touch-position and pain-temperature sensations are processed by
different pathways in the central nervous system. This hard-wired
distinction is maintained up to the cerebral cortex. Within the cerebral
cortex, sensations are linked with other cortical areas.
</p>
<h3><span class="mw-headline" id="Sensory_pathways">Sensory pathways</span></h3><p>Sensory
pathways from the periphery to the cortex are separate for
touch-position and pain-temperature sensations. All sensory information
is sent to specific nuclei in the <a href="https://en.wikipedia.org/wiki/Thalamus" title="Thalamus">thalamus</a>. Thalamic nuclei, in turn, send information to specific areas in the <a href="https://en.wikipedia.org/wiki/Cerebral_cortex" title="Cerebral cortex">cerebral cortex</a>. Each pathway consists of three bundles of nerve fibers connected in series:
</p>
<figure class="mw-default-size mw-halign-center"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Sensory_Pathways_III.png"><img alt="Flow chart from sensory receptors to the cerebral cortex" class="mw-file-element" data-file-height="22" data-file-width="519" height="22" src="https://upload.wikimedia.org/wikipedia/commons/6/60/Sensory_Pathways_III.png" width="519" /></a></figure>
<p>The secondary neurons in each pathway <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Decussate" title="Decussate">decussate</a>
(cross the spinal cord or brainstem), because the spinal cord develops
in segments. Decussated fibers later reach and connect these segments
with the higher centers. The <a href="https://en.wikipedia.org/wiki/Optic_chiasm" title="Optic chiasm">optic chiasm</a>
is the primary cause of decussation; nasal fibers of the optic nerve
cross (so each cerebral hemisphere receives
contralateral—opposite—vision) to keep the <a href="https://en.wikipedia.org/wiki/Interneuron" title="Interneuron">interneuronal</a>
connections responsible for processing information short. All sensory
and motor pathways converge and diverge to the contralateral hemisphere.
</p><p>Although sensory pathways are often depicted as chains of
individual neurons connected in series, this is an oversimplification.
Sensory information is processed and modified at each level in the chain
by interneurons and input from other areas of the nervous system. For
example, cells in the main trigeminal nucleus (Main V in the diagram
below) receive input from the <a href="https://en.wikipedia.org/wiki/Reticular_formation" title="Reticular formation">reticular formation</a> and cerebellar cortex. This information contributes to the final output of the cells in Main V to the thalamus.
</p>
<figure class="mw-halign-center"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Touch_Pain_Pathways.png"><img alt="Text-and-line diagram of sensory-nerve pathways" class="mw-file-element" data-file-height="357" data-file-width="696" height="308" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/ab/Touch_Pain_Pathways.png/600px-Touch_Pain_Pathways.png" width="600" /></a><figcaption>C = Cervical segment, S = Sacral segment, VPL = <a href="https://en.wikipedia.org/wiki/Ventral_posterolateral_nucleus" title="Ventral posterolateral nucleus">Ventral posterolateral nucleus</a>, SI = <a href="https://en.wikipedia.org/wiki/Primary_somatosensory_cortex" title="Primary somatosensory cortex">Primary somatosensory cortex</a>, VM = <a href="https://en.wikipedia.org/wiki/Ventromedial_prefrontal_cortex" title="Ventromedial prefrontal cortex">Ventromedial prefrontal cortex</a>, MD = <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medial_dorsal_thalamic_nucleus" title="Medial dorsal thalamic nucleus">Medial dorsal thalamic nucleus</a>, IL = <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intralaminar_nucleus" title="Intralaminar nucleus">Intralaminar nucleus</a>, VPM = <a href="https://en.wikipedia.org/wiki/Ventral_posteromedial_nucleus" title="Ventral posteromedial nucleus">Ventral posteromedial nucleus</a>, Main V = <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Main_trigeminal_nucleus" title="Main trigeminal nucleus">Main trigeminal nucleus</a>, Spinal V = <a href="https://en.wikipedia.org/wiki/Spinal_trigeminal_nucleus" title="Spinal trigeminal nucleus">Spinal trigeminal nucleus</a></figcaption></figure>
<p>Touch-position information from the body is carried to the thalamus by the <a href="https://en.wikipedia.org/wiki/Medial_lemniscus" title="Medial lemniscus">medial lemniscus</a>, and from the face by the <a href="https://en.wikipedia.org/wiki/Trigeminal_lemniscus" title="Trigeminal lemniscus">trigeminal lemniscus</a>
(both the anterior and posterior trigeminothalamic tracts).
Pain-temperature information from the body is carried to the thalamus by
the <a href="https://en.wikipedia.org/wiki/Spinothalamic_tract" title="Spinothalamic tract">spinothalamic tract</a>, and from the face by the anterior division of the <a href="https://en.wikipedia.org/wiki/Trigeminal_lemniscus" title="Trigeminal lemniscus">trigeminal lemniscus</a> (also called the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anterior_trigeminothalamic_tract" title="Anterior trigeminothalamic tract">anterior trigeminothalamic tract</a>).
</p><p>Pathways for touch-position and pain-temperature sensations from
the face and body merge in the brainstem, and touch-position and
pain-temperature sensory maps of the entire body are projected onto the
thalamus. From the thalamus, touch-position and pain-temperature
information is projected onto the cerebral cortex.
</p>
<h3><span class="mw-headline" id="Summary">Summary</span></h3><p>The
complex processing of pain-temperature information in the thalamus and
cerebral cortex (as opposed to the relatively simple, straightforward
processing of touch-position information) reflects a <a href="https://en.wikipedia.org/wiki/Phylogenetics" title="Phylogenetics">phylogenetically</a>
older, more primitive sensory system. The detailed information received
from peripheral touch-position receptors is superimposed on a
background of awareness, memory and emotions partially set by peripheral
pain-temperature receptors.
</p><p>Although thresholds for touch-position perception are relatively
easy to measure, those for pain-temperature perception are difficult to
define and measure. "Touch" is an objective sensation, but "pain" is an
individualized sensation which varies among different people and is
conditioned by memory and emotion. Anatomical differences between the
pathways for touch-position perception and pain-temperature sensation
help explain why pain, especially chronic pain, is difficult to manage.
</p>
<h2><span class="mw-headline" id="Trigeminal_nuclei">Trigeminal nuclei</span></h2><figure class="mw-default-size mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gray696_Trigeminal.svg"><img alt="Diagram of the brainstem" class="mw-file-element" data-file-height="591" data-file-width="323" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e2/Gray696_Trigeminal.svg/220px-Gray696_Trigeminal.svg.png" width="218" /></a><figcaption>Brainstem nuclei: Red = Motor; Blue = Sensory; Dark blue = Trigeminal nucleus</figcaption></figure>
<p>All sensory information from the face, both touch-position and pain-temperature, is sent to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Trigeminal_nucleus" title="Trigeminal nucleus">trigeminal nucleus</a>.
In classical anatomy most sensory information from the face is carried
by the fifth nerve, but sensation from parts of the mouth, parts of the
ear and parts of the <a href="https://en.wikipedia.org/wiki/Meninges" title="Meninges">meninges</a> is carried by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/General_somatic_afferent_fibers" title="General somatic afferent fibers">general somatic afferent fibers</a> in cranial nerves VII (the <a href="https://en.wikipedia.org/wiki/Facial_nerve" title="Facial nerve">facial nerve</a>), IX (the <a href="https://en.wikipedia.org/wiki/Glossopharyngeal_nerve" title="Glossopharyngeal nerve">glossopharyngeal nerve</a>) and X (the <a href="https://en.wikipedia.org/wiki/Vagus_nerve" title="Vagus nerve">vagus nerve</a>).
</p><p>All sensory fibers from these nerves terminate in the trigeminal
nucleus. On entering the brainstem, sensory fibers from V, VII, IX and X
are sorted and sent to the trigeminal nucleus (which contains a sensory
map of the face and mouth). The spinal counterparts of the trigeminal
nucleus (cells in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Posterior_horn_of_spinal_cord" title="Posterior horn of spinal cord">dorsal horn</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_column" title="Dorsal column">dorsal column</a> nuclei of the spinal cord) contain a sensory map of the rest of the body.
</p><p>The trigeminal nucleus extends throughout the brainstem, from the
midbrain to the medulla, continuing into the cervical cord (where it
merges with the dorsal horn cells of the spinal cord). The nucleus is
divided into three parts, visible in microscopic sections of the
brainstem. From caudal to rostral (ascending from the medulla to the
midbrain), they are the <a href="https://en.wikipedia.org/wiki/Spinal_trigeminal_nucleus" title="Spinal trigeminal nucleus">spinal trigeminal</a>, the <a href="https://en.wikipedia.org/wiki/Principal_sensory_nucleus_of_trigeminal_nerve" title="Principal sensory nucleus of trigeminal nerve">principal sensory</a> and the <a href="https://en.wikipedia.org/wiki/Mesencephalic_nucleus_of_trigeminal_nerve" title="Mesencephalic nucleus of trigeminal nerve">mesencephalic</a>
nuclei. The parts of the trigeminal nucleus receive different types of
sensory information; the spinal trigeminal nucleus receives
pain-temperature fibers, the principal sensory nucleus receives
touch-position fibers and the mesencephalic nucleus receives
proprioceptor and mechanoreceptor fibers from the jaws and teeth.
</p>
<h3><span class="mw-headline" id="Spinal_trigeminal_nucleus">Spinal trigeminal nucleus</span></h3><p>The <a href="https://en.wikipedia.org/wiki/Spinal_trigeminal_nucleus" title="Spinal trigeminal nucleus">spinal trigeminal nucleus</a> represents pain-temperature sensation from the face. Pain-temperature fibers from peripheral <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nociceptors" title="Nociceptors">nociceptors</a>
are carried in cranial nerves V, VII, IX and X. On entering the
brainstem, sensory fibers are grouped and sent to the spinal trigeminal
nucleus. This bundle of incoming fibers can be identified in
cross-sections of the pons and medulla as the spinal tract of the
trigeminal nucleus, which parallels the spinal trigeminal nucleus. The
spinal tract of V is analogous to, and continuous with, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lissauer%27s_tract" title="Lissauer's tract">Lissauer's tract</a> in the spinal cord.
</p><p>The spinal trigeminal nucleus contains a pain-temperature sensory
map of the face and mouth. From the spinal trigeminal nucleus,
secondary fibers cross the midline and ascend in the trigeminothalamic
(quintothalamic) tract to the contralateral thalamus. Pain-temperature
fibers are sent to multiple thalamic nuclei. The central processing of
pain-temperature information differs from the processing of
touch-position information.
</p>
<h4><span class="mw-headline" id="Somatotopic_representation">Somatotopic representation</span></h4><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Onionskinddistribution.svg"><img alt="The head in profile, with trigeminal-nerve distribution illustrated" class="mw-file-element" data-file-height="1052" data-file-width="744" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/64/Onionskinddistribution.svg/220px-Onionskinddistribution.svg.png" width="283" /></a><figcaption>Onion-skin distribution of the trigeminal nerve</figcaption></figure>
<p>Exactly how pain-temperature fibers from the face are distributed to
the spinal trigeminal nucleus is disputed. The present general
understanding is that pain-temperature information from all areas of the
human body is represented in the spinal cord and brainstem in an
ascending, <a href="https://en.wikipedia.org/wiki/Anatomical_terms_of_location#Anterior_and_posterior" title="Anatomical terms of location">caudal-to-rostral</a>
fashion. Information from the lower extremities is represented in the
lumbar cord, and that from the upper extremities in the thoracic cord.
Information from the neck and the back of the head is represented in the
cervical cord, and that from the face and mouth in the spinal
trigeminal nucleus.
</p><p>Within the spinal trigeminal nucleus, information is represented
in a layered, or "onion-skin" fashion. The lowest levels of the nucleus
(in the upper cervical cord and lower medulla) represent peripheral
areas of the face (the scalp, ears and chin). Higher levels (in the
upper medulla) represent central areas (nose, cheeks and lips). The
highest levels (in the pons) represent the mouth, teeth and pharyngeal
cavity.
</p><p>The onion skin distribution differs from the dermatome
distribution of the peripheral branches of the fifth nerve. Lesions
which destroy lower areas of the spinal trigeminal nucleus (but spare
higher areas) preserve pain-temperature sensation in the nose (V<sub>1</sub>), upper lip (V<sub>2</sub>) and mouth (V<sub>3</sub>) and remove pain-temperature sensation from the forehead (V<sub>1</sub>), cheeks (V<sub>2</sub>) and chin (V<sub>3</sub>).
Although analgesia in this distribution is "nonphysiologic" in the
traditional sense (because it crosses several dermatomes), this
analgesia is found in humans after surgical sectioning of the spinal
tract of the trigeminal nucleus.
</p><p>The spinal trigeminal nucleus sends pain-temperature information to the <a href="https://en.wikipedia.org/wiki/Thalamus" title="Thalamus">thalamus</a> and sends information to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mesencephalon" title="Mesencephalon">mesencephalon</a> and the <a href="https://en.wikipedia.org/wiki/Reticular_formation" title="Reticular formation">reticular formation</a>
of the brainstem. The latter pathways are analogous to the
spinomesencephalic and spinoreticular tracts of the spinal cord, which
send pain-temperature information from the rest of the body to the same
areas. The mesencephalon modulates painful input before it reaches the
level of consciousness. The reticular formation is responsible for the
automatic (unconscious) orientation of the body to painful stimuli.
Incidentally, <a href="https://en.wikipedia.org/wiki/Sulfur" title="Sulfur">Sulfur</a>-containing compounds found in plants in the <a href="https://en.wikipedia.org/wiki/Onion" title="Onion">onion</a> family stimulate receptors found in trigeminal ganglia, bypassing the <a href="https://en.wikipedia.org/wiki/Olfactory_system" title="Olfactory system">olfactory system</a>.
</p>
<h3><span class="mw-headline" id="Principal_nucleus"><span class="anchor" id="Main_trigeminal_nucleus"></span>Principal nucleus</span></h3><p>The <a href="https://en.wikipedia.org/wiki/Principal_sensory_nucleus_of_trigeminal_nerve" title="Principal sensory nucleus of trigeminal nerve">principal nucleus</a>
represents touch-pressure sensation from the face. It is located in the
pons, near the entrance for the fifth nerve. Fibers carrying
touch-position information from the face and mouth via cranial nerves V,
VII, IX, and X are sent to this nucleus when they enter the brainstem.
</p><p>The principal nucleus contains a touch-position sensory map of
the face and mouth, just as the spinal trigeminal nucleus contains a
complete pain-temperature map. This nucleus is analogous to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_column" title="Dorsal column">dorsal column</a> nuclei (the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gracile_nucleus" title="Gracile nucleus">gracile</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cuneate_nucleus" title="Cuneate nucleus">cuneate</a> nuclei) of the spinal cord, which contain a touch-position map of the rest of the body.
</p><p>From the principal nucleus, secondary fibers cross the midline and ascend in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Anterior_trigeminothalamic_tract" title="Anterior trigeminothalamic tract">ventral trigeminothalamic tract</a> to the contralateral <a href="https://en.wikipedia.org/wiki/Thalamus" title="Thalamus">thalamus</a>. The ventral trigeminothalamic tract runs parallel to the <a href="https://en.wikipedia.org/wiki/Medial_lemniscus" title="Medial lemniscus">medial lemniscus</a>, which carries touch-position information from the rest of the body to the thalamus.
</p><p>Some sensory information from the teeth and jaws is sent from the principal nucleus to the <a href="https://en.wikipedia.org/wiki/Anatomical_terms_of_location#Other_directional_terms" title="Anatomical terms of location">ipsilateral</a> thalamus via the small <a href="https://en.wikipedia.org/wiki/Dorsal_trigeminal_tract" title="Dorsal trigeminal tract">dorsal trigeminal tract</a>.
Touch-position information from the teeth and jaws of one side of the
face is represented bilaterally in the thalamus and cortex.
</p>
<h3><span class="mw-headline" id="Mesencephalic_nucleus"><span class="anchor" id="Mesencephalic_trigeminal_nucleus"></span>Mesencephalic nucleus</span></h3><p>The <a href="https://en.wikipedia.org/wiki/Mesencephalic_nucleus_of_trigeminal_nerve" title="Mesencephalic nucleus of trigeminal nerve">mesencephalic nucleus</a> is not a true <a href="https://en.wikipedia.org/wiki/Nucleus_(neuroanatomy)" title="Nucleus (neuroanatomy)">nucleus</a>; it is a sensory <a href="https://en.wikipedia.org/wiki/Ganglion" title="Ganglion">ganglion</a> (like the <a href="https://en.wikipedia.org/wiki/Trigeminal_ganglion" title="Trigeminal ganglion">trigeminal ganglion</a>) embedded in the brainstem
and the sole exception to the rule that sensory information passes
through peripheral sensory ganglia before entering the central nervous
system. It has been found in all <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebrates" title="Vertebrates">vertebrates</a> except <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lampreys" title="Lampreys">lampreys</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hagfishes" title="Hagfishes">hagfishes</a>.
They are the only vertebrates without jaws and have specific cells in
their brainstems. These "internal ganglion" cells were discovered in the
late 19th century by medical student <a href="https://en.wikipedia.org/wiki/Sigmund_Freud" title="Sigmund Freud">Sigmund Freud</a>.
</p><p>Two types of sensory fibers have cell bodies in the mesencephalic nucleus: <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">proprioceptor</a>
fibers from the jaw and mechanoreceptor fibers from the teeth. Some of
these incoming fibers go to the motor nucleus of the trigeminal nerve
(V), bypassing the pathways for conscious perception. The <a href="https://en.wikipedia.org/wiki/Jaw_jerk_reflex" title="Jaw jerk reflex">jaw jerk reflex</a>
is an example; tapping the jaw elicits a reflex closure of the jaw in
the same way that tapping the knee elicits a reflex kick of the lower
leg. Other incoming fibers from the teeth and jaws go to the main
nucleus of V. This information is projected bilaterally to the thalamus
and available for conscious perception.
</p><p>Activities such as biting, chewing and swallowing require
symmetrical, simultaneous coordination of both sides of the body. They
are automatic activities, requiring little conscious attention and
involving a sensory component (feedback about touch-position) processed
at the unconscious level in the mesencephalic nucleus.
</p>
<h3><span class="mw-headline" id="Pathways_to_the_thalamus_and_cortex"><span class="anchor" id="Pathways_to_the_thalamus_and_the_cortex"></span>Pathways to the thalamus and cortex</span></h3><p>Sensation
has been defined as the conscious perception of touch-position and
pain-temperature information. With the exception of smell, all sensory
input (touch-position, pain-temperature, sight, taste, hearing and
balance) is sent to the thalamus and then the cortex. The thalamus is
anatomically subdivided into nuclei.
</p>
<h3><span class="mw-headline" id="Touch-position_sensation"><span class="anchor" id="Touch/position_sensation"></span>Touch-position sensation</span></h3><figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Sensory_Homunculus.png"><img alt="Diagram of functions controlled by the cerebral cortex" class="mw-file-element" data-file-height="1579" data-file-width="1355" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/13/Sensory_Homunculus.png/250px-Sensory_Homunculus.png" width="344" /></a><figcaption>Cortical homunculus</figcaption></figure>
<p>Touch-position information from the body is sent to the <a href="https://en.wikipedia.org/wiki/Ventral_posterolateral_nucleus" title="Ventral posterolateral nucleus">ventral posterolateral nucleus</a> (VPL) of the thalamus. Touch-position information from the face is sent to the <a href="https://en.wikipedia.org/wiki/Ventral_posteromedial_nucleus" title="Ventral posteromedial nucleus">ventral posteromedial nucleus</a> (VPM) of the thalamus. From the VPL and VPM, information is projected to the <a href="https://en.wikipedia.org/wiki/Postcentral_gyrus" title="Postcentral gyrus">primary somatosensory cortex</a> (SI) in the <a href="https://en.wikipedia.org/wiki/Parietal_lobe" title="Parietal lobe">parietal lobe</a>.
</p><p>The representation of sensory information in the postcentral gyrus is organized <a href="https://en.wikipedia.org/wiki/Somatotopic_arrangement" title="Somatotopic arrangement">somatotopically</a>.
Adjacent areas of the body are represented by adjacent areas in the
cortex. When body parts are drawn in proportion to the density of their
innervation, the result is a "little man": the <a href="https://en.wikipedia.org/wiki/Cortical_homunculus" title="Cortical homunculus">cortical homunculus</a>.
</p><p>Many textbooks have reproduced the outdated <a href="https://en.wikipedia.org/wiki/Wilder_Penfield" title="Wilder Penfield">Penfield</a>-Rasmussen diagram [ref?], with the toes and genitals on the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dental_terminology#Mesial" title="Dental terminology">mesial</a> surface of the cortex when they are actually represented on the convexity.
The classic diagram implies a single primary sensory map of the body,
when there are multiple primary maps. At least four separate,
anatomically distinct sensory homunculi have been identified in the
postcentral gyrus. They represent combinations of input from surface and
deep receptors and rapidly and slowly adapting peripheral receptors;
smooth objects will activate certain cells, and rough objects will
activate other cells.
</p><p>Information from all four maps in SI is sent to the secondary
sensory cortex (SII) in the parietal lobe. SII contains two more sensory
homunculi. Information from one side of the body is generally
represented on the opposite side in SI, but on both sides in SII.
Functional MRI imaging of a defined stimulus (for example, stroking the
skin with a toothbrush) "lights up" a single focus in SI and two foci in
SII.
</p>
<h3><span class="mw-headline" id="Pain-temperature_sensation"><span class="anchor" id="Pain/temperature_sensation"></span>Pain-temperature sensation</span></h3><p>Pain-temperature
information is sent to the VPL (body) and VPM (face) of the thalamus
(the same nuclei which receive touch-position information). From the
thalamus, pain-temperature and touch-position information is projected
onto SI.
</p><p>Unlike touch-position information, however, pain-temperature
information is also sent to other thalamic nuclei and projected onto
additional areas of the cerebral cortex. Some pain-temperature fibers
are sent to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medial_dorsal_thalamic_nucleus" title="Medial dorsal thalamic nucleus">medial dorsal thalamic nucleus</a> (MD), which projects to the anterior <a href="https://en.wikipedia.org/wiki/Cingulate_cortex" title="Cingulate cortex">cingulate cortex</a>. Other fibers are sent to the ventromedial (VM) nucleus of the thalamus, which projects to the <a href="https://en.wikipedia.org/wiki/Insular_cortex" title="Insular cortex">insular cortex</a>. Finally, some fibers are sent to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intralaminar_nucleus" title="Intralaminar nucleus">intralaminar nucleus</a> (IL) of the thalamus via the <a href="https://en.wikipedia.org/wiki/Reticular_formation" title="Reticular formation">reticular formation</a>. The IL projects diffusely to all parts of the cerebral cortex.
</p><p>The insular and cingulate cortices are parts of the brain which
represent touch-position and pain-temperature in the context of other
simultaneous perceptions (sight, smell, taste, hearing and balance) in
the context of memory and emotional state. Peripheral pain-temperature
information is channeled directly to the brain at a deep level, without
prior processing. Touch-position information is handled differently.
Diffuse thalamic projections from the IL and other thalamic nuclei are
responsible for a given level of consciousness, with the thalamus and
reticular formation "activating" the brain; peripheral pain-temperature
information also feeds directly into this system.
</p>
<h2><span class="mw-headline" id="Clinical_significance">Clinical significance</span></h2><ul><li><a href="https://en.wikipedia.org/wiki/Trigeminal_neuralgia" title="Trigeminal neuralgia">Trigeminal neuralgia</a></li><li><a href="https://en.wikipedia.org/wiki/Cluster_headache" title="Cluster headache">Cluster headache</a></li><li><a href="https://en.wikipedia.org/wiki/Migraine" title="Migraine">Migraine</a></li></ul>
<h3><span class="mw-headline" id="Lateral_medullary_syndrome">Lateral medullary syndrome</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Lateral_medullary_syndrome" title="Lateral medullary syndrome">Lateral medullary syndrome</a></div>
<p><a href="https://en.wikipedia.org/wiki/Lateral_medullary_syndrome" title="Lateral medullary syndrome">Lateral medullary syndrome</a>
(Wallenberg syndrome) is a clinical demonstration of the anatomy of the
trigeminal nerve, summarizing how it processes sensory information. A
stroke usually affects only one side of the body; loss of sensation due
to a stroke will be lateralized to the right or the left side of the
body. The only exceptions to this rule are certain spinal-cord lesions
and the medullary syndromes, of which Wallenberg syndrome is the
best-known example. In this syndrome, a stroke causes a loss of
pain-temperature sensation from one side of the face and the other side
of the body.
</p><p>This is explained by the anatomy of the brainstem. In the medulla, the ascending <a href="https://en.wikipedia.org/wiki/Spinothalamic_tract" title="Spinothalamic tract">spinothalamic tract</a>
(which carries pain-temperature information from the opposite side of
the body) is adjacent to the ascending spinal tract of the trigeminal
nerve (which carries pain-temperature information from the same side of
the face). A stroke which cuts off the blood supply to this area (for
example, a clot in the posterior inferior cerebellar artery) destroys
both tracts simultaneously. The result is a loss of pain-temperature
(but not touch-position) sensation in a "checkerboard" pattern
(ipsilateral face, contralateral body), facilitating diagnosis.
</p>
<h3><span class="mw-headline" id="Sensory_neuronopathy">Sensory neuronopathy</span></h3><a href="https://en.wikipedia.org/wiki/Sensory_neuronopathy" title="Sensory neuronopathy">Sensory neuronopathy</a> (also known as sensory ganglionopathy) is a type of peripheral neuropathy in which sensory nerve cell bodies in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_root_ganglia" title="Dorsal root ganglia">dorsal root ganglia</a>, commonly including the <a href="https://en.wikipedia.org/wiki/Trigeminal_ganglion" title="Trigeminal ganglion">trigeminal ganglion</a> of the trigeminal nerve, are damaged due to a variety of mechanisms leading to sensory symptoms such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Parasthesias" title="Parasthesias">parasthesias</a>, <a href="https://en.wikipedia.org/wiki/Dysesthesia" title="Dysesthesia">dysesthesias</a>, or <a href="https://en.wikipedia.org/wiki/Hyperalgesia" title="Hyperalgesia">hyperalgesia</a> in the affected nerve distribution including the distribution of the trigeminal nerve.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-84090291087576943332024-03-27T17:12:00.004-04:002024-03-27T17:12:22.392-04:00Reflex syncope<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Reflex_syncope">https://en.wikipedia.org/wiki/Reflex_syncope</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Reflex syncope</th></tr><tr><th class="infobox-label" scope="row">Other names</th><td class="infobox-data">Neurally mediated syncope, neurocardiogenic syncope</td></tr><tr><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gray793.png"><img class="mw-file-element" data-file-height="1000" data-file-width="432" height="640" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4b/Gray793.png/220px-Gray793.png" width="277" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2"><a href="https://en.wikipedia.org/wiki/Vagus_nerve" title="Vagus nerve">Vagus nerve</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Neurology" title="Neurology">Neurology</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular" title="Cardiovascular">cardiovascular</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Signs_and_symptoms" title="Signs and symptoms">Symptoms</a></th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Loss_of_consciousness" title="Loss of consciousness">Loss of consciousness</a> before which there may be sweating, decreased ability to see, <a href="https://en.wikipedia.org/wiki/Tinnitus" title="Tinnitus">ringing in the ears</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Complication_(medicine)" title="Complication (medicine)">Complications</a></th><td class="infobox-data">Injury</td></tr><tr><th class="infobox-label" scope="row">Duration</th><td class="infobox-data">Brief</td></tr><tr><th class="infobox-label" scope="row">Types</th><td class="infobox-data">Vasovagal, situational, carotid sinus syncope</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_diagnosis" title="Medical diagnosis">Diagnostic method</a></th><td class="infobox-data">Based on symptoms after ruling out other possible causes</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">Differential diagnosis</a></th><td class="infobox-data"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heart_arrhythmia" title="Heart arrhythmia">Arrhythmia</a>, <a href="https://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">orthostatic hypotension</a>, <a href="https://en.wikipedia.org/wiki/Seizure" title="Seizure">seizure</a>, <a href="https://en.wikipedia.org/wiki/Hypoglycemia" title="Hypoglycemia">hypoglycemia</a></td></tr><tr><th class="infobox-label" scope="row">Treatment</th><td class="infobox-data">Avoiding triggers, drinking sufficient fluids, exercise, <a href="https://en.wikipedia.org/wiki/Cardiac_pacemaker" title="Cardiac pacemaker">cardiac pacemaker</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medication" title="Medication">Medication</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">Midodrine</a>, <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a></td></tr><tr><th class="infobox-label" scope="row">Frequency</th><td class="infobox-data">> 1 per 1,000 people per year</td></tr></tbody></table>
<p><b>Reflex syncope</b> is a brief <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Loss_of_consciousness" title="Loss of consciousness">loss of consciousness</a> due to a <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">neurologically</a> induced drop in <a href="https://en.wikipedia.org/wiki/Blood_pressure" title="Blood pressure">blood pressure</a> and/or a decrease in heart rate. Before an affected person passes out, there may be sweating, a decreased ability to see, or <a href="https://en.wikipedia.org/wiki/Tinnitus" title="Tinnitus">ringing in the ears</a>. Occasionally, the person may twitch while unconscious. Complications of reflex syncope include injury due to a fall.
</p><p>Reflex syncope is divided into three types: vasovagal, situational, and carotid sinus. Vasovagal syncope is typically triggered by seeing <a href="https://en.wikipedia.org/wiki/Blood" title="Blood">blood</a>, pain, emotional stress, or prolonged standing. Situational syncope is often triggered by <a href="https://en.wikipedia.org/wiki/Urination" title="Urination">urination</a>, swallowing, or coughing. Carotid sinus syncope is due to pressure on the <a href="https://en.wikipedia.org/wiki/Carotid_sinus" title="Carotid sinus">carotid sinus</a> in the neck. The underlying mechanism involves the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a> slowing the heart rate and dilating blood vessels, resulting in low blood pressure and thus not enough blood flow to the brain. Diagnosis is based on the symptoms after ruling out other possible causes.
</p><p>Recovery from a reflex syncope episode happens without specific treatment. Prevention of episodes involves avoiding a person's triggers. Drinking sufficient fluids, salt, and exercise may also be useful. If this is insufficient for treating vasovagal syncope, medications such as <a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">midodrine</a> or <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a> may be tried. Occasionally, a <a href="https://en.wikipedia.org/wiki/Cardiac_pacemaker" title="Cardiac pacemaker">cardiac pacemaker</a> may be used as treatment. Reflex syncope affects at least 1 in 1,000 people per year. It is the most common type of <a href="https://en.wikipedia.org/wiki/Syncope_(medicine)" title="Syncope (medicine)">syncope</a>, making up more than 50% of all cases.
</p>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2></div></div></div><p>Episodes
of vasovagal syncope are typically recurrent and usually occur when the
predisposed person is exposed to a specific trigger. Before losing
consciousness, the individual frequently experiences early signs or
symptoms such as <a href="https://en.wikipedia.org/wiki/Lightheadedness" title="Lightheadedness">lightheadedness</a>, nausea, the feeling of being extremely hot or cold (accompanied by sweating), <a href="https://en.wikipedia.org/wiki/Tinnitus" title="Tinnitus">ringing in the ears</a>,
an uncomfortable feeling in the heart, fuzzy thoughts, confusion, a
slight inability to speak or form words (sometimes combined with mild
stuttering), weakness and visual disturbances such as lights seeming too
bright, fuzzy or tunnel vision, black cloud-like spots in vision, and a
feeling of nervousness can occur as well. The symptoms may become more
intense over several seconds to several minutes before the loss of
consciousness (if it is lost). Onset usually occurs when a person is
sitting up or standing.
</p><p>When people lose consciousness, they fall down (unless prevented
from doing so) and, when in this position, effective blood flow to the
brain is immediately restored, allowing the person to regain
consciousness. If the person does not fall into a fully flat, supine
position, and the head remains elevated above the trunk, a state similar
to a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epileptic_seizure" title="Epileptic seizure">seizure</a>
may result from the blood's inability to return quickly to the brain,
and the neurons in the body will fire off and generally cause muscles to
twitch very slightly but mostly remain very tense.
</p><p>The <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nervous system</a>'s physiological state (see below) leading to loss of consciousness may persist for several minutes, so
</p>
<ul><li>If patients try to sit or stand when they wake up, they may pass out again</li><li>The person may be nauseated, pale, and sweaty for several minutes or hours</li></ul>
<h2><span class="mw-headline" id="Causes">Causes</span></h2><p>Reflex
syncope occurs in response to a trigger due to dysfunction of the heart
rate and blood pressure regulating mechanism. When heart rate slows or
blood pressure drops, the resulting lack of blood to the brain causes
fainting.
</p>
<h3><span class="mw-headline" id="Vasovagal">Vasovagal</span></h3><p>Typical triggers include:
</p>
<ul><li>Prolonged standing</li><li>Emotional stress</li><li>Pain</li><li><a href="https://en.wikipedia.org/wiki/Blood_phobia" title="Blood phobia">The sight of blood</a></li><li><a href="https://en.wikipedia.org/wiki/Fear_of_needles" title="Fear of needles">Fear of needles</a> Time varying magnetic field (i.e. <a href="https://en.wikipedia.org/wiki/Transcranial_magnetic_stimulation" title="Transcranial magnetic stimulation">transcranial magnetic stimulation</a>)</li></ul>
<h3><span class="mw-headline" id="Situational">Situational</span></h3><ul><li>After or during urination (<a href="https://en.wikipedia.org/wiki/Micturition_syncope" title="Micturition syncope">micturition syncope</a>)</li><li>Straining, such as to have a bowel movement</li><li>Coughing</li><li>Swallowing</li><li>Lifting a heavy weight</li></ul>
<h3><span class="mw-headline" id="Carotid_sinus">Carotid sinus</span></h3><p>Pressing upon a certain spot in the neck. This may happen when wearing a tight collar, shaving, or turning the head.
</p>
<h2><span class="mw-headline" id="Pathophysiology">Pathophysiology</span></h2><p>Regardless of the trigger, the mechanism of syncope is similar in the various vasovagal syncope syndromes. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nucleus_tractus_solitarii" title="Nucleus tractus solitarii">nucleus tractus solitarii</a> of the <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a> is activated directly or indirectly by the triggering stimulus, resulting in simultaneous enhancement of <a href="https://en.wikipedia.org/wiki/Parasympathetic_nervous_system" title="Parasympathetic nervous system">parasympathetic nervous system</a> (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vagal" title="Vagal">vagal</a>) tone and withdrawal of <a href="https://en.wikipedia.org/wiki/Sympathetic_nervous_system" title="Sympathetic nervous system">sympathetic nervous system</a> tone.
</p><p>This results in a spectrum of hemodynamic responses:
</p>
<ol><li>On one end of the spectrum is the cardioinhibitory response, characterized by a drop in heart rate (negative <a href="https://en.wikipedia.org/wiki/Chronotropic" title="Chronotropic">chronotropic</a> effect) and in contractility (negative <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Inotropic" title="Inotropic">inotropic</a>
effect) leading to a decrease in cardiac output that is significant
enough to result in a loss of consciousness. It is thought that this
response results primarily from enhancement in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Parasympathetic_tone" title="Parasympathetic tone">parasympathetic tone</a>.</li><li>On the other end of the spectrum is the vasodepressor response,
caused by a drop in blood pressure (to as low as 80/20) without much
change in heart rate. This phenomenon occurs due to <a href="https://en.wikipedia.org/wiki/Vasodilation" title="Vasodilation">dilation of the blood vessels</a>, probably as a result of withdrawal of <a href="https://en.wikipedia.org/wiki/Sympathetic_nervous_system" title="Sympathetic nervous system">sympathetic nervous system</a> tone.</li><li>The majority of people with vasovagal syncope have a mixed response somewhere between these two ends of the spectrum.</li></ol>
<p>One account for these physiological responses is the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bezold-Jarisch_reflex" title="Bezold-Jarisch reflex">Bezold-Jarisch reflex</a>.
</p><p>Vasovagal syncope may be part of an evolved response, specifically, the <a href="https://en.wikipedia.org/wiki/Fight-or-flight_response" title="Fight-or-flight response">fight-or-flight response</a>.
</p>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><p>In addition to the mechanism described above, a number of other medical conditions may cause <a href="https://en.wikipedia.org/wiki/Syncope_(medicine)" title="Syncope (medicine)">syncope</a>.
Making the correct diagnosis for loss of consciousness is difficult.
The core of the diagnosis of vasovagal syncope rests upon a clear
description of a typical pattern of triggers, symptoms, and time course.
</p><p>It is pertinent to differentiate <a href="https://en.wikipedia.org/wiki/Lightheadedness" title="Lightheadedness">lightheadedness</a>, seizures, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertigo_(medical)" title="Vertigo (medical)">vertigo</a>, and <a href="https://en.wikipedia.org/wiki/Hypoglycemia" title="Hypoglycemia">low blood sugar</a> as other causes.
</p><p>In people with recurrent vasovagal syncope, diagnostic accuracy
can often be improved with one of the following diagnostic tests:
</p>
<ul><li>A <a href="https://en.wikipedia.org/wiki/Tilt_table_test" title="Tilt table test">tilt table test</a>
(results should be interpreted in the context of patients' clinical
presentations and with an understanding of the sensitivity and
specificity of the test)</li><li>Implantation of an <a href="https://en.wikipedia.org/wiki/Implantable_loop_recorder" title="Implantable loop recorder">insertable loop recorder</a></li><li>A <a href="https://en.wikipedia.org/wiki/Holter_monitor" title="Holter monitor">Holter monitor</a> or event monitor</li><li>An <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Echocardiogram" title="Echocardiogram">echocardiogram</a></li><li>An <a href="https://en.wikipedia.org/wiki/Electrophysiology_study" title="Electrophysiology study">electrophysiology study</a></li></ul>
<h2><span class="mw-headline" id="Treatment">Treatment</span></h2><p>Treatment
for reflex syncope focuses on avoidance of triggers, restoring blood
flow to the brain during an impending episode, and measures that
interrupt or prevent the <a href="https://en.wikipedia.org/wiki/Reflex_syncope#Pathophysiology_and_mechanism">pathophysiologic mechanism</a> described above.
</p>
<h3><span class="mw-headline" id="Lifestyle_changes">Lifestyle changes</span></h3><ul><li>The
cornerstone of treatment is avoidance of triggers known to cause
syncope in that person. However, research has shown that people show
great reductions in vasovagal syncope through exposure-based exercises
with therapists if the trigger is mental or emotional, e.g., sight of
blood. However, if the trigger is a specific drug, then avoidance is the only treatment.</li><li>A technique known as "applied tension" may be additionally useful in those who have syncope with exposure to blood.
The technique is done by tightening the skeletal muscles for about 15
seconds when the exposure occurs and then slowing releasing them. This is then repeated every 30 seconds for a few minutes.</li><li>Because vasovagal syncope causes a decrease in blood pressure, relaxing the entire body as a mode of avoidance is not favorable.
A person can move or cross their legs and tighten leg muscles to keep
blood pressure from dropping so significantly before an injection.</li><li>Before known triggering events, the affected person may increase
consumption of salt and fluids to increase blood volume. Sports drinks
or drinks with electrolytes may be helpful.</li><li>People should be educated on how to respond to further episodes of syncope, especially if they experience <a href="https://en.wikipedia.org/wiki/Prodrome" title="Prodrome">prodromal</a>
warning signs: they should lie down and raise their legs, or at least
lower their head to increase blood flow to the brain. At the very least,
upon the onset of initial symptoms the patient should try to relocate
to a 'safe', perhaps cushioned, location in case of losing
consciousness. Positioning themselves in a way where the impact from
falling or collapsing would be minimized is ideal. The 'safe' area
should be within close proximity, since, time is of the essence and
these symptoms usually climax to loss of consciousness within a matter
of minutes. If the individual has lost consciousness, he or she should
be laid down in the <a href="https://en.wikipedia.org/wiki/Recovery_position" title="Recovery position">recovery position</a>.
Tight clothing should be loosened. If the inciting factor is known, it
should be removed if possible (for instance, the cause of pain).</li><li>Wearing graded compression stockings may be helpful.</li></ul>
<h3><span class="mw-headline" id="Medications">Medications</span></h3><ul><li>Certain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Medications" title="Medications">medications</a> may also be helpful:
<ul><li><a href="https://en.wikipedia.org/wiki/Beta_blocker" title="Beta blocker">Beta blockers</a>
(β-adrenergic antagonists) were once the most common medication given;
however, they have been shown to be ineffective in a variety of studies
and are thus no longer prescribed. In addition, they may cause the
syncope by lowering the blood pressure and heart rate.</li><li>Medications which may be effective include: CNS stimulants <a href="https://en.wikipedia.org/wiki/Fludrocortisone" title="Fludrocortisone">fludrocortisone</a>, <a href="https://en.wikipedia.org/wiki/Midodrine" title="Midodrine">midodrine</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/SSRI" title="SSRI">SSRIs</a> such as <a href="https://en.wikipedia.org/wiki/Paroxetine" title="Paroxetine">paroxetine</a> or <a href="https://en.wikipedia.org/wiki/Sertraline" title="Sertraline">sertraline</a>, <a href="https://en.wikipedia.org/wiki/Disopyramide" title="Disopyramide">disopyramide</a>, and, in health-care settings where a syncope is anticipated, <a href="https://en.wikipedia.org/wiki/Atropine" title="Atropine">atropine</a> or epinephrine (adrenaline).</li></ul></li><li>For people with the cardioinhibitory form of vasovagal syncope, implantation of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Artificial_pacemaker" title="Artificial pacemaker">permanent pacemaker</a> may be beneficial or even curative.</li></ul>
<p>Types of long-term therapy for vasovagal syncope include
</p>
<ul><li>Preload agents</li><li>Vasoconstrictors</li><li>Anticholinergic agents</li><li>Negative cardiac inotropes</li><li>Central agents</li><li>Mechanical device</li><li>Discontinuation of medications known to lower blood pressure may be helpful, but stopping <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antihypertensive_drugs" title="Antihypertensive drugs">antihypertensive drugs</a>
can also be dangerous in some people. Taking antihypertensive drugs may
worsen the syncope, as the hypertension may have been the body's way to
compensate for the low blood pressure.</li></ul>
<h2><span class="mw-headline" id="Prognosis">Prognosis</span></h2><p>Brief
periods of unconsciousness usually cause no lasting harm to health.
Reflex syncope can occur in otherwise healthy individuals, and has many
possible causes, often trivial ones such as prolonged standing with the
legs locked.
</p><p>The main danger of vasovagal syncope (or dizzy spells from
vertigo) is the risk of injury by falling while unconscious. Medication
therapy could possibly prevent future vasovagal responses; however, for
some individuals medication is ineffective and they will continue to
have fainting episodes.</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-91011127170111445192024-03-27T13:04:00.005-04:002024-03-27T13:04:48.324-04:00Peripheral neuropathy<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Peripheral_neuropathy">https://en.wikipedia.org/wiki/Peripheral_neuropathy</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Peripheral neuropathy</th></tr><tr align="center"><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Vasculitic_neuropathy_-_plastics_-_intermed_mag.jpg"><img class="mw-file-element" data-file-height="2848" data-file-width="4272" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/76/Vasculitic_neuropathy_-_plastics_-_intermed_mag.jpg/220px-Vasculitic_neuropathy_-_plastics_-_intermed_mag.jpg" width="400" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2"><a href="https://en.wikipedia.org/wiki/Micrograph" title="Micrograph">Micrograph</a> showing a <a href="https://en.wikipedia.org/wiki/Vasculitis" title="Vasculitis">vasculitic</a> peripheral neuropathy; <a href="https://en.wikipedia.org/wiki/Histology#Alternative_techniques" title="Histology">plastic embedded</a>; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Toluidine_blue_stain" title="Toluidine blue stain">Toluidine blue stain</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Neurology" title="Neurology">Neurology</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Signs_and_symptoms" title="Signs and symptoms">Symptoms</a></th><td class="infobox-data">Shooting <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>, <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">numbness</a>, tingling, tremors, bladder problems, <a href="https://en.wikipedia.org/wiki/Balance_disorder" title="Balance disorder">unsteadiness</a></td></tr></tbody></table>
<p><b>Peripheral neuropathy</b>, often shortened to <b>neuropathy</b>, refers to damage or disease affecting the <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerves</a>.
Damage to nerves may impair sensation, movement, gland function, and/or
organ function depending on which nerves are affected. Neuropathies
affecting <a href="https://en.wikipedia.org/wiki/Motor_nerve" title="Motor nerve">motor</a>, <a href="https://en.wikipedia.org/wiki/Sensory_nervous_system" title="Sensory nervous system">sensory</a>, or <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nerves</a>
result in different symptoms. More than one type of nerve may be
affected simultaneously. Peripheral neuropathy may be acute (with sudden
onset, rapid progress) or chronic (symptoms begin subtly and progress
slowly), and may be reversible or permanent.
</p><p>Common causes include systemic diseases (such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes</a> or <a href="https://en.wikipedia.org/wiki/Leprosy" title="Leprosy">leprosy</a>), hyperglycemia-induced <a href="https://en.wikipedia.org/wiki/Glycation" title="Glycation">glycation</a>, <a href="https://en.wikipedia.org/wiki/Vitamin_deficiency" title="Vitamin deficiency">vitamin deficiency</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pharmaceutical_drug" title="Pharmaceutical drug">medication</a> (e.g., <a href="https://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapy</a>, or commonly prescribed <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibiotics" title="Antibiotics">antibiotics</a> including <a href="https://en.wikipedia.org/wiki/Metronidazole" title="Metronidazole">metronidazole</a> and the <a href="https://en.wikipedia.org/wiki/Quinolone_antibiotic" title="Quinolone antibiotic">fluoroquinolone</a> class of antibiotics (such as <a href="https://en.wikipedia.org/wiki/Ciprofloxacin" title="Ciprofloxacin">ciprofloxacin</a>, <a href="https://en.wikipedia.org/wiki/Levofloxacin" title="Levofloxacin">levofloxacin</a>, <a href="https://en.wikipedia.org/wiki/Moxifloxacin" title="Moxifloxacin">moxifloxacin</a>)), traumatic <a href="https://en.wikipedia.org/wiki/Injury" title="Injury">injury</a>, <a href="https://en.wikipedia.org/wiki/Ischemia" title="Ischemia">ischemia</a>, <a href="https://en.wikipedia.org/wiki/Radiation_therapy" title="Radiation therapy">radiation therapy</a>, excessive alcohol consumption, <a href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">immune system disease</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Celiac_disease" title="Celiac disease">celiac disease</a>, <a href="https://en.wikipedia.org/wiki/Non-celiac_gluten_sensitivity" title="Non-celiac gluten sensitivity">non-celiac gluten sensitivity</a>, or viral infection. It can also be <a href="https://en.wikipedia.org/wiki/Genetic_disorder" title="Genetic disorder">genetic</a> (present from birth) or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Idiopathy" title="Idiopathy">idiopathic</a> (no known cause). In conventional medical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Usage" title="Usage">usage</a>, the word <i>neuropathy</i> (<a class="extiw" href="https://en.wiktionary.org/wiki/neuro-#English" title="wikt:neuro-">neuro-</a>, "nervous system" and <a class="extiw" href="https://en.wiktionary.org/wiki/-pathy#English" title="wikt:-pathy">-pathy</a>, "disease of") without modifier usually means <i>peripheral neuropathy</i>.
</p><p>Neuropathy affecting just one nerve is called "mononeuropathy"
and neuropathy involving nerves in roughly the same areas on both sides
of the body is called "symmetrical polyneuropathy" or simply "<a href="https://en.wikipedia.org/wiki/Polyneuropathy" title="Polyneuropathy">polyneuropathy</a>".
When two or more (typically just a few, but sometimes many) separate
nerves in disparate areas of the body are affected it is called "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mononeuritis_multiplex" title="Mononeuritis multiplex">mononeuritis multiplex</a>", "multifocal mononeuropathy", or "multiple mononeuropathy".
</p><p>Neuropathy may cause painful <a href="https://en.wikipedia.org/wiki/Cramp" title="Cramp">cramps</a>, <a href="https://en.wikipedia.org/wiki/Fasciculation" title="Fasciculation">fasciculations</a> (fine muscle twitching), muscle loss, bone degeneration, and changes in the skin, hair, and nails. Additionally, <b>motor neuropathy</b> may cause impaired balance and coordination or, most commonly, muscle weakness; <b>sensory neuropathy</b> may cause numbness to touch and vibration, reduced <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">position sense</a>
causing poorer coordination and balance, reduced sensitivity to
temperature change and pain, spontaneous tingling or burning pain, or <a href="https://en.wikipedia.org/wiki/Allodynia" title="Allodynia">allodynia</a> (pain from normally nonpainful stimuli, such as light touch); and <b><a href="https://en.wikipedia.org/wiki/Autonomic_neuropathy" title="Autonomic neuropathy">autonomic neuropathy</a></b>
may produce diverse symptoms, depending on the affected glands and
organs, but common symptoms are poor bladder control, abnormal blood
pressure or heart rate, and reduced ability to sweat normally.
</p>
<div class="toclimit-3"></div>
<h2><span class="mw-headline" id="Classification">Classification</span></h2></div></div></div><p>Peripheral
neuropathy may be classified according to the number and distribution
of nerves affected (mononeuropathy, mononeuritis multiplex, or
polyneuropathy), the type of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nerve_fiber" title="Nerve fiber">nerve fiber</a> predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (<a href="https://en.wikipedia.org/wiki/Neuritis" title="Neuritis">neuritis</a>), compression (<a href="https://en.wikipedia.org/wiki/Nerve_compression_syndrome" title="Nerve compression syndrome">compression neuropathy</a>), chemotherapy (<a href="https://en.wikipedia.org/wiki/Chemotherapy-induced_peripheral_neuropathy" title="Chemotherapy-induced peripheral neuropathy">chemotherapy-induced peripheral neuropathy</a>).
The affected nerves are found in an EMG (electromyography) / NCS (nerve
conduction study) test and the classification is applied upon
completion of the exam.
</p>
<h3><span class="mw-headline" id="Mononeuropathy">Mononeuropathy</span></h3><div class="hatnote navigation-not-searchable" role="note">See also: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Compression_neuropathy" title="Compression neuropathy">Compression neuropathy</a> and <a href="https://en.wikipedia.org/wiki/Ulnar_neuropathy" title="Ulnar neuropathy">Ulnar neuropathy</a></div>
<p><b>Mononeuropathy</b> is a type of neuropathy that only affects a single <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerve</a>.
Diagnostically, it is important to distinguish it from polyneuropathy
because when a single nerve is affected, it is more likely to be due to
localized trauma or infection.
</p><p>The most common cause of mononeuropathy is physical compression of the nerve, known as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Compression_neuropathy" title="Compression neuropathy">compression neuropathy</a>. <a href="https://en.wikipedia.org/wiki/Carpal_tunnel_syndrome" title="Carpal tunnel syndrome">Carpal tunnel syndrome</a> and <a href="https://en.wikipedia.org/wiki/Axillary_nerve_palsy" title="Axillary nerve palsy">axillary nerve palsy</a> are examples. Direct injury to a nerve, interruption of its blood supply resulting in (<a href="https://en.wikipedia.org/wiki/Ischemia" title="Ischemia">ischemia</a>), or <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a> also may cause mononeuropathy.
</p>
<h3><span class="mw-headline" id="Polyneuropathy">Polyneuropathy</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Polyneuropathy" title="Polyneuropathy">Polyneuropathy</a></div>
<p>"<i>Polyneuropathy</i>" is a pattern of nerve damage that is quite
different from mononeuropathy, often more serious and affecting more
areas of the body. The term "peripheral neuropathy" sometimes is used
loosely to refer to polyneuropathy. In cases of polyneuropathy, many
nerve cells in various parts of the body are affected, without regard to
the <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerve</a> through which they pass; not all nerve cells are affected in any particular case. In <a href="https://en.wikipedia.org/wiki/Polyneuropathy" title="Polyneuropathy">distal axonopathy</a>, one common pattern is that the cell bodies of neurons remain intact, but the <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a> are affected in proportion to their length; the longest axons are the most affected. <a href="https://en.wikipedia.org/wiki/Diabetic_neuropathy" title="Diabetic neuropathy">Diabetic neuropathy</a> is the most common cause of this pattern. In demyelinating polyneuropathies, the <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a>
sheath around axons is damaged, which affects the ability of the axons
to conduct electrical impulses. The third and least common pattern
affects the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cell_bodies" title="Cell bodies">cell bodies</a> of neurons directly. This affects the <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neurons</a> (known as <i><a href="https://en.wikipedia.org/wiki/Sensory_neuronopathy" title="Sensory neuronopathy">sensory neuronopathy</a></i> or <i>dorsal root ganglionopathy</i>).
</p><p>The effect of this is to cause symptoms in more than one part of
the body, often symmetrically on left and right sides. As for any
neuropathy, the chief symptoms include motor symptoms such as weakness
or clumsiness of movement; and sensory symptoms such as unusual or
unpleasant sensations such as <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">tingling or burning</a>; <a href="https://en.wikipedia.org/wiki/Hypoesthesia" title="Hypoesthesia">reduced ability to feel sensations</a>
such as texture or temperature, and impaired balance when standing or
walking. In many polyneuropathies, these symptoms occur first and most
severely in the feet. Autonomic symptoms also may occur, such as
dizziness on standing up, <a href="https://en.wikipedia.org/wiki/Erectile_dysfunction" title="Erectile dysfunction">erectile dysfunction</a>, and difficulty controlling urination.
</p><p>Polyneuropathies usually are caused by processes that affect the body as a whole. <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">Diabetes</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Impaired_glucose_tolerance" title="Impaired glucose tolerance">impaired glucose tolerance</a> are the most common causes. Hyperglycemia-induced formation of advanced <a href="https://en.wikipedia.org/wiki/Glycation" title="Glycation">glycation</a> end products (AGEs) is related to diabetic neuropathy.
Other causes relate to the particular type of polyneuropathy, and there
are many different causes of each type, including inflammatory diseases
such as <a href="https://en.wikipedia.org/wiki/Lyme_disease" title="Lyme disease">Lyme disease</a>, vitamin deficiencies, blood disorders, and toxins (including alcohol and certain prescribed drugs).
</p><p>Most types of polyneuropathy progress fairly slowly, over months
or years, but rapidly progressive polyneuropathy also occurs. It is
important to recognize that at one time it was thought that many of the
cases of <a href="https://en.wikipedia.org/wiki/Small_fiber_peripheral_neuropathy" title="Small fiber peripheral neuropathy">small fiber peripheral neuropathy</a> with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glucose_intolerance" title="Glucose intolerance">glucose intolerance</a>
before a diagnosis of diabetes or pre-diabetes. However, in August
2015, the Mayo Clinic published a scientific study in the Journal of the
Neurological Sciences showing "no significant increase
in...symptoms...in the prediabetes group", and stated that "A search for
alternate neuropathy causes is needed in patients with prediabetes."
</p><p>The treatment of polyneuropathies is aimed firstly at eliminating
or controlling the cause, secondly at maintaining muscle strength and
physical function, and thirdly at controlling symptoms such as <a href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">neuropathic pain</a>.
</p>
<h3><span class="mw-headline" id="Mononeuritis_multiplex">Mononeuritis multiplex</span></h3><p><b>Mononeuritis multiplex</b>, occasionally termed <b>polyneuritis multiplex</b>, is simultaneous or sequential involvement of individual noncontiguous <a href="https://en.wikipedia.org/wiki/Spinal_nerve" title="Spinal nerve">nerve trunks</a>,
either partially or completely, evolving over days to years and
typically presenting with acute or subacute loss of sensory and motor
function of individual <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nerves" title="Nerves">nerves</a>.
The pattern of involvement is asymmetric. However, as the disease
progresses, deficit(s) becomes more confluent and symmetrical, making it
difficult to differentiate from polyneuropathy. Therefore, attention to the pattern of early symptoms is important.
</p><p>Mononeuritis multiplex is sometimes associated with a deep,
aching pain that is worse at night and frequently in the lower back,
hip, or leg. In people with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a>,
mononeuritis multiplex typically is encountered as acute, unilateral,
and severe thigh pain followed by anterior muscle weakness and loss of
knee reflex.
</p><p><a href="https://en.wikipedia.org/wiki/Electrodiagnostic_medicine" title="Electrodiagnostic medicine">Electrodiagnostic medicine</a> studies will show multifocal sensory motor <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axonal</a> neuropathy.
</p><p>It is caused by, or associated with, several medical conditions:
</p>
<div class="div-col" style="column-width: 30em;">
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">Diabetes mellitus</a></li><li><a href="https://en.wikipedia.org/wiki/Vasculitis" title="Vasculitis">Vasculitides</a>: <a href="https://en.wikipedia.org/wiki/Polyarteritis_nodosa" title="Polyarteritis nodosa">polyarteritis nodosa</a>, <a href="https://en.wikipedia.org/wiki/Granulomatosis_with_polyangiitis" title="Granulomatosis with polyangiitis">granulomatosis with polyangiitis</a> and <a href="https://en.wikipedia.org/wiki/Eosinophilic_granulomatosis_with_polyangiitis" title="Eosinophilic granulomatosis with polyangiitis">eosinophilic granulomatosis with polyangiitis</a>. This results in <a href="https://en.wikipedia.org/wiki/Vasculitic_neuropathy" title="Vasculitic neuropathy">vasculitic neuropathy</a>.</li><li>Immune-mediated diseases, such as <a href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis">rheumatoid arthritis</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Systemic_lupus_erythematosus" title="Systemic lupus erythematosus">systemic lupus erythematosus</a> (SLE)</li><li>Infections: <a href="https://en.wikipedia.org/wiki/Leprosy" title="Leprosy">leprosy</a>, <a href="https://en.wikipedia.org/wiki/Lyme_disease" title="Lyme disease">lyme disease</a>, <a href="https://en.wikipedia.org/wiki/Parvovirus_B19" title="Parvovirus B19">parvovirus B19</a>, <a href="https://en.wikipedia.org/wiki/HIV" title="HIV">HIV</a></li><li><a href="https://en.wikipedia.org/wiki/Sarcoidosis" title="Sarcoidosis">Sarcoidosis</a></li><li><a href="https://en.wikipedia.org/wiki/Cryoglobulinemia" title="Cryoglobulinemia">Cryoglobulinemia</a></li><li>Reactions to exposure to chemical agents, including <a href="https://en.wikipedia.org/wiki/Trichloroethylene" title="Trichloroethylene">trichloroethylene</a> and <a href="https://en.wikipedia.org/wiki/Dapsone" title="Dapsone">dapsone</a></li><li>Rarely, following the sting of certain <a href="https://en.wikipedia.org/wiki/Jellyfish" title="Jellyfish">jellyfish</a>, such as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sea_nettle" title="Sea nettle">sea nettle</a></li></ul></div>
<h3><span class="mw-headline" id="Autonomic_neuropathy">Autonomic neuropathy</span></h3><p><b>Autonomic neuropathy</b> is a form of polyneuropathy that affects the non-voluntary, non-sensory <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a> (i.e., the <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nervous system</a>), affecting mostly the internal organs such as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urinary_bladder" title="Urinary bladder">bladder</a> muscles, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular_system" title="Cardiovascular system">cardiovascular system</a>, the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Digestive_tract" title="Digestive tract">digestive tract</a>, and the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genital" title="Genital">genital</a>
organs. These nerves are not under a person's conscious control and
function automatically. Autonomic nerve fibers form large collections in
the thorax, abdomen, and pelvis outside the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>.
They have connections with the spinal cord and ultimately the brain,
however. Most commonly autonomic neuropathy is seen in persons with
long-standing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a>
type 1 and 2. In most—but not all—cases, autonomic neuropathy occurs
alongside other forms of neuropathy, such as sensory neuropathy.
</p><p>Autonomic neuropathy is one cause of malfunction of the autonomic
nervous system, but not the only one; some conditions affecting the
brain or spinal cord also may cause <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autonomic_dysfunction" title="Autonomic dysfunction">autonomic dysfunction</a>, such as <a href="https://en.wikipedia.org/wiki/Multiple_system_atrophy" title="Multiple system atrophy">multiple system atrophy</a>, and therefore, may cause similar symptoms to autonomic neuropathy.
</p><p>The signs and symptoms of autonomic neuropathy include the following:
</p>
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urinary_bladder" title="Urinary bladder">Urinary bladder</a> conditions: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bladder_incontinence" title="Bladder incontinence">bladder incontinence</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Urine_retention" title="Urine retention">urine retention</a></li><li><a href="https://en.wikipedia.org/wiki/Gastrointestinal_tract" title="Gastrointestinal tract">Gastrointestinal tract</a>: <a href="https://en.wikipedia.org/wiki/Dysphagia" title="Dysphagia">dysphagia</a>, <a href="https://en.wikipedia.org/wiki/Abdominal_pain" title="Abdominal pain">abdominal pain</a>, <a href="https://en.wikipedia.org/wiki/Nausea" title="Nausea">nausea</a>, <a href="https://en.wikipedia.org/wiki/Vomiting" title="Vomiting">vomiting</a>, <a href="https://en.wikipedia.org/wiki/Malabsorption" title="Malabsorption">malabsorption</a>, <a href="https://en.wikipedia.org/wiki/Fecal_incontinence" title="Fecal incontinence">fecal incontinence</a>, <a href="https://en.wikipedia.org/wiki/Gastroparesis" title="Gastroparesis">gastroparesis</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diarrhoea" title="Diarrhoea">diarrhoea</a>, <a href="https://en.wikipedia.org/wiki/Constipation" title="Constipation">constipation</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular_system" title="Cardiovascular system">Cardiovascular system</a>: disturbances of heart rate (<a href="https://en.wikipedia.org/wiki/Tachycardia" title="Tachycardia">tachycardia</a>, <a href="https://en.wikipedia.org/wiki/Bradycardia" title="Bradycardia">bradycardia</a>), <a href="https://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">orthostatic hypotension</a>, inadequate increase of heart rate on exertion</li><li><a href="https://en.wikipedia.org/wiki/Respiratory_system" title="Respiratory system">Respiratory system</a>: impairments in the signals associated with regulation of breathing and <a href="https://en.wikipedia.org/wiki/Gas_exchange" title="Gas exchange">gas exchange</a> (<a href="https://en.wikipedia.org/wiki/Central_sleep_apnea" title="Central sleep apnea">central sleep apnea</a>, <a href="https://en.wikipedia.org/wiki/Hypopnea" title="Hypopnea">hypopnea</a>, <a href="https://en.wikipedia.org/wiki/Bradypnea" title="Bradypnea">bradypnea</a>).</li><li>Skin : thermal regulation, dryness through sweat disturbances</li><li>Other areas: <a href="https://en.wikipedia.org/wiki/Hypoglycemia" title="Hypoglycemia">hypoglycemia</a> unawareness, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genital" title="Genital">genital</a> impotence</li></ul>
<h3><span class="mw-headline" id="Neuritis">Neuritis</span></h3><p><b>Neuritis</b> is a general term for inflammation of a <a href="https://en.wikipedia.org/wiki/Nerve" title="Nerve">nerve</a> or the general <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a> of the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a>. Symptoms depend on the nerves involved, but may include <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>, <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">paresthesia</a> (pins-and-needles), <a href="https://en.wikipedia.org/wiki/Paresis" title="Paresis">paresis</a> (weakness), <a href="https://en.wikipedia.org/wiki/Hypoesthesia" title="Hypoesthesia">hypoesthesia</a> (numbness), <a href="https://en.wikipedia.org/wiki/Anesthesia" title="Anesthesia">anesthesia</a>, <a href="https://en.wikipedia.org/wiki/Paralysis" title="Paralysis">paralysis</a>, wasting, and disappearance of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Reflexes" title="Reflexes">reflexes</a>.
</p><p>Causes of neuritis include:
</p>
<div class="div-col" style="column-width: 30em;">
<ul><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Physical_injury" title="Physical injury">Physical injury</a></li><li><a href="https://en.wikipedia.org/wiki/Infection" title="Infection">Infection</a>
<ul><li><a href="https://en.wikipedia.org/wiki/Diphtheria" title="Diphtheria">Diphtheria</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Herpes_zoster" title="Herpes zoster">Herpes zoster</a> (shingles)</li><li><a href="https://en.wikipedia.org/wiki/Leprosy" title="Leprosy">Leprosy</a></li><li><a href="https://en.wikipedia.org/wiki/Lyme_disease" title="Lyme disease">Lyme disease</a></li></ul></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chemical" title="Chemical">Chemical</a> injury such as <a href="https://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapy</a></li><li><a href="https://en.wikipedia.org/wiki/Radiation_therapy" title="Radiation therapy">Radiation therapy</a></li></ul>
<p>Types of neuritis include:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Brachial_plexus_injury" title="Brachial plexus injury">Brachial neuritis</a></li><li><a href="https://en.wikipedia.org/wiki/Cranial_nerves" title="Cranial nerves">Cranial neuritis</a> such as <a href="https://en.wikipedia.org/wiki/Bell%27s_palsy" title="Bell's palsy">Bell's palsy</a></li><li><a href="https://en.wikipedia.org/wiki/Optic_neuritis" title="Optic neuritis">Optic neuritis</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vestibular_neuritis" title="Vestibular neuritis">Vestibular neuritis</a></li><li><a href="https://en.wikipedia.org/wiki/Wartenberg%27s_migratory_sensory_neuropathy" title="Wartenberg's migratory sensory neuropathy">Wartenberg's migratory sensory neuropathy</a></li><li>Underlying conditions including:
<ul><li><a href="https://en.wikipedia.org/wiki/Alcoholism" title="Alcoholism">Alcoholism</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Autoimmune" title="Autoimmune">Autoimmune</a> disease, especially <a href="https://en.wikipedia.org/wiki/Multiple_sclerosis" title="Multiple sclerosis">multiple sclerosis</a> and <a href="https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome" title="Guillain–Barré syndrome">Guillain–Barré syndrome</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Beriberi" title="Beriberi">Beriberi</a> (<a href="https://en.wikipedia.org/wiki/Thiamine" title="Thiamine">vitamin B<sub>1</sub></a> deficiency)</li><li><a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">Cancer</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Celiac_disease" title="Celiac disease">Celiac disease</a></li><li><a href="https://en.wikipedia.org/wiki/Non-celiac_gluten_sensitivity" title="Non-celiac gluten sensitivity">Non-celiac gluten sensitivity</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">Diabetes mellitus</a> (<a href="https://en.wikipedia.org/wiki/Diabetic_neuropathy" title="Diabetic neuropathy">Diabetic neuropathy</a>)</li><li><a href="https://en.wikipedia.org/wiki/Hypothyroidism" title="Hypothyroidism">Hypothyroidism</a></li><li><a href="https://en.wikipedia.org/wiki/Porphyria" title="Porphyria">Porphyria</a></li><li><a href="https://en.wikipedia.org/wiki/Vitamin_B12" title="Vitamin B12">Vitamin B<sub>12</sub></a> deficiency</li><li><a href="https://en.wikipedia.org/wiki/Vitamin_B6" title="Vitamin B6">Vitamin B<sub>6</sub></a> excess</li></ul></li></ul></div>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2><p>Those
with diseases or dysfunctions of their nerves may present with problems
in any of the normal nerve functions. Symptoms vary depending on the
types of nerve fiber involved. In terms of sensory function, symptoms commonly include loss of function ("negative") symptoms, including <a class="extiw" href="https://en.wiktionary.org/wiki/numb" title="wikt:numb">numbness</a>, <a href="https://en.wikipedia.org/wiki/Tremor" title="Tremor">tremor</a>, impairment of balance, and <a href="https://en.wikipedia.org/wiki/Gait_abnormality" title="Gait abnormality">gait abnormality</a>. Gain of function (positive) symptoms include <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">tingling</a>, <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>, <a href="https://en.wikipedia.org/wiki/Itch" title="Itch">itching</a>, crawling, and <a href="https://en.wikipedia.org/wiki/Paresthesia" title="Paresthesia">pins-and-needles</a>. Motor symptoms include loss of function ("negative") symptoms of weakness, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatigue_(physical)" title="Fatigue (physical)">tiredness</a>, <a href="https://en.wikipedia.org/wiki/Muscle_atrophy" title="Muscle atrophy">muscle atrophy</a>, and <a href="https://en.wikipedia.org/wiki/Gait_abnormality" title="Gait abnormality">gait abnormalities</a>; and gain of function ("positive") symptoms of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cramps" title="Cramps">cramps</a>, and muscle twitch (<a href="https://en.wikipedia.org/wiki/Fasciculation" title="Fasciculation">fasciculations</a>).
</p><p>In the most common form, length-dependent peripheral neuropathy, pain and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Parasthesia" title="Parasthesia">parasthesia</a>
appears symmetrically and generally at the terminals of the longest
nerves, which are in the lower legs and feet. Sensory symptoms generally
develop before motor symptoms such as weakness. Length-dependent
peripheral neuropathy symptoms make a slow ascent of the lower limbs,
while symptoms may never appear in the upper limbs; if they do, it will
be around the time that leg symptoms reach the knee. When the nerves of the <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nervous system</a> are affected, symptoms may include constipation, dry mouth, difficulty urinating, and <a href="https://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">dizziness when standing</a>.
</p>
<h3><span class="mw-headline" id="CAP-PRI_scale_for_diagnosis">CAP-PRI scale for diagnosis</span></h3><p>A
user-friendly, disease-specific, quality-of-life scale can be used to
monitor how someone is doing living with the burden of chronic,
sensorimotor polyneuropathy. This scale, called the Chronic, Acquired
Polyneuropathy - Patient-reported Index (CAP-PRI), contains only 15
items and is completed by the person affected by polyneuropathy. The
total score and individual item scores can be followed over time, with
item scoring used by the patient and care-provider to estimate clinical
status of some of the more common life domains and symptoms impacted by
polyneuropathy.
</p>
<h2><span class="mw-headline" id="Causes">Causes</span></h2><p>The causes are grouped broadly as follows:
</p>
<div class="div-col" style="column-width: 30em;">
<ul><li>Ribose-5-Phosphate Isomerase Deficiency</li><li>Surgery: <a href="https://en.wikipedia.org/wiki/LASIK" title="LASIK">LASIK</a> (corneal neuropathy — 20 to 55% of people).</li><li>Genetic diseases: <a href="https://en.wikipedia.org/wiki/Friedreich%27s_ataxia" title="Friedreich's ataxia">Friedreich's ataxia</a>, <a href="https://en.wikipedia.org/wiki/Fabry_disease" title="Fabry disease">Fabry disease</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Charcot-Marie-Tooth_disease" title="Charcot-Marie-Tooth disease">Charcot-Marie-Tooth disease</a>, <a href="https://en.wikipedia.org/wiki/Hereditary_neuropathy_with_liability_to_pressure_palsy" title="Hereditary neuropathy with liability to pressure palsy">hereditary neuropathy with liability to pressure palsy</a></li><li>Hyperglycemia-induced formation of advanced <a href="https://en.wikipedia.org/wiki/Glycation" title="Glycation">glycation</a> end products (AGEs)</li><li>Metabolic and endocrine diseases: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chronic_kidney_failure" title="Chronic kidney failure">chronic kidney failure</a>, <a href="https://en.wikipedia.org/wiki/Porphyria" title="Porphyria">porphyria</a>, <a href="https://en.wikipedia.org/wiki/Amyloidosis" title="Amyloidosis">amyloidosis</a>, <a href="https://en.wikipedia.org/wiki/Liver_failure" title="Liver failure">liver failure</a>, <a href="https://en.wikipedia.org/wiki/Hypothyroidism" title="Hypothyroidism">hypothyroidism</a></li><li><a href="https://en.wikipedia.org/wiki/Idiopathic_disease" title="Idiopathic disease">Idiopathic peripheral neuropathy</a> refers to neuropathy with no known cause.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Toxic" title="Toxic">Toxic</a> causes: drugs (<a href="https://en.wikipedia.org/wiki/Vincristine" title="Vincristine">vincristine</a>, metronidazole, <a href="https://en.wikipedia.org/wiki/Phenytoin" title="Phenytoin">phenytoin</a>, <a href="https://en.wikipedia.org/wiki/Nitrofurantoin" title="Nitrofurantoin">nitrofurantoin</a>, <a href="https://en.wikipedia.org/wiki/Isoniazid" title="Isoniazid">isoniazid</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ethyl_alcohol" title="Ethyl alcohol">ethyl alcohol</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Statins" title="Statins">statins</a>), organic herbicides <a href="https://en.wikipedia.org/wiki/2,3,7,8-Tetrachlorodibenzodioxin" title="2,3,7,8-Tetrachlorodibenzodioxin">TCDD dioxin</a>, organic metals, <a href="https://en.wikipedia.org/wiki/Heavy_metals" title="Heavy metals">heavy metals</a>, excess intake of <a href="https://en.wikipedia.org/wiki/Pyridoxine" title="Pyridoxine">vitamin B<sub>6</sub></a> (pyridoxine). Peripheral neuropathies also may result from long term (more than 21 days) treatment with <a href="https://en.wikipedia.org/wiki/Linezolid" title="Linezolid">linezolid</a>.</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Adverse_effects_of_fluoroquinolones" title="Adverse effects of fluoroquinolones">Adverse effects of fluoroquinolones</a>: irreversible neuropathy is a serious adverse reaction of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fluoroquinolone" title="Fluoroquinolone">fluoroquinolone</a> drugs</li><li><a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">Inflammatory</a> diseases: <a href="https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome" title="Guillain–Barré syndrome">Guillain–Barré syndrome</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Systemic_lupus_erythematosus" title="Systemic lupus erythematosus">systemic lupus erythematosus</a>, <a href="https://en.wikipedia.org/wiki/Leprosy" title="Leprosy">leprosy</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sj%C3%B6gren%27s_syndrome" title="Sjögren's syndrome">Sjögren's syndrome</a>, <a href="https://en.wikipedia.org/wiki/Babesiosis" title="Babesiosis">Babesiosis</a>, <a href="https://en.wikipedia.org/wiki/Lyme_disease" title="Lyme disease">Lyme disease</a>, <a href="https://en.wikipedia.org/wiki/Vasculitis" title="Vasculitis">vasculitis</a>, <a href="https://en.wikipedia.org/wiki/Sarcoidosis" title="Sarcoidosis">sarcoidosis</a>. <a href="https://en.wikipedia.org/wiki/Multiple_sclerosis" title="Multiple sclerosis">Multiple sclerosis</a> may also be causal.</li><li><a href="https://en.wikipedia.org/wiki/Vitamin_deficiency" title="Vitamin deficiency">Vitamin deficiency</a> states: <a href="https://en.wikipedia.org/wiki/Methylcobalamin" title="Methylcobalamin">Vitamin B<sub>12</sub></a> (Methylcobalamin), <a href="https://en.wikipedia.org/wiki/Vitamin_A" title="Vitamin A">vitamin A</a>, <a href="https://en.wikipedia.org/wiki/Vitamin_E" title="Vitamin E">vitamin E</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thiamin" title="Thiamin">vitamin B<sub>1</sub></a> (thiamin)</li><li>Physical trauma: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Compression_neuropathy" title="Compression neuropathy">compression</a>,
automobile accident, sports injury, sports pinching, cutting,
projectile injuries (for example, gunshot wound), strokes including
prolonged occlusion of blood flow, electric discharge, including
lightning strikes</li><li>Effect of <a href="https://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapy</a> – see <a href="https://en.wikipedia.org/wiki/Chemotherapy-induced_peripheral_neuropathy" title="Chemotherapy-induced peripheral neuropathy">Chemotherapy-induced peripheral neuropathy</a></li><li>Exposure to <a href="https://en.wikipedia.org/wiki/Agent_Orange" title="Agent Orange">Agent Orange</a></li><li>Others: <a href="https://en.wikipedia.org/wiki/Carpal_tunnel_syndrome" title="Carpal tunnel syndrome">Carpal tunnel syndrome</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electric_shock#Neurological_effects" title="Electric shock">electric shock</a>, <a href="https://en.wikipedia.org/wiki/HIV" title="HIV">HIV</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Malignant" title="Malignant">malignant</a> disease, <a href="https://en.wikipedia.org/wiki/Radiation" title="Radiation">radiation</a>, <a href="https://en.wikipedia.org/wiki/Shingles" title="Shingles">shingles</a>, MGUS (<a href="https://en.wikipedia.org/wiki/Monoclonal_gammopathy_of_undetermined_significance" title="Monoclonal gammopathy of undetermined significance">Monoclonal gammopathy of undetermined significance</a>).</li></ul></div>
<h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><p>Peripheral
neuropathy may first be considered when an individual reports symptoms
of numbness, tingling, and pain in feet. After ruling out a lesion in
the central nervous system as a cause, diagnosis may be made on the
basis of symptoms, laboratory and additional testing, clinical history,
and a detailed examination.
</p><p>During <a href="https://en.wikipedia.org/wiki/Physical_examination" title="Physical examination">physical examination</a>, specifically a <a href="https://en.wikipedia.org/wiki/Neurological_examination" title="Neurological examination">neurological examination</a>,
those with generalized peripheral neuropathies most commonly have
distal sensory or motor and sensory loss, although those with a <a href="https://en.wikipedia.org/wiki/Pathology" title="Pathology">pathology</a> (problem) of the nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies, such as <a href="https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome" title="Guillain–Barré syndrome">Guillain–Barré syndrome</a>; or may show focal sensory disturbance or weakness, such as in mononeuropathies. Classically, <a href="https://en.wikipedia.org/wiki/Ankle_jerk_reflex" title="Ankle jerk reflex">ankle jerk reflex</a> is absent in peripheral neuropathy.
</p><p>A physical examination will involve testing the <a href="https://en.wikipedia.org/wiki/Neurological_examination#List_of_tests" title="Neurological examination">deep ankle reflex</a> as well as examining the feet for any <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ulceration" title="Ulceration">ulceration</a>.
For large fiber neuropathy, an exam will usually show an abnormally
decreased sensation to vibration, which is tested with a 128-Hz <a href="https://en.wikipedia.org/wiki/Tuning_fork" title="Tuning fork">tuning fork</a>, and decreased sensation of light touch when touched by a nylon monofilament.
</p><p>Diagnostic tests include <a href="https://en.wikipedia.org/wiki/Electromyography" title="Electromyography">electromyography</a> (EMG) and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nerve_conduction_studies" title="Nerve conduction studies">nerve conduction studies</a> (NCSs), which assess large myelinated nerve fibers. Testing for small-fiber peripheral neuropathies often relates to the <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nervous system</a>
function of small thinly- and unmyelinated fibers. These tests include a
sweat test and a tilt table test. Diagnosis of small fiber involvement
in peripheral neuropathy may also involve a skin biopsy in which a
3 mm-thick section of skin is removed from the calf by a <a href="https://en.wikipedia.org/wiki/Skin_biopsy#Punch_biopsy" title="Skin biopsy">punch biopsy</a>,
and is used to measure the skin intraepidermal nerve fiber density
(IENFD), the density of nerves in the outer layer of the skin. Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.
</p><p>In EMG testing, demyelinating neuropathy characteristically shows
a reduction in conduction velocity and prolongation of distal and
F-wave latencies, whereas axonal neuropathy shows a reduction in
amplitude.
</p><p>Laboratory tests include blood tests for <a href="https://en.wikipedia.org/wiki/Vitamin_B12" title="Vitamin B12">vitamin B<sub>12</sub></a> levels, a <a href="https://en.wikipedia.org/wiki/Complete_blood_count" title="Complete blood count">complete blood count</a>, measurement of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thyroid_stimulating_hormone" title="Thyroid stimulating hormone">thyroid stimulating hormone</a> levels, a <a href="https://en.wikipedia.org/wiki/Comprehensive_metabolic_panel" title="Comprehensive metabolic panel">comprehensive metabolic panel</a> screening for diabetes and pre-diabetes, and a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Serum_immunofixation_test" title="Serum immunofixation test">serum immunofixation test</a>, which tests for antibodies in the blood.
</p>
<h2><span class="mw-headline" id="Treatment">Treatment</span></h2><p>The
treatment of peripheral neuropathy varies based on the cause of the
condition, and treating the underlying condition can aid in the
management of neuropathy. When peripheral neuropathy results from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a> or <a href="https://en.wikipedia.org/wiki/Prediabetes" title="Prediabetes">prediabetes</a>,
blood sugar management is key to treatment. In prediabetes in
particular, strict blood sugar control can significantly alter the
course of neuropathy. In peripheral neuropathy that stems from immune-mediated diseases, the underlying condition is treated with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Intravenous_immunoglobulin" title="Intravenous immunoglobulin">intravenous immunoglobulin</a> or steroids. When peripheral neuropathy results from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vitamin_deficiencies" title="Vitamin deficiencies">vitamin deficiencies</a> or other disorders, those are treated as well.
</p>
<h3><span class="mw-headline" id="Medications">Medications</span></h3><p>A
range of medications that act on the central nervous system have been
used to symptomatically treat neuropathic pain. Commonly used
medications include <a href="https://en.wikipedia.org/wiki/Tricyclic_antidepressant" title="Tricyclic antidepressant">tricyclic antidepressants</a> (such as <a href="https://en.wikipedia.org/wiki/Nortriptyline" title="Nortriptyline">nortriptyline</a>, <a href="https://en.wikipedia.org/wiki/Amitriptyline" title="Amitriptyline">amitriptyline</a>. <a href="https://en.wikipedia.org/wiki/Imipramine" title="Imipramine">imapramine</a>, and <a href="https://en.wikipedia.org/wiki/Desipramine" title="Desipramine">desipramine</a>,) <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Serotonin-norepinephrine_reuptake_inhibitor" title="Serotonin-norepinephrine reuptake inhibitor">serotonin-norepinephrine reuptake inhibitor</a> (SNRI) medications (<a href="https://en.wikipedia.org/wiki/Duloxetine" title="Duloxetine">duloxetine</a>, <a href="https://en.wikipedia.org/wiki/Venlafaxine" title="Venlafaxine">venlafaxine</a>, and <a href="https://en.wikipedia.org/wiki/Milnacipran" title="Milnacipran">milnacipran</a>) and <a href="https://en.wikipedia.org/wiki/Anticonvulsant" title="Anticonvulsant">antiepileptic medications</a> (<a href="https://en.wikipedia.org/wiki/Gabapentin" title="Gabapentin">gabapentin</a>, <a href="https://en.wikipedia.org/wiki/Pregabalin" title="Pregabalin">pregabalin</a>, <a href="https://en.wikipedia.org/wiki/Oxcarbazepine" title="Oxcarbazepine">oxcarbazepine</a> <a href="https://en.wikipedia.org/wiki/Zonisamide" title="Zonisamide">zonisamide</a> <a href="https://en.wikipedia.org/wiki/Levetiracetam" title="Levetiracetam">levetiracetam</a>, <a href="https://en.wikipedia.org/wiki/Lamotrigine" title="Lamotrigine">lamotrigine</a>, <a href="https://en.wikipedia.org/wiki/Topiramate" title="Topiramate">topiramate</a>, <a href="https://en.wikipedia.org/wiki/Clonazepam" title="Clonazepam">clonazepam</a>, <a href="https://en.wikipedia.org/wiki/Phenytoin" title="Phenytoin">phenytoin</a>, <a href="https://en.wikipedia.org/wiki/Lacosamide" title="Lacosamide">lacosamide</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sodium_valproate" title="Sodium valproate">sodium valproate</a> and <a href="https://en.wikipedia.org/wiki/Carbamazepine" title="Carbamazepine">carbamazepine</a>). <a href="https://en.wikipedia.org/wiki/Opioid" title="Opioid">Opioid</a> and <a href="https://en.wikipedia.org/wiki/Opiate" title="Opiate">opiate</a> medications (such as <a href="https://en.wikipedia.org/wiki/Buprenorphine" title="Buprenorphine">buprenorphine</a>, <a href="https://en.wikipedia.org/wiki/Morphine" title="Morphine">morphine</a>, <a href="https://en.wikipedia.org/wiki/Methadone" title="Methadone">methadone</a>, <a href="https://en.wikipedia.org/wiki/Fentanyl" title="Fentanyl">fentanyl</a>, <a href="https://en.wikipedia.org/wiki/Hydromorphone" title="Hydromorphone">hydromorphone</a>, <a href="https://en.wikipedia.org/wiki/Tramadol" title="Tramadol">tramadol</a> and <a href="https://en.wikipedia.org/wiki/Oxycodone" title="Oxycodone">oxycodone</a>) are also often used to treat neuropathic pain.
</p><p>As is revealed in many of the Cochrane systematic reviews listed
below, studies of these medications for the treatment of neuropathic
pain are often methodologically flawed and the evidence is potentially
subject to major bias. In general, the evidence does not support the
usage of antiepileptic and antidepressant medications for the treatment
of neuropathic pain. Better designed clinical trials and further review
from non-biased third parties are necessary to gauge just how useful for
patients these medications truly are. Reviews of these systematic
reviews are also necessary to assess for their failings.
</p><p>It is also often the case that the aforementioned medications are
prescribed for neuropathic pain conditions for which they had not been
explicitly tested on or for which controlled research is severely
lacking; or even for which evidence suggests that these medications are
not effective. The NHS for example explicitly state that amitriptyline and gabapentin can be used for treating the pain of sciatica. This is despite both the lack of high quality evidence that demonstrates efficacy of these medications for that symptom,
and also the prominence of generally moderate to high quality evidence
that reveals that antiepileptics in specific, including gabapentin,
demonstrate no efficacy in treating it.
</p>
<h4><span class="mw-headline" id="Antidepressants">Antidepressants</span></h4><p>In
general, according to Cochrane's systematic reviews, antidepressants
have shown to either be ineffective for the treatment of neuropathic
pain or the evidence available is inconclusive. Evidence also tends to be tainted by bias or issues with the methodology.
</p><p>Cochrane systematically reviewed the evidence for the
antidepressants nortriptyline, desipramine, venlafaxine and milnacipran
and in all these cases found scant evidence to support their use for the
treatment of neuropathic pain. All reviews were done between 2014 and
2015.
</p><p>A 2015 Cochrane systematic review of amitriptyline found that there was no evidence supporting the use of <a href="https://en.wikipedia.org/wiki/Amitriptyline" title="Amitriptyline">amitriptyline</a>
that did not possess inherent bias. The authors believe amitriptyline
may have an effect in some patients but that the effect is
overestimated.
A 2014 Cochrane systematic review of imipramine notes that the evidence
suggesting benefit were "methodologically flawed and potentially
subject to major bias."
</p><p>A 2017 Cochrane systematic review assessed the benefit of
antidepressant medications for several types of chronic non-cancer pains
(including neuropathic pain) in children and adolescents and the
authors found the evidence inconclusive.
</p>
<h4><span class="mw-headline" id="Antiepileptics">Antiepileptics</span></h4><p>A
2017 Cochrane systematic review found that daily dosages between
1800–3600 mg of gabapentin could provide good pain relief for pain
associated with diabetic neuropathy only. This relief occurred for
roughly 30–40% of treated patients, while placebo had a 10–20% response.
Three of the seven authors of the review had conflicts of interest
declared.
In a 2019 Cochrane review of pregabalin the authors conclude that there
is some evidence of efficacy in the treatment of pain deriving from
post-herpetic neuralgia, diabetic neuropathy and post-traumatic
neuropathic pain only. They also warned that many patients treated will
have no benefit. Two of the five authors declared receiving payments
from pharmaceutical companies.
</p><p>A 2017 Cochrane systematic review found that oxcarbazepine had
little evidence to support its use for treating diabetic neuropathy,
radicular pain and other neuropathies. The authors also call for better
studies.
In a 2015 Cochrane systematic review the authors found a lack of
evidence showing any effectiveness of zonisamide for the treatment of
pain deriving from any peripheral neuropathy.
A 2014 Cochrane review found that studies of levetiracetam showed no
indication for its effectiveness at treating pain from any neuropathy.
The authors also found that the evidence was possibly biased and that
some patients experienced adverse events.
</p><p>A 2013 Cochrane systematic review concluded that there was high
quality evidence to suggest that lamotrigine is not effective for
treating neuropathic pain, even at high dosages 200–400 mg.
A 2013 Cochrane systematic review of topimirate found that the included
data had a strong likelihood of major bias; despite this, it found no
effectiveness for the drug in treating the pain associated with diabetic
neuropathy. It had not been tested for any other type of neuropathy.
Cochrane reviews from 2012 of clonazepam and phenytoin uncovered no
evidence of sufficient quality to support their use in chronic
neuropathic pain."
</p><p>A 2012 Cochrane systematic review of lacosamide found it very
likely that the drug is ineffective for treating neuropathic pain. The
authors caution against positive interpretations of the evidence.
For sodium valproate the authors of a 2011 Cochrane review found that
"three studies no more than hint that sodium valproate may reduce pain
in diabetic neuropathy". They discuss how there is a probable
overestimate of effect due to the inherent problems with the data and
conclude that the evidence does not support its usage.
In a 2014 systematic review of carbamazepine the authors believe the
drug to be of benefit for some people. No trials were considered greater
than level III evidence; none were longer than 4 weeks in length or
were deemed as having good reporting quality.
</p><p>A 2017 Cochrane systematic review aiming to assess the benefit of
antiepileptic medications for several types of chronic non-cancer pains
(including neuropathic pain) in children and adolescents found the
evidence inconclusive. Two of the ten authors of this study declared
receiving payments from pharmaceutical companies.
</p>
<h4><span class="mw-headline" id="Opioids">Opioids</span></h4><p>A
Cochrane review of buprenorphine, fentanyl, hydromorphone and morphine,
all dated between 2015 and 2017, and all for the treatment of
neuropathic pain, found that there was insufficient evidence to comment
on their efficacy. Conflicts of interest were declared by the authors in
this review.
A 2017 Cochrane review of methadone found very low quality evidence,
three studies of limited quality, of its efficacy and safety. They could
not formulate any conclusions about its relative efficacy and safety
compared to a placebo.
</p><p>For tramadol, Cochrane found that there was only modest
information about the benefits of its usage for neuropathic pain.
Studies were small, had potential risks of bias and apparent benefits
increased with risk of bias. Overall the evidence was of low or very low
quality and the authors state that it "does not provide a reliable
indication of the likely effect".
For oxycodone the authors found very low quality evidence showing its
usefulness in treating diabetic neuropathy and postherpetic neuralgia
only. One of the four authors declared receiving payments from
pharmaceutical companies.
</p><p>More generally, a large scale 2013 review found opioids to be
more effective for intermediate term use than short term use, but
couldn't properly assess effectiveness for chronic use because of
insufficient data. Most recent guidelines on the pharmacotherapy of
neuropathic pain however are in agreement with the results of this
review and recommend the use of opioids.
A 2017 Cochrane review examining mainly propoxyphene therapy as a
treatment for many non-cancer pain syndromes (including neuropathic
pain) concluded, "There was no evidence from randomised controlled
trials to support or refute the use of opioids to treat chronic
non-cancer pain in children and adolescents."
</p>
<h4><span class="mw-headline" id="Others">Others</span></h4><p>A 2016 Cochrane review of <a href="https://en.wikipedia.org/wiki/Paracetamol" title="Paracetamol">paracetamol</a>
for the treatment of neuropathic pain concluded that its benefit alone
or in combination with codeine or dihydrocodeine is unknown.
</p><p>Few studies have examined whether <a href="https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">nonsteroidal anti-inflammatory drugs</a> are effective in treating peripheral neuropathy.
</p><p>There is some evidence that symptomatic relief from the pain of peripheral neuropathy may be obtained by application of topical <a href="https://en.wikipedia.org/wiki/Capsaicin" title="Capsaicin">capsaicin</a>.
Capsaicin is the factor that causes heat in chili peppers. However, the
evidence suggesting that capsaicin applied to the skin reduces pain for
peripheral neuropathy is of moderate to low quality and should be
interpreted carefully before using this treatment option.
</p><p>Evidence supports the use of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cannabinoids" title="Cannabinoids">cannabinoids</a> for some forms of neuropathic pain.
A 2018 Cochrane review of cannabis-based medicines for the treatment of
chronic neuropathic pain included 16 studies. All of these studies
included <a href="https://en.wikipedia.org/wiki/Tetrahydrocannabinol" title="Tetrahydrocannabinol">THC</a>
as a pharmacological component of the test group. The authors rated the
quality of evidence as very low to moderate. The primary outcome was
quoted as, "<a href="https://en.wikipedia.org/wiki/Cannabis_(drug)" title="Cannabis (drug)">Cannabis</a>-based
medicines may increase the number of people achieving 50% or greater
pain relief compared with placebo" but "the evidence for improvement in
Patient Global Impression of Change (PGIC) with cannabis to be of very
low quality". The authors also conclude, "The potential benefits of
cannabis-based medicine... might be outweighed by their potential
harms."
</p><p>A 2014 Cochrane review of topical <a href="https://en.wikipedia.org/wiki/Lidocaine" title="Lidocaine">lidocaine</a>
for the treatment of various peripheral neuropathies found its usage
supported by a few low quality studies. The authors state that there are
no high quality randomised control trials demonstrating its efficacy or
safety profile.
</p><p>A 2015 (updated in 2022) Cochrane review of topical <a href="https://en.wikipedia.org/wiki/Clonidine" title="Clonidine">clonidine</a>
for the treatment of diabetic neuropathy included two studies of 8 and
12 weeks in length; both of which compared topical clonidine to placebo
and both of which were funded by the same drug manufacturer. The review
found that topical clonidine may provide some benefit versus placebo.
However, the authors state that the included trials are potentially
subject to significant bias and that the evidence is of low to moderate
quality.
</p><p>A 2007 Cochrane review of <a href="https://en.wikipedia.org/wiki/Aldose_reductase_inhibitor" title="Aldose reductase inhibitor">aldose reductase inhibitors</a> for the treatment of the pain deriving from diabetic polyneuropathy found it no better than placebo.
</p>
<h3><span class="mw-headline" id="Medical_devices">Medical devices</span></h3><p><a href="https://en.wikipedia.org/wiki/Transcutaneous_electrical_nerve_stimulation" title="Transcutaneous electrical nerve stimulation">Transcutaneous electrical nerve stimulation</a>
(TENS) therapy is often used to treat various types of neuropathy. A
2010 review of three trials, for the treatment of diabetic neuropathy
explicitly, involving a total of 78 patients found some improvement in
pain scores after 4 and 6, but not 12 weeks of treatment and an overall
improvement in neuropathic symptoms at 12 weeks.
Another 2010 review of four trials, for the treatment of diabetic
neuropathy, found significant improvement in pain and overall symptoms,
with 38% of patients in one trial becoming asymptomatic. The treatment
remains effective even after prolonged use, but symptoms return to
baseline within a month of cessation of treatment.
</p><p>These older reviews can be balanced with a more recent 2017
review of TENS for neuropathic pain by Cochrane which concluded that,
"This review is unable to state the effect of TENS versus sham TENS for
pain relief due to the very low quality of the included evidence... The
very low quality of evidence means we have very limited confidence in
the effect estimate reported." A very low quality of evidence means,
'multiple sources of potential bias' with a 'small number and size of
studies'.
</p>
<h3><span class="mw-headline" id="Surgery">Surgery</span></h3><p>In people with diabetic peripheral neuropathy, two reviews make a case for <a href="https://en.wikipedia.org/wiki/Nerve_decompression" title="Nerve decompression">nerve decompression</a> surgery as an effective means of pain relief and support claims for protection from foot ulceration.
There is less evidence for efficacy of surgery for non-diabetic
peripheral neuropathy of the legs and feet. One uncontrolled study did
before/after comparisons with a minimum of one-year follow-up and
reported improvements for pain relief, impaired balance and numbness.
"There was no difference in outcomes between patients with diabetic
versus idiopathic neuropathy in response to nerve decompression." There are no placebo-controlled trials for idiopathic peripheral neuropathy in the published scientific literature.
</p>
<h3><span class="mw-headline" id="Diet">Diet</span></h3><p>According to a review, <a href="https://en.wikipedia.org/wiki/Gluten-free_diet" title="Gluten-free diet">strict gluten-free diet</a>
is an effective treatment when neuropathy is caused by gluten
sensitivity, with or without the presence of digestive symptoms or
intestinal injury.
</p>
<h3><span class="mw-headline" id="Counselling">Counselling</span></h3><p>A 2015 review on the treatment of neuropathic pain with <a href="https://en.wikipedia.org/wiki/Psychotherapy" title="Psychotherapy">psychological therapy</a>
concluded that, "There is insufficient evidence of the efficacy and
safety of psychological interventions for chronic neuropathic pain. The
two available studies show no benefit of treatment over either waiting
list or placebo control groups."
</p>
<h3><span class="mw-headline" id="Alternative_medicine">Alternative medicine</span></h3><p>A 2019 Cochrane review of the treatment of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Herbalism" title="Herbalism">herbal medicinal</a>
products for people with neuropathic pain for at least three months
concluded that, "There was insufficient evidence to determine whether <a href="https://en.wikipedia.org/wiki/Nutmeg" title="Nutmeg">nutmeg</a> or <a href="https://en.wikipedia.org/wiki/Hypericum_perforatum" title="Hypericum perforatum">St John's wort</a>
has any meaningful efficacy in neuropathic pain conditions.The quality
of the current evidence raises serious uncertainties about the estimates
of effect observed, therefore, we have very little confidence in the
effect estimate; the true effect is likely to be substantially different
from the estimate of effect."
</p><p>A 2017 Cochrane review on the usage of <a href="https://en.wikipedia.org/wiki/Acupuncture" title="Acupuncture">acupuncture</a>
as a treatment for neuropathic pain concludes, "Due to the limited data
available, there is insufficient evidence to support or refute the use
of acupuncture for neuropathic pain in general, or for any specific
neuropathic pain condition when compared with sham acupuncture or other
active therapies." Also, "Most studies included a small sample size
(fewer than 50 participants per treatment arm) and all studies were at
high risk of bias for blinding of participants and personnel." Also, the
authors state, "we did not identify any study comparing acupuncture
with treatment as usual."
</p><p>Alpha <a href="https://en.wikipedia.org/wiki/Lipoic_acid" title="Lipoic acid">lipoic acid</a> (ALA) with benfotiamine is a proposed pathogenic treatment for painful diabetic neuropathy only.
The results of two systematic reviews state that oral ALA produced no
clinically significant benefit, intravenous ALA administered over the
course of three weeks may improve symptoms and that long-term treatment
has not been investigated.
</p>
<h2><span class="mw-headline" id="Research">Research</span></h2><p>A 2008 literature review concluded that, "based on principles of <a href="https://en.wikipedia.org/wiki/Evidence-based_medicine" title="Evidence-based medicine">evidence-based medicine</a> and evaluations of methodology, there is only a 'possible' association of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Celiac_disease" title="Celiac disease">celiac disease</a>
and peripheral neuropathy due to lower levels of evidence and
conflicting evidence. There is not yet convincing evidence of
causality."
</p><p>A 2019 review concluded that "gluten neuropathy is a slowly
progressive condition. About 25% of the patients will have evidence of
enteropathy on biopsy (CD [celiac disease]) but the presence or absence
of an enteropathy does not influence the positive effect of a strict
gluten-free diet."
</p><p><a href="https://en.wikipedia.org/wiki/Stem-cell_therapy" title="Stem-cell therapy">Stem-cell therapy</a> is also being looked at as a possible means to repair peripheral nerve damage, however efficacy has not yet been demonstrated.<sup class="reference" id="cite_ref-113"><a href="https://en.wikipedia.org/wiki/Peripheral_neuropathy#cite_note-113"></a></sup></p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-53840445552676601032024-03-27T12:34:00.002-04:002024-03-27T12:34:07.302-04:00Nerve<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
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<div class="hatnote navigation-not-searchable" role="note"><a href="https://en.wikipedia.org/wiki/Nerve">https://en.wikipedia.org/wiki/Nerve</a></div><div class="hatnote navigation-not-searchable" role="note"> <br /></div>
<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background-color: lemonchiffon;">Nerve</th></tr><tr><td class="infobox-image" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Nerves_of_the_left_upper_extremity.gif"><img class="mw-file-element" data-file-height="1000" data-file-width="524" height="477" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a7/Nerves_of_the_left_upper_extremity.gif/250px-Nerves_of_the_left_upper_extremity.gif" width="250" /></a></span><div class="infobox-caption">Nerves (yellow) in the arm</div></td></tr></tbody></table>
<p>A <b>nerve</b> is an enclosed, cable-like bundle of nerve fibers (called <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a>) in the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a>.
</p><p>
Nerves have historically been considered the basic units of the
peripheral nervous system. A nerve provides a common pathway for the <a href="https://en.wikipedia.org/wiki/Electrochemistry" title="Electrochemistry">electrochemical</a> nerve impulses called <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potentials</a> that are transmitted along each of the <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a> to peripheral organs or, in the case of <a href="https://en.wikipedia.org/wiki/Sensory_nerve" title="Sensory nerve">sensory nerves</a>, from the periphery back to the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>. Each axon, within the nerve, is an extension of an individual <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuron</a>, along with other supportive cells such as some <a href="https://en.wikipedia.org/wiki/Schwann_cell" title="Schwann cell">Schwann cells</a> that coat the axons in <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a>. </p><figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Complete_neuron_cell_diagram_en.svg"><img alt="need to" class="mw-file-element" data-file-height="596" data-file-width="819" height="290" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a9/Complete_neuron_cell_diagram_en.svg/171px-Complete_neuron_cell_diagram_en.svg.png" width="400" /></a><figcaption>Nerve cell and organization</figcaption></figure>
<p>Within a nerve, each axon is surrounded by a layer of connective tissue called the <a href="https://en.wikipedia.org/wiki/Endoneurium" title="Endoneurium">endoneurium</a>. The axons are bundled together into groups called <a href="https://en.wikipedia.org/wiki/Nerve_fascicle" title="Nerve fascicle">fascicles</a>, and each fascicle is wrapped in a layer of connective tissue called the <a href="https://en.wikipedia.org/wiki/Perineurium" title="Perineurium">perineurium</a>. Finally, the entire nerve is wrapped in a layer of connective tissue called the <a href="https://en.wikipedia.org/wiki/Epineurium" title="Epineurium">epineurium</a>. Nerve cells (often called neurons) are further classified as <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory</a>, <a href="https://en.wikipedia.org/wiki/Motor_neuron" title="Motor neuron">motor</a>, or <a href="https://en.wikipedia.org/wiki/Mixed_nerve" title="Mixed nerve">mixed nerves</a>.
</p><p>In the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>, the analogous structures are known as <a href="https://en.wikipedia.org/wiki/Nerve_tract" title="Nerve tract">nerve tracts</a>.
</p>
<h2><span class="mw-headline" id="Structure">Structure</span></h2></div></div></div><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:1319_Nerve_StructureN.jpg"><img class="mw-file-element" data-file-height="1069" data-file-width="895" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/ac/1319_Nerve_StructureN.jpg/220px-1319_Nerve_StructureN.jpg" width="335" /></a><figcaption>Cross-section of a nerve</figcaption></figure>
<p>Each nerve is covered on the outside by a dense sheath of <a href="https://en.wikipedia.org/wiki/Connective_tissue" title="Connective tissue">connective tissue</a>, the <a href="https://en.wikipedia.org/wiki/Epineurium" title="Epineurium">epineurium</a>. Beneath this is a layer of fat cells, the <a href="https://en.wikipedia.org/wiki/Perineurium" title="Perineurium">perineurium</a>,
which forms a complete sleeve around a bundle of axons. Perineurial
septae extend into the nerve and subdivide it into several bundles of
fibres. Surrounding each such fibre is the <a href="https://en.wikipedia.org/wiki/Endoneurium" title="Endoneurium">endoneurium</a>.
This forms an unbroken tube from the surface of the spinal cord to the
level where the axon synapses with its muscle fibres, or ends in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sensory_receptor" title="Sensory receptor">sensory receptors</a>. The endoneurium consists of an inner sleeve of material called the <a href="https://en.wikipedia.org/wiki/Glycocalyx" title="Glycocalyx">glycocalyx</a> and an outer, delicate, meshwork of <a href="https://en.wikipedia.org/wiki/Collagen" title="Collagen">collagen</a> fibres. Nerves are bundled and often travel along with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Blood_vessels" title="Blood vessels">blood vessels</a>, since the neurons of a nerve have fairly high energy requirements.
</p><p>Within the endoneurium, the individual nerve fibres are surrounded by a low-protein liquid called <b>endoneurial fluid</b>. This acts in a similar way to the <a href="https://en.wikipedia.org/wiki/Cerebrospinal_fluid" title="Cerebrospinal fluid">cerebrospinal fluid</a> in the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> and constitutes a <b>blood-nerve barrier</b> similar to the <a href="https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier" title="Blood–brain barrier">blood–brain barrier</a>. Molecules are thereby prevented from crossing the blood into the endoneurial fluid. During the development of nerve <a href="https://en.wikipedia.org/wiki/Edema" title="Edema">edema</a>
from nerve irritation (or injury), the amount of endoneurial fluid may
increase at the site of irritation. This increase in fluid can be
visualized using <a href="https://en.wikipedia.org/wiki/Magnetic_resonance_neurography" title="Magnetic resonance neurography">magnetic resonance neurography</a>, and thus MR neurography can identify nerve irritation and/or injury.
</p>
<h3><span class="mw-headline" id="Categories">Categories</span></h3><p>Nerves are categorized into three groups based on the direction that signals are conducted:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Afferent_nerve_fiber" title="Afferent nerve fiber">Afferent nerves</a> conduct signals from <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neurons</a> to the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>, for example from the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mechanoreceptors" title="Mechanoreceptors">mechanoreceptors</a> in <a href="https://en.wikipedia.org/wiki/Skin" title="Skin">skin</a>.</li><li><a href="https://en.wikipedia.org/wiki/Efferent_nerve_fiber" title="Efferent nerve fiber">Efferent nerves</a> conduct signals from the central nervous system along <a href="https://en.wikipedia.org/wiki/Motor_neuron" title="Motor neuron">motor neurons</a> to their target <a href="https://en.wikipedia.org/wiki/Muscle" title="Muscle">muscles</a> and <a href="https://en.wikipedia.org/wiki/Gland" title="Gland">glands</a>.</li><li><a href="https://en.wikipedia.org/wiki/Mixed_nerve" title="Mixed nerve">Mixed nerves</a> contain both afferent and efferent axons, and thus conduct both incoming <a href="https://en.wikipedia.org/wiki/Sense" title="Sense">sensory</a>
information and outgoing muscle commands in the same bundle. All spinal
nerves are mixed nerves, and some of the cranial nerves are also mixed
nerves.</li></ul>
<p>Nerves can be categorized into two groups based on where they connect to the central nervous system:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Spinal_nerve" title="Spinal nerve">Spinal nerves</a> innervate (distribute to/stimulate) much of the body, and connect through the <a href="https://en.wikipedia.org/wiki/Vertebral_column" title="Vertebral column">vertebral column</a> to the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a> and thus to the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>. They are given letter-number designations according to the <a href="https://en.wikipedia.org/wiki/Vertebra" title="Vertebra">vertebra</a> through which they connect to the spinal column.</li><li><a href="https://en.wikipedia.org/wiki/Cranial_nerves" title="Cranial nerves">Cranial nerves</a> innervate parts of the head, and connect directly to the <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> (especially to the <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a>). They are typically assigned <a href="https://en.wikipedia.org/wiki/Roman_numerals" title="Roman numerals">Roman numerals</a> from 1 to 12, although <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cranial_nerve_zero" title="Cranial nerve zero">cranial nerve zero</a> is sometimes included. In addition, cranial nerves have descriptive names.</li></ul>
<h3><span class="mw-headline" id="Terminology">Terminology</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Anatomical_terms_of_neuroanatomy" title="Anatomical terms of neuroanatomy">Anatomical terms of neuroanatomy</a></div>
<p>Specific terms are used to describe nerves and their actions. A nerve
that supplies information to the brain from an area of the body, or
controls an action of the body is said to <i>innervate</i> that section
of the body or organ. Other terms relate to whether the nerve affects
the same side ("ipsilateral") or opposite side ("contralateral") of the
body, to the part of the brain that supplies it.
</p>
<h2><span class="mw-headline" id="Development">Development</span></h2><p>Nerve growth normally ends in adolescence, but can be re-stimulated with a molecular mechanism known as "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Notch_signaling" title="Notch signaling">Notch signaling</a>".
</p>
<h3><span class="mw-headline" id="Regeneration">Regeneration</span></h3><p>If the axons of a <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuron</a> are damaged, as long as <a href="https://en.wikipedia.org/wiki/Soma_(biology)" title="Soma (biology)">the cell body</a> of the neuron is not damaged, the axons can regenerate and remake the synaptic connections with neurons with the help of <a href="https://en.wikipedia.org/wiki/Guidepost_cells" title="Guidepost cells">guidepost cells</a>. This is also referred to as <a href="https://en.wikipedia.org/wiki/Neuroregeneration" title="Neuroregeneration">neuroregeneration</a>.
</p><p>The nerve begins the process by destroying the nerve <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Distal" title="Distal">distal</a>
to the site of injury allowing Schwann cells, basal lamina, and the
neurilemma near the injury to begin producing a regeneration tube. Nerve
growth factors are produced causing many nerve sprouts to bud. When
one of the growth processes finds the regeneration tube, it begins to
grow rapidly towards its original destination guided the entire time by
the regeneration tube. Nerve regeneration is very slow and can take up
to several months to complete. While this process does repair some
nerves, there will still be some functional deficit as the repairs are
not perfect.
</p>
<h2><span class="mw-headline" id="Function">Function</span></h2><p>A nerve conveys information in the form of electrochemical impulses (as nerve impulses known as <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potentials</a>) carried by the individual neurons that make up the nerve. These impulses are extremely fast, with some <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myelinated" title="Myelinated">myelinated</a> neurons conducting at speeds up to 120 m/s. The impulses travel from one neuron to another by crossing a <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapse</a>, where the message is converted from <a href="https://en.wikipedia.org/wiki/Electrical_synapse" title="Electrical synapse">electrical</a> to <a href="https://en.wikipedia.org/wiki/Chemical_synapse" title="Chemical synapse">chemical</a> and then back to electrical.
</p><p>Nerves can be categorized into two groups based on function:
</p>
<ul><li>An <a href="https://en.wikipedia.org/wiki/Afferent_nerve_fiber" title="Afferent nerve fiber">afferent nerve fiber</a> conducts sensory information from a <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neuron</a> to the central nervous system, where the information is then processed. Bundles of fibres or <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a>, in the peripheral nervous system are called nerves, and bundles of afferent fibers are known as <i>sensory nerves</i>.</li><li>An <a href="https://en.wikipedia.org/wiki/Efferent_nerve_fiber" title="Efferent nerve fiber">efferent nerve fiber</a> conducts signals from a <a href="https://en.wikipedia.org/wiki/Motor_neuron" title="Motor neuron">motor neuron</a> in the central nervous system to muscles. Bundles of these fibres are known as <i>efferent nerves</i>.</li></ul>
<h3><span class="mw-headline" id="Nervous_system">Nervous system</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">Nervous system</a></div>
<p>The <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a> is the part of an <a href="https://en.wikipedia.org/wiki/Animal" title="Animal">animal</a> that coordinates its actions by transmitting <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">signals</a> to and from different parts of its body. In vertebrates it consists of two main parts, the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> (CNS) and the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a> (PNS). The CNS consists of the <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a>, <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a> and <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a>, that connect the CNS to all remaining body parts.
</p><p>Nerves that transmit signals from the CNS are called <i><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Motor_nerve_fibers" title="Motor nerve fibers">motor</a></i> or <i><a href="https://en.wikipedia.org/wiki/Efferent_nerve_fiber" title="Efferent nerve fiber">efferent</a></i> nerves, while those nerves that transmit information from the body to the CNS are called <i>sensory</i> or <i>afferent</i>. <a href="https://en.wikipedia.org/wiki/Spinal_nerve" title="Spinal nerve">Spinal nerves</a> serve both functions and are called <i>mixed</i> nerves. The PNS is divided into three separate subsystems, the <a href="https://en.wikipedia.org/wiki/Somatic_nervous_system" title="Somatic nervous system">somatic</a>, <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic</a>, and <a href="https://en.wikipedia.org/wiki/Enteric_nervous_system" title="Enteric nervous system">enteric</a> nervous systems. Somatic nerves mediate voluntary movement.
</p><p>The autonomic nervous system is further subdivided into the <a href="https://en.wikipedia.org/wiki/Sympathetic_nervous_system" title="Sympathetic nervous system">sympathetic</a> and the <a href="https://en.wikipedia.org/wiki/Parasympathetic_nervous_system" title="Parasympathetic nervous system">parasympathetic</a>
nervous systems. The sympathetic nervous system is activated in cases
of emergencies to mobilize energy, while the parasympathetic nervous
system is activated when organisms are in a relaxed state. The enteric
nervous system functions to control the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gastrointestinal" title="Gastrointestinal">gastrointestinal</a> system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called <a href="https://en.wikipedia.org/wiki/Cranial_nerves" title="Cranial nerves">cranial nerves</a> while those exiting from the spinal cord are called <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spinal_nerves" title="Spinal nerves">spinal nerves</a>.
</p>
<h2><span class="mw-headline" id="Clinical_significance">Clinical significance</span></h2><figure class="mw-default-size mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Prostatic_adenocarcinoma_with_perineural_invasion.JPG"><img class="mw-file-element" data-file-height="2848" data-file-width="4272" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4c/Prostatic_adenocarcinoma_with_perineural_invasion.JPG/220px-Prostatic_adenocarcinoma_with_perineural_invasion.JPG" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Micrograph" title="Micrograph">Micrograph</a> demonstrating <a href="https://en.wikipedia.org/wiki/Perineural_invasion" title="Perineural invasion">perineural invasion</a> of <a href="https://en.wikipedia.org/wiki/Prostate_cancer" title="Prostate cancer">prostate cancer</a>. <a href="https://en.wikipedia.org/wiki/H%26E_stain" title="H&E stain">H&E stain</a>.</figcaption></figure>
<p><a href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">Cancer</a> can spread by invading the spaces around nerves. This is particularly common in <a href="https://en.wikipedia.org/wiki/Head_and_neck_cancer" title="Head and neck cancer">head and neck cancer</a>, <a href="https://en.wikipedia.org/wiki/Prostate_cancer" title="Prostate cancer">prostate cancer</a> and <a href="https://en.wikipedia.org/wiki/Colorectal_cancer" title="Colorectal cancer">colorectal cancer</a>.
</p><p>Nerves can be damaged by physical injury as well as conditions like <a href="https://en.wikipedia.org/wiki/Carpal_tunnel_syndrome" title="Carpal tunnel syndrome">carpal tunnel syndrome</a> (CTS) and <a href="https://en.wikipedia.org/wiki/Repetitive_strain_injury" title="Repetitive strain injury">repetitive strain injury</a>. <a href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">Autoimmune diseases</a> such as <a href="https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome" title="Guillain–Barré syndrome">Guillain–Barré syndrome</a>, <a href="https://en.wikipedia.org/wiki/Neurodegenerative_disease" title="Neurodegenerative disease">neurodegenerative diseases</a>, <a href="https://en.wikipedia.org/wiki/Polyneuropathy" title="Polyneuropathy">polyneuropathy</a>, infection, <a href="https://en.wikipedia.org/wiki/Neuritis" title="Neuritis">neuritis</a>, <a href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a>, or failure of the blood vessels surrounding the nerve all cause <a href="https://en.wikipedia.org/wiki/Nerve_injury" title="Nerve injury">nerve damage</a>, which can vary in severity.
</p><p><a href="https://en.wikipedia.org/wiki/Multiple_sclerosis" title="Multiple sclerosis">Multiple sclerosis</a> is a disease associated with extensive nerve damage. It occurs when the <a href="https://en.wikipedia.org/wiki/Macrophage" title="Macrophage">macrophages</a> of an individual's own immune system damage the myelin sheaths that insulate the axon of the nerve.
</p><p>A <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pinched_nerve" title="Pinched nerve">pinched nerve</a> occurs when pressure is placed on a nerve, usually from swelling due to an injury, or pregnancy and can result in <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>,
weakness, numbness or paralysis, an example being CTS. Symptoms can be
felt in areas far from the actual site of damage, a phenomenon called <a href="https://en.wikipedia.org/wiki/Referred_pain" title="Referred pain">referred pain</a>. Referred pain can happen when the damage causes altered signalling to other areas.
</p><p><a href="https://en.wikipedia.org/wiki/Neurology" title="Neurology">Neurologists</a> usually diagnose disorders of nerves by a <a href="https://en.wikipedia.org/wiki/Physical_examination" title="Physical examination">physical examination</a>, including the testing of <a href="https://en.wikipedia.org/wiki/Reflex" title="Reflex">reflexes</a>, <a href="https://en.wikipedia.org/wiki/Walking" title="Walking">walking</a> and other directed movements, <a href="https://en.wikipedia.org/wiki/Muscle_weakness" title="Muscle weakness">muscle weakness</a>, <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">proprioception</a>, and the sense of <a href="https://en.wikipedia.org/wiki/Somatosensory_system" title="Somatosensory system">touch</a>. This initial exam can be followed with tests such as <a href="https://en.wikipedia.org/wiki/Nerve_conduction_study" title="Nerve conduction study">nerve conduction study</a>, <a href="https://en.wikipedia.org/wiki/Electromyography" title="Electromyography">electromyography</a> (EMG), and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Computed_tomography" title="Computed tomography">computed tomography</a> (CT).
</p>
<h2><span class="mw-headline" id="Other_animals">Other animals</span></h2><p>A neuron is called <i>identified</i>
if it has properties that distinguish it from every other neuron in the
same animal—properties such as location, neurotransmitter, gene
expression pattern, and connectivity—and if every individual organism
belonging to the same species has exactly one neuron with the same set
of properties.
In vertebrate nervous systems, very few neurons are "identified" in
this sense. Researchers believe humans have none—but in simpler nervous
systems, some or all neurons may be thus unique.
</p><p>In vertebrates, the best known identified neurons are the gigantic <a href="https://en.wikipedia.org/wiki/Mauthner_cell" title="Mauthner cell">Mauthner cells</a> of fish.
Every fish has two Mauthner cells, located in the bottom part of the
brainstem, one on the left side and one on the right. Each Mauthner
cell has an axon that crosses over, innervating (stimulating) neurons at
the same brain level and then travelling down through the spinal cord,
making numerous connections as it goes. The synapses generated by a
Mauthner cell are so powerful that a single action potential gives rise
to a major behavioral response: within milliseconds the fish curves its
body into a <a href="https://en.wikipedia.org/wiki/Mauthner_cell#The_C-start_behavior" title="Mauthner cell">C-shape</a>,
then straightens, thereby propelling itself rapidly forward.
Functionally this is a fast escape response, triggered most easily by a
strong sound wave or pressure wave impinging on the lateral line organ
of the fish. Mauthner cells are not the only identified neurons in
fish—there are about 20 more types, including pairs of "Mauthner cell
analogs" in each spinal segmental nucleus. Although a Mauthner cell is
capable of bringing about an escape response all by itself, in the
context of ordinary behavior other types of cells usually contribute to
shaping the amplitude and direction of the response.
</p><p>Mauthner cells have been described as <a href="https://en.wikipedia.org/wiki/Command_neuron" title="Command neuron">command neurons</a>.
A command neuron is a special type of identified neuron, defined as a
neuron that is capable of driving a specific behavior all by itself.<sup> </sup>Such neurons appear most commonly in the fast escape systems of various species—the <a href="https://en.wikipedia.org/wiki/Squid_giant_axon" title="Squid giant axon">squid giant axon</a> and <a href="https://en.wikipedia.org/wiki/Squid_giant_synapse" title="Squid giant synapse">squid giant synapse</a>,
used for pioneering experiments in neurophysiology because of their
enormous size, both participate in the fast escape circuit of the squid.
The concept of a command neuron has, however, become controversial,
because of studies showing that some neurons that initially appeared to
fit the description were really only capable of evoking a response in a
limited set of circumstances.
</p><p>In organisms of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Radial_symmetry" title="Radial symmetry">radial symmetry</a>, <a href="https://en.wikipedia.org/wiki/Nerve_net" title="Nerve net">nerve nets</a>
serve for the nervous system. There is no brain or centralised head
region, and instead there are interconnected neurons spread out in nerve
nets. These are found in <a href="https://en.wikipedia.org/wiki/Cnidaria" title="Cnidaria">Cnidaria</a>, <a href="https://en.wikipedia.org/wiki/Ctenophora" title="Ctenophora">Ctenophora</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Echinodermata" title="Echinodermata">Echinodermata</a>.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/History_of_neurology_and_neurosurgery" title="History of neurology and neurosurgery">History of neurology and neurosurgery</a></div>
<p><a href="https://en.wikipedia.org/wiki/Herophilos" title="Herophilos">Herophilos</a> (335–280 BC) described the functions of the <a href="https://en.wikipedia.org/wiki/Optic_nerve" title="Optic nerve">optic nerve</a> in sight and the <a href="https://en.wikipedia.org/wiki/Oculomotor_nerve" title="Oculomotor nerve">oculomotor nerve</a> in eye movement. Analysis of the nerves in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cranium" title="Cranium">cranium</a> enabled him to differentiate between <a href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a> and nerves (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ancient_Greek_language" title="Ancient Greek language">Ancient Greek</a>: <span lang="grc"><a class="extiw" href="https://en.wiktionary.org/wiki/%CE%BD%CE%B5%E1%BF%A6%CF%81%CE%BF%CE%BD" title="wiktionary:νεῦρον">νεῦρον (neûron)</a></span> "string, plant fiber, nerve").
</p><p>Modern research has not confirmed <a href="https://en.wikipedia.org/wiki/William_Cullen" title="William Cullen">William Cullen</a>'s 1785 hypothesis associating mental states with physical nerves, although popular or lay medicine may still invoke "nerves" in diagnosing or blaming any sort of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Psychological" title="Psychological">psychological</a> worry or hesitancy, as in the common traditional phrases "my poor nerves",
"<a class="extiw" href="https://en.wiktionary.org/wiki/high-strung" title="wikt:high-strung">high-strung</a>", and "<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nervous_breakdown" title="Nervous breakdown">nervous breakdown</a>".</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-71996881752921999332024-03-27T09:52:00.003-04:002024-03-27T09:52:48.222-04:00Motor neuron<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div><div class="noprint" id="siteSub"><a href="https://en.wikipedia.org/wiki/Motor_neuron">https://en.wikipedia.org/wiki/Motor_neuron</a> <br /></div>
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<div class="mw-body-content" id="mw-content-text"></div></div><p>Motor neurons begin to develop early in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryogenesis" title="Embryogenesis">embryonic development</a>, and motor function continues to develop well into childhood. In the <a href="https://en.wikipedia.org/wiki/Neural_tube#Ventral-dorsal_patterning" title="Neural tube">neural tube</a> cells are specified to either the rostral-caudal axis or ventral-dorsal axis. The <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a> of motor neurons begin to appear in the fourth week of development from the ventral region of the ventral-dorsal axis (the <a href="https://en.wikipedia.org/wiki/Basal_plate_(neural_tube)" title="Basal plate (neural tube)">basal plate</a>). This homeodomain is known as the motor neural progenitor domain (pMN). <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">Transcription factors</a> here include <a href="https://en.wikipedia.org/wiki/PAX6" title="PAX6">Pax6</a>, <a href="https://en.wikipedia.org/wiki/OLIG2" title="OLIG2">OLIG2</a>, <a href="https://en.wikipedia.org/wiki/NKX6-1" title="NKX6-1">Nkx-6.1</a>, and <a href="https://en.wikipedia.org/wiki/NKX6-2" title="NKX6-2">Nkx-6.2</a>, which are regulated by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sonic_hedgehog" title="Sonic hedgehog">sonic hedgehog</a> (Shh). The OLIG2 gene being the most important due to its role in promoting <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurogenin#Motor_neuron_fate" title="Neurogenin">Ngn2 expression</a>,
a gene that causes cell cycle exiting as well as promoting further
transcription factors associated with motor neuron development.
</p><p>Further specification of motor neurons occurs when <a href="https://en.wikipedia.org/wiki/Retinoic_acid" title="Retinoic acid">retinoic acid</a>, <a href="https://en.wikipedia.org/wiki/Fibroblast_growth_factor" title="Fibroblast growth factor">fibroblast growth factor</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Wnt_signalling_pathway" title="Wnt signalling pathway">Wnts</a>, and <a href="https://en.wikipedia.org/wiki/Transforming_growth_factor" title="Transforming growth factor">TGFb</a>, are integrated into the various <a href="https://en.wikipedia.org/wiki/Hox_gene" title="Hox gene">Hox</a>
transcription factors. There are 13 Hox transcription factors and along
with the signals, determine whether a motor neuron will be more rostral
or caudal in character. In the spinal column, Hox 4-11 sort motor
neurons to one of the five motor columns.
</p>
<table border="1">
<caption>Motor columns of spinal cord
</caption>
<tbody><tr>
<td><b>Motor column</b>
</td>
<td><b>Location in spinal cord</b>
</td>
<td><b>Target</b>
</td></tr>
<tr>
<td>Median motor column
</td>
<td>Present entire length
</td>
<td>Axial muscles
</td></tr>
<tr>
<td>Hypaxial motor column
</td>
<td>Thoracic region
</td>
<td>Body wall muscles
</td></tr>
<tr>
<td>Preganglionic motor column
</td>
<td>Thoracic region
</td>
<td>Sympathetic ganglion
</td></tr>
<tr>
<td>Lateral motor column
</td>
<td>Brachial and lumbar region (both regions are further divided into medial and lateral domains)
</td>
<td>Muscles of the limbs
</td></tr>
<tr>
<td>Phrenic motor column
</td>
<td>Cervical region
</td>
<td>Diaphragm
</td></tr></tbody></table>
<h2><span class="mw-headline" id="Anatomy_and_physiology">Anatomy and physiology</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Spinal_cord_tracts_-_English.svg"><img class="mw-file-element" data-file-height="376" data-file-width="874" height="228" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/b2/Spinal_cord_tracts_-_English.svg/530px-Spinal_cord_tracts_-_English.svg.png" width="530" /></a><figcaption>Spinal cord tracts</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Polio_spinal_diagram-en.svg"><img class="mw-file-element" data-file-height="927" data-file-width="1273" height="291" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/bc/Polio_spinal_diagram-en.svg/220px-Polio_spinal_diagram-en.svg.png" width="400" /></a><figcaption>Location of lower motor neurons in spinal cord</figcaption></figure>
<h3><span class="mw-headline" id="Upper_motor_neurons">Upper motor neurons</span></h3><p><a href="https://en.wikipedia.org/wiki/Upper_motor_neuron" title="Upper motor neuron">Upper motor neurons</a> originate in the <a href="https://en.wikipedia.org/wiki/Motor_cortex" title="Motor cortex">motor cortex</a> located in the <a href="https://en.wikipedia.org/wiki/Precentral_gyrus" title="Precentral gyrus">precentral gyrus</a>. The cells that make up the <a href="https://en.wikipedia.org/wiki/Primary_motor_cortex" title="Primary motor cortex">primary motor cortex</a> are <a href="https://en.wikipedia.org/wiki/Betz_cell" title="Betz cell">Betz cells</a>, which are giant <a href="https://en.wikipedia.org/wiki/Pyramidal_cell" title="Pyramidal cell">pyramidal cells</a>. The axons of these cells descend from the cortex to form the <a href="https://en.wikipedia.org/wiki/Corticospinal_tract" title="Corticospinal tract">corticospinal tract</a>. <a href="https://en.wikipedia.org/wiki/Primary_motor_cortex#Corticomotorneurons" title="Primary motor cortex">Corticomotorneurons</a> project from the primary cortex directly onto motor neurons in the ventral horn of the spinal cord. Their axons synapse on the spinal motor neurons of multiple muscles as well as on spinal <a href="https://en.wikipedia.org/wiki/Interneuron" title="Interneuron">interneurons</a>. They are unique to primates and it has been suggested that their function is the adaptive control of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hands" title="Hands">hands</a> including the relatively independent control of individual fingers. Corticomotorneurons have so far only been found in the primary motor cortex and not in secondary motor areas.
</p>
<h3><span class="mw-headline" id="Nerve_tracts">Nerve tracts</span></h3><p><a href="https://en.wikipedia.org/wiki/Nerve_tract" title="Nerve tract">Nerve tracts</a> are bundles of axons as <a href="https://en.wikipedia.org/wiki/White_matter" title="White matter">white matter</a>, that carry <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potentials</a>
to their effectors. In the spinal cord these descending tracts carry
impulses from different regions. These tracts also serve as the place of
origin for lower motor neurons. There are seven major descending motor
tracts to be found in the spinal cord:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Lateral_corticospinal_tract" title="Lateral corticospinal tract">Lateral corticospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Rubrospinal_tract" title="Rubrospinal tract">Rubrospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Reticular_formation#Medial_and_lateral_tracts" title="Reticular formation">Lateral reticulospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Vestibulospinal_tract" title="Vestibulospinal tract">Vestibulospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Reticular_formation#Medial_and_lateral_tracts" title="Reticular formation">Medial reticulospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Tectospinal_tract" title="Tectospinal tract">Tectospinal tract</a></li><li><a href="https://en.wikipedia.org/wiki/Anterior_corticospinal_tract" title="Anterior corticospinal tract">Anterior corticospinal tract</a></li></ul>
<h3><span class="mw-headline" id="Lower_motor_neurons">Lower motor neurons</span></h3><p><a href="https://en.wikipedia.org/wiki/Lower_motor_neuron" title="Lower motor neuron">Lower motor neurons</a>
are those that originate in the spinal cord and directly or indirectly
innervate effector targets. The target of these neurons varies, but in
the somatic nervous system the target will be some sort of muscle fiber.
There are three primary categories of lower motor neurons, which can be
further divided in sub-categories.
</p><p>According to their targets, motor neurons are classified into three broad categories:
</p>
<ul><li>Somatic motor neurons</li><li>Special visceral motor neurons</li><li>General visceral motor neurons</li></ul>
<h4><span class="mw-headline" id="Somatic_motor_neurons">Somatic motor neurons</span></h4><p>Somatic motor neurons originate in the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>, project their <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Axons" title="Axons">axons</a> to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Skeletal_muscles" title="Skeletal muscles">skeletal muscles</a> (such as the muscles of the limbs, abdominal, and <a href="https://en.wikipedia.org/wiki/Intercostal_muscles" title="Intercostal muscles">intercostal muscles</a>), which are involved in <a href="https://en.wikipedia.org/wiki/Animal_locomotion" title="Animal locomotion">locomotion</a>. The three types of these neurons are the <i>alpha efferent neurons</i>, <i>beta efferent neurons</i>, and <i>gamma efferent neurons</i>. They are called <a href="https://en.wikipedia.org/wiki/Efferent_nerve_fiber" title="Efferent nerve fiber">efferent</a> to indicate the flow of information from the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> (CNS) to the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">periphery</a>.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Alpha_motor_neuron" title="Alpha motor neuron">Alpha motor neurons</a> innervate <a href="https://en.wikipedia.org/wiki/Extrafusal_muscle_fiber" title="Extrafusal muscle fiber">extrafusal muscle fibers</a>, which are the main force-generating component of a muscle. Their cell bodies are in the <a href="https://en.wikipedia.org/wiki/Anterior_grey_column" title="Anterior grey column">ventral horn</a> of the spinal cord and they are sometimes called <i>ventral horn cells</i>. A single motor neuron may synapse with 150 muscle fibers on average. The motor neuron and all of the muscle fibers to which it connects is a <a href="https://en.wikipedia.org/wiki/Motor_unit" title="Motor unit">motor unit</a>. Motor units are split up into 3 categories:
<ul><li>Slow (S) motor units stimulate small muscle fibers, which
contract very slowly and provide small amounts of energy but are very
resistant to fatigue, so they are used to sustain muscular contraction,
such as keeping the body upright. They gain their energy via oxidative
means and hence require oxygen. They are also called red fibers.</li><li>Fast fatiguing (FF) motor units stimulate larger muscle groups,
which apply large amounts of force but fatigue very quickly. They are
used for tasks that require large brief bursts of energy, such as
jumping or running. They gain their energy via glycolytic means and
hence do not require oxygen. They are called white fibers.</li><li>Fast fatigue-resistant motor units stimulate moderate-sized muscles
groups that do not react as fast as the FF motor units, but can be
sustained much longer (as implied by the name) and provide more force
than S motor units. These use both oxidative and glycolytic means to
gain energy.</li></ul></li></ul>
<p>In addition to voluntary skeletal muscle contraction, alpha motor neurons also contribute to <a href="https://en.wikipedia.org/wiki/Muscle_tone" title="Muscle tone">muscle tone</a>, the continuous force generated by noncontracting muscle to oppose stretching. When a muscle is stretched, <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neurons</a> within the <a href="https://en.wikipedia.org/wiki/Muscle_spindle" title="Muscle spindle">muscle spindle</a>
detect the degree of stretch and send a signal to the CNS. The CNS
activates alpha motor neurons in the spinal cord, which cause extrafusal
muscle fibers to contract and thereby resist further stretching. This
process is also called the <a href="https://en.wikipedia.org/wiki/Stretch_reflex" title="Stretch reflex">stretch reflex</a>.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Beta_motor_neuron" title="Beta motor neuron">Beta motor neurons</a> innervate <a href="https://en.wikipedia.org/wiki/Intrafusal_muscle_fiber" title="Intrafusal muscle fiber">intrafusal muscle fibers</a> of <a href="https://en.wikipedia.org/wiki/Muscle_spindle" title="Muscle spindle">muscle spindles</a>,
with collaterals to extrafusal fibres. There are two types of beta
motor neurons: Slow Contracting- These innervate extrafusal
fibers. Fast Contracting- These innervate intrafusal fibers.</li><li><a href="https://en.wikipedia.org/wiki/Gamma_motor_neuron" title="Gamma motor neuron">Gamma motor neurons</a>
innervate intrafusal muscle fibers found within the muscle spindle.
They regulate the sensitivity of the spindle to muscle stretching. With
activation of gamma neurons, intrafusal muscle fibers contract so that
only a small stretch is required to activate spindle sensory neurons and
the stretch reflex. There are two types of gamma motor neurons:
Dynamic- These focus on Bag1 fibers and enhance dynamic sensitivity.
Static- These focus on Bag2 fibers and enhance stretch sensitivity.</li><li>Regulatory factors of lower motor neurons
<ul><li><i>Size Principle</i> – this relates to the soma of the motor
neuron. This restricts larger neurons to receive a larger excitatory
signal in order to stimulate the muscle fibers it innervates. By
reducing unnecessary muscle fiber recruitment, the body is able to
optimize energy consumption.</li><li><i>Persistent Inward Current (PIC)</i> – recent animal study
research has shown that constant flow of ions such as calcium and sodium
through channels in the soma and dendrites influence the synaptic
input. An alternate way to think of this is that the post-synaptic
neuron is being primed before receiving an impulse.</li><li><i>After <a href="https://en.wikipedia.org/wiki/Hyperpolarization_(biology)" title="Hyperpolarization (biology)">Hyper-polarization</a> (AHP)</i>
– A trend has been identified that shows slow motor neurons to have
more intense AHPs for a longer duration. One way to remember this is
that slow muscle fibers can contract for longer, so it makes sense that
their corresponding motor neurons fire at a slower rate.</li></ul></li></ul>
<h4><span class="mw-headline" id="Special_visceral_motor_neurons">Special visceral motor neurons</span></h4><p>These are also known as <i>branchial motor neurons</i>, which are involved in facial expression, mastication, phonation, and swallowing. Associated cranial nerves are the <a href="https://en.wikipedia.org/wiki/Oculomotor_nerve" title="Oculomotor nerve">oculomotor</a>, <a href="https://en.wikipedia.org/wiki/Abducens_nerve" title="Abducens nerve">abducens</a>, <a href="https://en.wikipedia.org/wiki/Trochlear_nerve" title="Trochlear nerve">trochlear</a>, and <a href="https://en.wikipedia.org/wiki/Hypoglossal_nerve" title="Hypoglossal nerve">hypoglossal</a> nerves.
</p>
<table border="1" class="wikitable" style="float: right; margin-left: 1em;">
<tbody><tr bgcolor="#cccccc">
<th>Branch of NS
</th>
<th>Position
</th>
<th>Neurotransmitter
</th></tr>
<tr>
<td>Somatic
</td>
<td>n/a
</td>
<td><a href="https://en.wikipedia.org/wiki/Acetylcholine" title="Acetylcholine">Acetylcholine</a>
</td></tr>
<tr>
<td>Parasympathetic
</td>
<td>Preganglionic
</td>
<td>Acetylcholine
</td></tr>
<tr>
<td>Parasympathetic
</td>
<td>Ganglionic
</td>
<td>Acetylcholine
</td></tr>
<tr>
<td>Sympathetic
</td>
<td>Preganglionic
</td>
<td>Acetylcholine
</td></tr>
<tr>
<td>Sympathetic
</td>
<td>Ganglionic
</td>
<td><a href="https://en.wikipedia.org/wiki/Norepinephrine" title="Norepinephrine">Norepinephrine</a>*
</td></tr>
<tr>
<td align="center" colspan="3"><span style="font-size: 85%;">*Except fibers to <a href="https://en.wikipedia.org/wiki/Sweat_gland" title="Sweat gland">sweat glands</a> and certain <a href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a></span><br /><i>Motor neuron neurotransmitters</i>
</td></tr></tbody></table>
<h4><span class="mw-headline" id="General_visceral_motor_neurons">General visceral motor neurons</span></h4><p>These motor neurons indirectly innervate <a href="https://en.wikipedia.org/wiki/Cardiac_muscle" title="Cardiac muscle">cardiac muscle</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Smooth_muscles" title="Smooth muscles">smooth muscles</a> of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Viscera" title="Viscera">viscera</a> ( the muscles of the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Arteries" title="Arteries">arteries</a>): they <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapse</a> onto neurons located in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ganglia" title="Ganglia">ganglia</a> of the <a href="https://en.wikipedia.org/wiki/Autonomic_nervous_system" title="Autonomic nervous system">autonomic nervous system</a> (<a href="https://en.wikipedia.org/wiki/Sympathetic_nervous_system" title="Sympathetic nervous system">sympathetic</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Parasympathetic" title="Parasympathetic">parasympathetic</a>), located in the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a> (PNS), which themselves directly innervate visceral muscles (and also some gland cells).
</p><p>In consequence, the motor command of <a href="https://en.wikipedia.org/wiki/Skeletal_muscle" title="Skeletal muscle">skeletal</a> and branchial muscles is <i>monosynaptic</i> involving only one motor neuron, either <i>somatic</i> or <i>branchial</i>, which synapses onto the muscle. Comparatively, the command of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Visceral_muscles" title="Visceral muscles">visceral muscles</a> is <i>disynaptic</i> involving two neurons: the <i>general visceral motor neuron</i>, located in the CNS, synapses onto a ganglionic neuron, located in the PNS, which synapses onto the muscle.
</p><p>All vertebrate motor neurons are <a href="https://en.wikipedia.org/wiki/Cholinergic" title="Cholinergic">cholinergic</a>, that is, they release the neurotransmitter <a href="https://en.wikipedia.org/wiki/Acetylcholine" title="Acetylcholine">acetylcholine</a>. Parasympathetic ganglionic neurons are also cholinergic, whereas most sympathetic ganglionic neurons are <a href="https://en.wikipedia.org/wiki/Norepinephrine" title="Norepinephrine">noradrenergic</a>, that is, they release the neurotransmitter <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Noradrenaline" title="Noradrenaline">noradrenaline</a>. (see Table)
</p>
<h3><span class="mw-headline" id="Neuromuscular_junctions">Neuromuscular junctions</span></h3><p>A single motor neuron may innervate many <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myocyte" title="Myocyte">muscle fibres</a> and a muscle fibre can undergo many <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Action_potentials" title="Action potentials">action potentials</a> in the time taken for a single <a href="https://en.wikipedia.org/wiki/Muscle_contraction" title="Muscle contraction">muscle twitch</a>.
As a result, if an action potential arrives before a twitch has
completed, the twitches can superimpose on one another, either through <a href="https://en.wikipedia.org/wiki/Muscle_contraction#Gradation_of_skeletal_muscle_contractions" title="Muscle contraction">summation</a> or a <a href="https://en.wikipedia.org/wiki/Tetanic_contraction" title="Tetanic contraction">tetanic contraction</a>. In summation, the muscle is stimulated repetitively such that additional action potentials coming from the <a href="https://en.wikipedia.org/wiki/Somatic_nervous_system" title="Somatic nervous system">somatic nervous system</a>
arrive before the end of the twitch. The twitches thus superimpose on
one another, leading to a force greater than that of a single twitch. A
tetanic contraction is caused by constant, very high frequency
stimulation - the action potentials come at such a rapid rate that
individual twitches are indistinguishable, and tension rises smoothly
eventually reaching a plateau.
</p><p>The interface between a motor neuron and muscle fiber is a specialized <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapse</a> called the <a href="https://en.wikipedia.org/wiki/Neuromuscular_junction" title="Neuromuscular junction">neuromuscular junction</a>. Upon adequate stimulation, the motor neuron releases a flood of acetylcholine (Ach) <a href="https://en.wikipedia.org/wiki/Neurotransmitter" title="Neurotransmitter">neurotransmitters</a> from the axon terminals from synaptic vesicles bind with the plasma membrane. The acetylcholine molecules bind to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Postsynaptic" title="Postsynaptic">postsynaptic</a> <a href="https://en.wikipedia.org/wiki/Receptor_(biochemistry)" title="Receptor (biochemistry)">receptors</a>
found within the motor end plate. Once two acetylcholine receptors have
been bound, an ion channel is opened and sodium ions are allowed to
flow into the cell. The influx of sodium into the cell causes
depolarization and triggers a muscle action potential. T tubules of the
sarcolemma are then stimulated to elicit calcium ion release from the
sarcoplasmic reticulum. It is this chemical release that causes the
target muscle fiber to contract.
</p><p>In <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Invertebrates" title="Invertebrates">invertebrates</a>,
depending on the neurotransmitter released and the type of receptor it
binds, the response in the muscle fiber could be either excitatory or
inhibitory. For <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vertebrates" title="Vertebrates">vertebrates</a>,
however, the response of a muscle fiber to a neurotransmitter can only
be excitatory, in other words, contractile. Muscle relaxation and
inhibition of muscle contraction in vertebrates is obtained only by
inhibition of the motor neuron itself. This is how <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Muscle_relaxants" title="Muscle relaxants">muscle relaxants</a> work by acting on the motor neurons that innervate muscles (by decreasing their <a href="https://en.wikipedia.org/wiki/Electrophysiology" title="Electrophysiology">electrophysiological</a> activity) or on <a href="https://en.wikipedia.org/wiki/Acetylcholine" title="Acetylcholine">cholinergic</a> neuromuscular junctions, rather than on the muscles themselves.
</p>
<h3><span class="mw-headline" id="Synaptic_input_to_motor_neurons">Synaptic input to motor neurons</span></h3>Motor neurons receive synaptic input from premotor neurons. Premotor neurons can be 1) <a href="https://en.wikipedia.org/wiki/Spinal_interneuron" title="Spinal interneuron">spinal interneurons</a> that have cell bodies in the spinal cord, 2) <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neurons</a> that convey information from the periphery and <a href="https://en.wikipedia.org/wiki/Reflex" title="Reflex">synapse directly onto motoneurons</a>, 3) <a href="https://en.wikipedia.org/wiki/Descending_neuron" title="Descending neuron">descending neurons</a> that convey information from the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Corticomotor_neuron" title="Corticomotor neuron">brain</a> and <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a>. The synapses can be <a href="https://en.wikipedia.org/wiki/Excitatory_synapse" title="Excitatory synapse">excitatory</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Inhibitory_synapse" title="Inhibitory synapse">inhibitory</a>, <a href="https://en.wikipedia.org/wiki/Gap_junction" title="Gap junction">electrical</a>, or <a href="https://en.wikipedia.org/wiki/Stomatogastric_nervous_system" title="Stomatogastric nervous system">neuromodulatory</a>. For any given motor neuron, determining the relative contribution of different input sources is difficult, but advances in <a href="https://en.wikipedia.org/wiki/Connectomics" title="Connectomics">connectomics</a> have made it possible for <a href="https://en.wikipedia.org/wiki/Drosophila_melanogaster" title="Drosophila melanogaster">fruit fly</a> motor neurons. In the fly, motor neurons controlling the legs and wings are found in the <a href="https://en.wikipedia.org/wiki/Ventral_nerve_cord" title="Ventral nerve cord">ventral nerve cord</a>, homologous to the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>.
Fly motor neurons vary by over 100X in the total number of input
synapses. However, each motor neuron gets similar fractions of its
synapses from each premotor source: ~70% from neurons within the VNC,
~10% from descending neurons, ~3% from sensory neurons, and ~6% from VNC
neurons that also send a process up to the brain. The remaining 10% of
synapses come from neuronal fragments that are unidentified by current
image segmentation algorithms and require additional manual segmentation
to measure.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-68070866515115487472024-03-27T09:36:00.001-04:002024-03-27T09:36:16.934-04:00Sensory neuron<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div><div class="noprint" id="siteSub"><a href="https://en.wikipedia.org/wiki/Sensory_neuron">https://en.wikipedia.org/wiki/Sensory_neuron</a> </div>
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<figure class="mw-halign-right"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Structure_of_sensory_system_(4_models)_E.PNG"><img class="mw-file-element" data-file-height="980" data-file-width="1011" height="388" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/17/Structure_of_sensory_system_%284_models%29_E.PNG/300px-Structure_of_sensory_system_%284_models%29_E.PNG" width="400" /></a><figcaption>Four types of sensory neuron</figcaption></figure>
<p><b>Sensory neurons</b>, also known as <b>afferent neurons</b>, are <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neurons</a> in the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a>, that convert a specific type of <a href="https://en.wikipedia.org/wiki/Stimulus_(physiology)" title="Stimulus (physiology)">stimulus</a>, via their <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sensory_receptor" title="Sensory receptor">receptors</a>, into <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potentials</a> or <a href="https://en.wikipedia.org/wiki/Graded_potential" title="Graded potential">graded</a> <a href="https://en.wikipedia.org/wiki/Receptor_potential" title="Receptor potential">receptor potentials</a>. This process is called <a href="https://en.wikipedia.org/wiki/Transduction_(physiology)" title="Transduction (physiology)">sensory transduction</a>. The <a href="https://en.wikipedia.org/wiki/Soma_(biology)" title="Soma (biology)">cell bodies</a> of the sensory neurons are located in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_ganglion" title="Dorsal ganglion">dorsal ganglia</a> of the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>.
</p><p>The sensory information travels on the <a href="https://en.wikipedia.org/wiki/Afferent_nerve_fiber" title="Afferent nerve fiber">afferent nerve fibers</a> in a <a href="https://en.wikipedia.org/wiki/Sensory_nerve" title="Sensory nerve">sensory nerve</a>, to the <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> via the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>. Spinal nerves transmit external sensations via sensory nerves to the brain through the spinal cord. The stimulus can come from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Exteroreceptors" title="Exteroreceptors">exteroreceptors</a> outside the body, for example those that detect light and sound, or from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Interoreceptors" title="Interoreceptors">interoreceptors</a> inside the body, for example those that are responsive to <a href="https://en.wikipedia.org/wiki/Blood_pressure" title="Blood pressure">blood pressure</a> or the <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">sense of body position</a>.
</p>
<h2><span class="mw-headline" id="Types_and_function">Types and function</span></h2></div></div></div><p>Sensory neurons in <a href="https://en.wikipedia.org/wiki/Vertebrate" title="Vertebrate">vertebrates</a> are predominantly <a href="https://en.wikipedia.org/wiki/Pseudounipolar_neuron" title="Pseudounipolar neuron">pseudounipolar</a> or <a href="https://en.wikipedia.org/wiki/Bipolar_neuron" title="Bipolar neuron">bipolar</a>, and different types of sensory neurons have different <b>sensory receptors</b> that respond to different kinds of <a href="https://en.wikipedia.org/wiki/Stimulus_(physiology)" title="Stimulus (physiology)">stimuli</a>. There are at least six external and two internal sensory receptors:
</p>
<h3><span class="mw-headline" id="External_receptors">External receptors</span></h3><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Perception#Types_of_perception" title="Perception">Perception § Types of perception</a></div>
<p>External receptors that respond to stimuli from outside the body are called <b>exteroreceptors</b>. Exteroreceptors include <a href="https://en.wikipedia.org/wiki/Chemoreceptor" title="Chemoreceptor">chemoreceptors</a> such as <a href="https://en.wikipedia.org/wiki/Olfactory_receptor" title="Olfactory receptor">olfactory receptors</a> (<a href="https://en.wikipedia.org/wiki/Sense_of_smell" title="Sense of smell">smell</a>) and <a href="https://en.wikipedia.org/wiki/Taste_receptor" title="Taste receptor">taste receptors</a>, <a href="https://en.wikipedia.org/wiki/Photoreceptor_cell" title="Photoreceptor cell">photoreceptors</a> (<a href="https://en.wikipedia.org/wiki/Visual_perception" title="Visual perception">vision</a>), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Thermoreceptors" title="Thermoreceptors">thermoreceptors</a> (<a href="https://en.wikipedia.org/wiki/Thermoception" title="Thermoception">temperature</a>), <a href="https://en.wikipedia.org/wiki/Nociceptor" title="Nociceptor">nociceptors</a> (<a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>), <a href="https://en.wikipedia.org/wiki/Hair_cell" title="Hair cell">hair cells</a> (<a href="https://en.wikipedia.org/wiki/Hearing" title="Hearing">hearing</a> and <a href="https://en.wikipedia.org/wiki/Sense_of_balance" title="Sense of balance">balance</a>), and a number of other different <a href="https://en.wikipedia.org/wiki/Mechanoreceptor" title="Mechanoreceptor">mechanoreceptors</a> for <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Touch" title="Touch">touch</a> and <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">proprioception</a> (stretch, distortion and stress).
</p>
<h4><span class="mw-headline" id="Smell">Smell</span></h4><p>The sensory neurons involved in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Olfaction" title="Olfaction">smell</a> are called <a href="https://en.wikipedia.org/wiki/Olfactory_receptor_neuron" title="Olfactory receptor neuron">olfactory sensory neurons</a>. These neurons contain <a href="https://en.wikipedia.org/wiki/Receptor_(biochemistry)" title="Receptor (biochemistry)">receptors</a>, called <a href="https://en.wikipedia.org/wiki/Olfactory_receptor" title="Olfactory receptor">olfactory receptors</a>, that are activated by <a href="https://en.wikipedia.org/wiki/Odor" title="Odor">odor</a> molecules in the air. The molecules in the air are detected by enlarged <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cilia" title="Cilia">cilia</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Microvilli" title="Microvilli">microvilli</a>.<sup class="reference" id="cite_ref-5"><a href="https://en.wikipedia.org/wiki/Sensory_neuron#cite_note-5">[5]</a></sup> These sensory neurons produce action potentials. Their axons form the <a href="https://en.wikipedia.org/wiki/Olfactory_nerve" title="Olfactory nerve">olfactory nerve</a>, and they synapse directly onto neurons in the cerebral cortex (<a href="https://en.wikipedia.org/wiki/Olfactory_bulb" title="Olfactory bulb">olfactory bulb</a>).
They do not use the same route as other sensory systems, bypassing the
brain stem and the thalamus. The neurons in the olfactory bulb that
receive direct sensory nerve input, have connections to other parts of
the olfactory system and many parts of the limbic system. 9.
</p>
<h4><span class="mw-headline" id="Taste">Taste</span></h4><p>Taste
sensation is facilitated by specialized sensory neurons located in the
taste buds of the tongue and other parts of the mouth and throat. These
sensory neurons are responsible for detecting different taste qualities,
such as sweet, sour, salty, bitter, and savory. When you eat or drink
something, chemicals in the food or liquid interact with receptors on
these sensory neurons, triggering signals that are sent to the brain.
The brain then processes these signals and interprets them as specific
taste sensations, allowing you to perceive and enjoy the flavors of the
foods you consume. When taste receptor cells are stimulated by the binding of these
chemical compounds (tastants), it can lead to changes in the flow of
ions, such as sodium (Na+), calcium (Ca2+), and potassium (K+), across
the cell membrane. In response to tastant binding, ion channels on the taste receptor cell
membrane can open or close. This can lead to depolarization of the cell
membrane, creating an electrical signal.
</p><p>Similar to <a href="https://en.wikipedia.org/wiki/Olfactory_receptor" title="Olfactory receptor">olfactory receptors</a>, <a href="https://en.wikipedia.org/wiki/Taste_receptor" title="Taste receptor">taste receptors</a> (gustatory receptors) in <a href="https://en.wikipedia.org/wiki/Taste_bud" title="Taste bud">taste buds</a> interact with chemicals in food to produce an <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potential</a>.
</p>
<h4><span class="mw-headline" id="Vision">Vision</span></h4><p><a href="https://en.wikipedia.org/wiki/Photoreceptor_cell" title="Photoreceptor cell">Photoreceptor cells</a> are capable of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phototransduction" title="Phototransduction">phototransduction</a>, a process which converts light (<a href="https://en.wikipedia.org/wiki/Electromagnetic_radiation" title="Electromagnetic radiation">electromagnetic radiation</a>)
into electrical signals. These signals are refined and controlled by
the interactions with other types of neurons in the retina. The five
basic classes of neurons within the retina are <a href="https://en.wikipedia.org/wiki/Photoreceptor_cell" title="Photoreceptor cell">photoreceptor cells</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bipolar_cells" title="Bipolar cells">bipolar cells</a>, <a href="https://en.wikipedia.org/wiki/Retinal_ganglion_cell" title="Retinal ganglion cell">ganglion cells</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Horizontal_cells" title="Horizontal cells">horizontal cells</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Amacrine_cells" title="Amacrine cells">amacrine cells</a>. The basic circuitry of the retina incorporates a three-neuron chain consisting of the photoreceptor (either a <a href="https://en.wikipedia.org/wiki/Rod_cell" title="Rod cell">rod</a> or <a href="https://en.wikipedia.org/wiki/Cone_cell" title="Cone cell">cone</a>),
bipolar cell, and the ganglion cell. The first action potential occurs
in the retinal ganglion cell. This pathway is the most direct way for
transmitting visual information to the brain. There are three primary
types of photoreceptors: <a href="https://en.wikipedia.org/wiki/Cone_cell" title="Cone cell">Cones</a> are photoreceptors that respond significantly to <a href="https://en.wikipedia.org/wiki/Color" title="Color">color</a>.
In humans the three different types of cones correspond with a primary
response to short wavelength (blue), medium wavelength (green), and
long wavelength (yellow/red). <a href="https://en.wikipedia.org/wiki/Rod_cell" title="Rod cell">Rods</a>
are photoreceptors that are very sensitive to the intensity of light,
allowing for vision in dim lighting. The concentrations and ratio of
rods to cones is strongly correlated with whether an animal is <a href="https://en.wikipedia.org/wiki/Diurnality" title="Diurnality">diurnal</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nocturnal" title="Nocturnal">nocturnal</a>. In humans, rods outnumber cones by approximately 20:1, while in nocturnal animals, such as the <a href="https://en.wikipedia.org/wiki/Tawny_owl" title="Tawny owl">tawny owl</a>, the ratio is closer to 1000:1. <a href="https://en.wikipedia.org/wiki/Retinal_ganglion_cell" title="Retinal ganglion cell">Retinal ganglion cells</a> are involved in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sympathetic_response" title="Sympathetic response">sympathetic response</a>. Of the ~1.3 million ganglion cells present in the retina, 1-2% are believed to be photosensitive.
</p><p>Issues and decay of sensory neurons associated with vision lead to disorders such as:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Macular_degeneration" title="Macular degeneration">Macular degeneration</a>
– degeneration of the central visual field due to either cellular
debris or blood vessels accumulating between the retina and the choroid,
thereby disturbing and/or destroying the complex interplay of neurons
that are present there.</li><li><a href="https://en.wikipedia.org/wiki/Glaucoma" title="Glaucoma">Glaucoma</a> – loss of retinal ganglion cells which causes some loss of vision to blindness.</li><li><a href="https://en.wikipedia.org/wiki/Diabetic_retinopathy" title="Diabetic retinopathy">Diabetic retinopathy</a> – poor blood sugar control due to diabetes damages the tiny blood vessels in the retina.</li></ol>
<h4><span class="mw-headline" id="Auditory">Auditory</span></h4><p>The <a href="https://en.wikipedia.org/wiki/Auditory_system" title="Auditory system">auditory system</a> is responsible for converting pressure waves generated by vibrating air molecules or <a href="https://en.wikipedia.org/wiki/Sound" title="Sound">sound</a> into signals that can be interpreted by the brain.
</p><p>This mechanoelectrical transduction is mediated with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hair_cells" title="Hair cells">hair cells</a>
within the ear. Depending on the movement, the hair cell can either
hyperpolarize or depolarize. When the movement is towards the tallest <a href="https://en.wikipedia.org/wiki/Stereocilia" title="Stereocilia">stereocilia</a>, the Na<sup>+</sup> cation channels open allowing Na<sup>+</sup> to flow into cell and the resulting depolarization causes the Ca<sup>++</sup>
channels to open, thus releasing its neurotransmitter into the afferent
auditory nerve. There are two types of hair cells: inner and outer. The
inner hair cells are the sensory receptors .
</p><p>Problems with sensory neurons associated with the auditory system leads to disorders such as:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Auditory_processing_disorder" title="Auditory processing disorder">Auditory processing disorder</a>
– Auditory information in the brain is processed in an abnormal way.
Patients with auditory processing disorder can usually gain the
information normally, but their brain cannot process it properly,
leading to hearing disability.</li><li><a href="https://en.wikipedia.org/wiki/Auditory_verbal_agnosia" title="Auditory verbal agnosia">Auditory verbal agnosia</a>
– Comprehension of speech is lost but hearing, speaking, reading, and
writing ability is retained. This is caused by damage to the posterior
superior <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Temporal_lobes" title="Temporal lobes">temporal lobes</a>, again not allowing the brain to process auditory input correctly.</li></ol>
<h4><span class="mw-headline" id="Temperature">Temperature</span></h4><p><a href="https://en.wikipedia.org/wiki/Thermoreceptor" title="Thermoreceptor">Thermoreceptors</a> are sensory receptors, which respond to varying <a href="https://en.wikipedia.org/wiki/Temperature" title="Temperature">temperatures</a>. While the mechanisms through which these receptors operate is unclear, recent discoveries have shown that <a href="https://en.wikipedia.org/wiki/Mammal" title="Mammal">mammals</a> have at least two distinct types of thermoreceptors.
The <a href="https://en.wikipedia.org/wiki/Bulboid_corpuscle" title="Bulboid corpuscle">bulboid corpuscle</a>, is a <a href="https://en.wikipedia.org/wiki/Cutaneous_receptor" title="Cutaneous receptor">cutaneous receptor</a> a <i>cold-sensitive</i> receptor, that detects cold temperatures. The other type is a warmth-sensitive receptor.
</p>
<h4><span class="mw-headline" id="Mechanoreceptors">Mechanoreceptors</span></h4><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Mechanoreceptor" title="Mechanoreceptor">Mechanoreceptor</a></div>
<div class="hatnote navigation-not-searchable" role="note">Further information: <a href="https://en.wikipedia.org/wiki/Mechanosensation" title="Mechanosensation">Mechanosensation</a></div>
<p>Mechanoreceptors are sensory receptors which respond to mechanical forces, such as <a href="https://en.wikipedia.org/wiki/Pressure" title="Pressure">pressure</a> or <a href="https://en.wikipedia.org/wiki/Distortion" title="Distortion">distortion</a>.
</p><p>Specialized sensory receptor cells called mechanoreceptors often
encapsulate afferent fibers to help tune the afferent fibers to the
different types of somatic stimulation. Mechanoreceptors also help lower
thresholds for action potential generation in afferent fibers and thus
make them more likely to fire in the presence of sensory stimulation.
</p><p>Some types of mechanoreceptors fire action potentials when their membranes are physically stretched.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proprioceptors" title="Proprioceptors">Proprioceptors</a>
are another type of mechanoreceptors which literally means "receptors
for self". These receptors provide spatial information about limbs and
other body parts.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nociceptors" title="Nociceptors">Nociceptors</a>
are responsible for processing pain and temperature changes. The
burning pain and irritation experienced after eating a chili pepper (due
to its main ingredient, capsaicin), the cold sensation experienced
after ingesting a chemical such as menthol or icillin, as well as the
common sensation of pain are all a result of neurons with these
receptors.
</p><p>Problems with mechanoreceptors lead to disorders such as:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">Neuropathic pain</a> - a severe pain condition resulting from a damaged sensory nerve </li><li><a href="https://en.wikipedia.org/wiki/Hyperalgesia" title="Hyperalgesia">Hyperalgesia</a> - an increased sensitivity to pain caused by sensory ion channel, <a href="https://en.wikipedia.org/wiki/TRPM8" title="TRPM8">TRPM8</a>,
which is typically responds to temperatures between 23 and 26 degrees,
and provides the cooling sensation associated with menthol and icillin </li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phantom_limb_syndrome" title="Phantom limb syndrome">Phantom limb syndrome</a> - a sensory system disorder where pain or movement is experienced in a limb that does not exist </li></ol>
<h3><span class="mw-headline" id="Internal_receptors">Internal receptors</span></h3><p>Internal receptors that respond to changes inside the body are known as <b>interoceptors</b>.
</p>
<h4><span class="mw-headline" id="Blood">Blood</span></h4><p>The <a href="https://en.wikipedia.org/wiki/Aortic_body" title="Aortic body">aortic bodies</a> and <a href="https://en.wikipedia.org/wiki/Carotid_body" title="Carotid body">carotid bodies</a> contain clusters of <a href="https://en.wikipedia.org/wiki/Glomus_cell" title="Glomus cell">glomus cells</a> – <a href="https://en.wikipedia.org/wiki/Peripheral_chemoreceptors" title="Peripheral chemoreceptors">peripheral chemoreceptors</a> that detect changes in chemical properties in the blood such as <a href="https://en.wikipedia.org/wiki/Oxygen" title="Oxygen">oxygen</a> concentration. These receptors are <a href="https://en.wikipedia.org/wiki/Stimulus_modality#polymodality" title="Stimulus modality">polymodal</a> responding to a number of different stimuli.
</p>
<h4><span class="mw-headline" id="Nociceptors">Nociceptors</span></h4><p>Nociceptors respond to potentially <a href="https://en.wikipedia.org/wiki/Noxious_stimulus" title="Noxious stimulus">damaging stimuli</a> by sending signals to the spinal cord and brain. This process, called <a href="https://en.wikipedia.org/wiki/Nociception" title="Nociception">nociception</a>, usually causes the perception of <a href="https://en.wikipedia.org/wiki/Pain" title="Pain">pain</a>. They are found in internal organs as well as on the surface of the body to "detect and protect".
Nociceptors detect different kinds of noxious stimuli indicating
potential for damage, then initiate neural responses to withdraw from
the stimulus.
</p>
<ol><li><i>Thermal</i> nociceptors are activated by noxious heat or cold at various temperatures.</li><li><i>Mechanical</i> nociceptors respond to excess pressure or mechanical deformation, such as a <a href="https://en.wikipedia.org/wiki/Pinch_(action)" title="Pinch (action)">pinch</a>.</li><li><i>Chemical</i> nociceptors respond to a wide variety of chemicals,
some of which signal a response. They are involved in the detection of
some spices in food, such as the pungent ingredients in <a href="https://en.wikipedia.org/wiki/Brassicaceae" title="Brassicaceae">Brassica</a> and <a href="https://en.wikipedia.org/wiki/Allium" title="Allium">Allium</a> plants, which target the sensory neural receptor to produce acute pain and subsequent pain hypersensitivity.</li></ol>
<h2><span class="mw-headline" id="Connection_with_the_central_nervous_system">Connection with the central nervous system</span></h2><p>Information coming from the sensory neurons in the head enters the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> (CNS) through <a href="https://en.wikipedia.org/wiki/Cranial_nerves" title="Cranial nerves">cranial nerves</a>. Information from the sensory neurons below the head enters the spinal cord and passes towards the brain through the 31 <a href="https://en.wikipedia.org/wiki/Spinal_nerve" title="Spinal nerve">spinal nerves</a>.
The sensory information traveling through the spinal cord follows
well-defined pathways. The nervous system codes the differences among
the sensations in terms of which cells are active.
</p>
<h2><span class="mw-headline" id="Classification">Classification</span></h2><h3><span class="mw-headline" id="Adequate_stimulus">Adequate stimulus</span></h3><p>A sensory receptor's <a href="https://en.wikipedia.org/wiki/Adequate_stimulus" title="Adequate stimulus">adequate stimulus</a> is the <a href="https://en.wikipedia.org/wiki/Stimulus_modality" title="Stimulus modality">stimulus modality</a> for which it possesses the adequate <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sensory_transduction" title="Sensory transduction">sensory transduction</a> apparatus. Adequate stimulus can be used to classify sensory receptors:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Baroreceptor" title="Baroreceptor">Baroreceptors</a> respond to pressure in blood vessels</li><li><a href="https://en.wikipedia.org/wiki/Chemoreceptor" title="Chemoreceptor">Chemoreceptors</a> respond to chemical stimuli</li><li><a class="new" href="https://en.wikipedia.org/w/index.php?title=Electromagnetic_radiation_receptors&action=edit&redlink=1" title="Electromagnetic radiation receptors (page does not exist)">Electromagnetic radiation receptors</a> respond to <a href="https://en.wikipedia.org/wiki/Electromagnetic_radiation" title="Electromagnetic radiation">electromagnetic radiation</a>
<ol><li><a href="https://en.wikipedia.org/wiki/Infrared_sensing_in_snakes" title="Infrared sensing in snakes">Infrared receptors</a> respond to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Infrared_radiation" title="Infrared radiation">infrared radiation</a></li><li><a href="https://en.wikipedia.org/wiki/Photoreceptor_cell" title="Photoreceptor cell">Photoreceptors</a> respond to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Visible_light" title="Visible light">visible light</a></li><li><a class="new" href="https://en.wikipedia.org/w/index.php?title=Ultraviolet_receptor&action=edit&redlink=1" title="Ultraviolet receptor (page does not exist)">Ultraviolet receptors</a> respond to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ultraviolet_radiation" title="Ultraviolet radiation">ultraviolet radiation</a></li></ol></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electroreceptor" title="Electroreceptor">Electroreceptors</a> respond to <a href="https://en.wikipedia.org/wiki/Electric_field" title="Electric field">electric fields</a>
<ol><li><a href="https://en.wikipedia.org/wiki/Ampullae_of_Lorenzini" title="Ampullae of Lorenzini">Ampullae of Lorenzini</a> respond to electric fields, salinity, and to temperature, but function primarily as electroreceptors</li></ol></li><li><a class="new" href="https://en.wikipedia.org/w/index.php?title=Hydroreceptor&action=edit&redlink=1" title="Hydroreceptor (page does not exist)">Hydroreceptors</a> respond to changes in humidity</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Magnetoception" title="Magnetoception">Magnetoreceptors</a> respond to <a href="https://en.wikipedia.org/wiki/Magnetic_field" title="Magnetic field">magnetic fields</a></li><li><a href="https://en.wikipedia.org/wiki/Mechanoreceptor" title="Mechanoreceptor">Mechanoreceptors</a> respond to <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mechanical_stress" title="Mechanical stress">mechanical stress</a> or <a class="new" href="https://en.wikipedia.org/w/index.php?title=Mechanical_strain&action=edit&redlink=1" title="Mechanical strain (page does not exist)">mechanical strain</a></li><li><a href="https://en.wikipedia.org/wiki/Nociceptor" title="Nociceptor">Nociceptors</a> respond to damage, or threat of damage, to body tissues, leading (often but not always) to pain perception</li><li><a href="https://en.wikipedia.org/wiki/Osmoreceptor" title="Osmoreceptor">Osmoreceptors</a> respond to the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Osmolarity" title="Osmolarity">osmolarity</a> of fluids (such as in the hypothalamus)</li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proprioceptor" title="Proprioceptor">Proprioceptors</a> provide the sense of position</li><li><a href="https://en.wikipedia.org/wiki/Thermoreceptor" title="Thermoreceptor">Thermoreceptors</a> respond to temperature, either heat, cold or both</li></ol>
<h3><span class="mw-headline" id="Location">Location</span></h3><p>Sensory receptors can be classified by location:
</p>
<ol><li><a href="https://en.wikipedia.org/wiki/Cutaneous_receptor" title="Cutaneous receptor">Cutaneous receptors</a> are sensory receptors found in the <a href="https://en.wikipedia.org/wiki/Dermis" title="Dermis">dermis</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epidermis_(skin)" title="Epidermis (skin)">epidermis</a>.</li><li><a href="https://en.wikipedia.org/wiki/Muscle_spindle" title="Muscle spindle">Muscle spindles</a> contain mechanoreceptors that detect stretch in muscles.</li></ol>
<h3><span class="mw-headline" id="Morphology">Morphology</span></h3><p>Somatic sensory receptors near the surface of the skin can usually be divided into two groups based on morphology:
</p>
<ol><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Free_nerve_endings" title="Free nerve endings">Free nerve endings</a> characterize the <a href="https://en.wikipedia.org/wiki/Nociceptor" title="Nociceptor">nociceptors</a> and <a href="https://en.wikipedia.org/wiki/Thermoreceptor" title="Thermoreceptor">thermoreceptors</a> and are called thus because the terminal branches of the neuron are unmyelinated and spread throughout the <a href="https://en.wikipedia.org/wiki/Dermis" title="Dermis">dermis</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epidermis_(skin)" title="Epidermis (skin)">epidermis</a>.</li><li><a class="new" href="https://en.wikipedia.org/w/index.php?title=Encapsulated_receptor&action=edit&redlink=1" title="Encapsulated receptor (page does not exist)">Encapsulated receptors</a> consist of the remaining types of cutaneous receptors. Encapsulation exists for specialized functioning.</li></ol>
<h3><span class="mw-headline" id="Rate_of_adaptation">Rate of adaptation</span></h3><ol><li>A <a href="https://en.wikipedia.org/wiki/Tonic_(physiology)#Tonic_sensory_receptors" title="Tonic (physiology)">tonic receptor</a> is a sensory receptor that adapts slowly to a stimulus and continues to produce <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">action potentials</a> over the duration of the stimulus.
In this way it conveys information about the duration of the stimulus.
Some tonic receptors are permanently active and indicate a background
level. Examples of such tonic receptors are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pain_receptors" title="Pain receptors">pain receptors</a>, <a href="https://en.wikipedia.org/wiki/Joint_capsule" title="Joint capsule">joint capsule</a>, and <a href="https://en.wikipedia.org/wiki/Muscle_spindle" title="Muscle spindle">muscle spindle</a>.</li><li>A <b>phasic receptor</b> is a sensory receptor that adapts rapidly to a stimulus. The response of the cell diminishes very quickly and then stops. It does not provide information on the duration of the stimulus; instead some of them convey information on rapid changes in stimulus intensity and rate. An example of a phasic receptor is the <a href="https://en.wikipedia.org/wiki/Pacinian_corpuscle" title="Pacinian corpuscle">Pacinian corpuscle</a>.</li></ol>
<h2><span class="mw-headline" id="Drugs">Drugs</span></h2><p>There are many drugs currently on the market that are used to manipulate or treat sensory system disorders. For instance, <a href="https://en.wikipedia.org/wiki/Gabapentin" title="Gabapentin">gabapentin</a>
is a drug that is used to treat neuropathic pain by interacting with
one of the voltage-dependent calcium channels present on non-receptive
neurons.
Some drugs may be used to combat other health problems, but can have
unintended side effects on the sensory system. Dysfunction in the hair
cell mechanotransduction complex, along with the potential loss of
specialized ribbon synapses, can lead to hair cell death, often caused
by ototoxic drugs like aminoglycoside antibiotics poisoning the cochlea. Through the use of these toxins, the K+ pumping hair cells cease their function. Thus, the energy generated by the <a href="https://en.wikipedia.org/wiki/Endocochlear_potential" title="Endocochlear potential">endocochlear potential</a> which drives the auditory signal transduction process is lost, leading to hearing loss.
</p>
<h2><span class="mw-headline" id="Neuroplasticity">Neuroplasticity</span></h2><p>Ever since scientists observed <a href="https://en.wikipedia.org/wiki/Cortical_remapping" title="Cortical remapping">cortical remapping</a> in the brain of <a href="https://en.wikipedia.org/wiki/Edward_Taub" title="Edward Taub">Taub's</a> <a href="https://en.wikipedia.org/wiki/Silver_Spring_monkeys" title="Silver Spring monkeys">Silver Spring monkeys</a>, there has been a large amount of research into <a href="https://en.wikipedia.org/wiki/Neuroplasticity" title="Neuroplasticity">sensory system plasticity</a>. Huge strides have been made in treating disorders of the sensory system. Techniques such as <a href="https://en.wikipedia.org/wiki/Constraint-induced_movement_therapy" title="Constraint-induced movement therapy">constraint-induced movement therapy</a>
developed by Taub have helped patients with paralyzed limbs regain use
of their limbs by forcing the sensory system to grow new <a href="https://en.wikipedia.org/wiki/Neural_pathway" title="Neural pathway">neural pathways</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phantom_limb_syndrome" title="Phantom limb syndrome">Phantom limb syndrome</a>
is a sensory system disorder in which amputees perceive that their
amputated limb still exists and they may still be experiencing pain in
it. The <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mirror_box" title="Mirror box">mirror box</a> developed by V.S. Ramachandran, has enabled patients with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phantom_limb_syndrome" title="Phantom limb syndrome">phantom limb syndrome</a>
to relieve the perception of paralyzed or painful phantom limbs. It is a
simple device which uses a mirror in a box to create an illusion in
which the sensory system perceives that it is seeing two hands instead
of one, therefore allowing the sensory system to control the "phantom
limb". By doing this, the sensory system can gradually get acclimated to
the amputated limb, and thus alleviate this syndrome.
</p>
<h2><span class="mw-headline" id="Other_animals">Other animals</span></h2><a href="https://en.wikipedia.org/wiki/Hydrodynamic_reception" title="Hydrodynamic reception">Hydrodynamic reception</a> is a form of mechanoreception used in a range of animal species.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-15226322437243691232024-03-27T09:24:00.001-04:002024-03-27T09:24:05.513-04:00Major prion protein<div class="vector-column-end">
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</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Major_prion_protein">https://en.wikipedia.org/wiki/Major_prion_protein</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th colspan="4" style="font-size: 125%; font-weight: bold; text-align: center;"></th></tr><tr><td colspan="4" style="text-align: center;"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:PRNP_.png"><img class="mw-file-element" data-file-height="2100" data-file-width="2100" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/84/PRNP_.png/250px-PRNP_.png" width="400" /></a></span></td></tr><tr><td colspan="4" style="background-color: #eeeeee; text-align: center;"></td></tr></tbody></table></div></div></div>
<p><b>Major prion protein</b> (<b>PrP</b>) is encoded in the human body by the <i>PRNP</i> <a href="https://en.wikipedia.org/wiki/Gene" title="Gene">gene</a> also known as <b>CD230</b> (<a href="https://en.wikipedia.org/wiki/Cluster_of_differentiation" title="Cluster of differentiation">cluster of differentiation</a> 230). Expression of the <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> is most predominant in the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a> but occurs in many other tissues throughout the body.
</p><p>The protein can exist in multiple <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Isoforms" title="Isoforms">isoforms</a>: the normal <b>PrP<sup>C</sup></b> form, and the <a href="https://en.wikipedia.org/wiki/Protease" title="Protease">protease</a>-resistant form designated <b>PrP<sup>Res</sup></b> such as the disease-causing <b>PrP<sup>Sc</sup></b> (scrapie) and an isoform located in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria">mitochondria</a>. The <a href="https://en.wikipedia.org/wiki/Protein_folding#Protein_misfolding_and_neurodegenerative_disease" title="Protein folding">misfolded</a> version PrP<sup>Sc</sup> is associated with a variety of <a href="https://en.wikipedia.org/wiki/Cognitive_disorder" title="Cognitive disorder">cognitive disorders</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegeneration" title="Neurodegeneration">neurodegenerative</a> diseases such as in animals: <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ovine" title="Ovine">ovine</a> <a href="https://en.wikipedia.org/wiki/Scrapie" title="Scrapie">scrapie</a>, <a href="https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy" title="Bovine spongiform encephalopathy">bovine spongiform encephalopathy</a> (BSE, mad cow disease), <a href="https://en.wikipedia.org/wiki/Feline_spongiform_encephalopathy" title="Feline spongiform encephalopathy">feline spongiform encephalopathy</a>, <a href="https://en.wikipedia.org/wiki/Transmissible_mink_encephalopathy" title="Transmissible mink encephalopathy">transmissible mink encephalopathy</a> (TME), <a href="https://en.wikipedia.org/wiki/Exotic_ungulate_encephalopathy" title="Exotic ungulate encephalopathy">exotic ungulate encephalopathy</a>, <a href="https://en.wikipedia.org/wiki/Chronic_wasting_disease" title="Chronic wasting disease">chronic wasting disease</a> (CWD) which affects <a href="https://en.wikipedia.org/wiki/Deer" title="Deer">deer</a>; and in humans: <a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">Creutzfeldt–Jakob disease</a> (CJD), <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatal_familial_insomnia" title="Fatal familial insomnia">fatal familial insomnia</a> (FFI), <a href="https://en.wikipedia.org/wiki/Gerstmann%E2%80%93Str%C3%A4ussler%E2%80%93Scheinker_syndrome" title="Gerstmann–Sträussler–Scheinker syndrome">Gerstmann–Sträussler–Scheinker syndrome</a> (GSS), <a href="https://en.wikipedia.org/wiki/Kuru_(disease)" title="Kuru (disease)">kuru</a>, and <a href="https://en.wikipedia.org/wiki/Variant_Creutzfeldt%E2%80%93Jakob_disease" title="Variant Creutzfeldt–Jakob disease">variant Creutzfeldt–Jakob disease</a>
(vCJD). Similarities exist between kuru, thought to be due to human
ingestion of diseased individuals, and vCJD, thought to be due to human
ingestion of BSE-tainted cattle products.
</p>
<h2><span class="mw-headline" id="Gene">Gene</span></h2><figure class="mw-halign-left"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Location_of_PRNP-gene_in_chromosome_20.svg"><img class="mw-file-element" data-file-height="365" data-file-width="275" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/70/Location_of_PRNP-gene_in_chromosome_20.svg/150px-Location_of_PRNP-gene_in_chromosome_20.svg.png" width="302" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Chromosome_20" title="Chromosome 20">Chromosome 20</a></figcaption></figure>
<p>The human <i>PRNP</i> gene is located on the short (p) arm of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chromosome_20_(human)" title="Chromosome 20 (human)">chromosome 20</a> between the end (terminus) of the arm and position 13, from <a href="https://en.wikipedia.org/wiki/Base_pair" title="Base pair">base pair</a> 4,615,068 to base pair 4,630,233.
</p>
<h2><span class="mw-headline" id="Structure">Structure</span></h2><p>PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice. Comparison between primates is especially similar, ranging from 92.9-99.6% similarity in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Peptide_sequence" title="Peptide sequence">amino acid sequences</a>. The human protein structure consists of a globular domain with three <a href="https://en.wikipedia.org/wiki/Alpha_helix" title="Alpha helix">α-helices</a> and a two-strand <a href="https://en.wikipedia.org/wiki/Antiparallel_(biochemistry)" title="Antiparallel (biochemistry)">antiparallel</a> <a href="https://en.wikipedia.org/wiki/Beta_sheet" title="Beta sheet">β-sheet</a>, an <a href="https://en.wikipedia.org/wiki/Amine" title="Amine">NH<sub>2</sub></a>-terminal tail, and a short <a href="https://en.wikipedia.org/wiki/Carboxylic_acid" title="Carboxylic acid">COOH</a>-terminal tail. A <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glycophosphatidylinositol" title="Glycophosphatidylinositol">glycophosphatidylinositol</a> (GPI) membrane anchor at the COOH-terminal tethers PrP to <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">cell membranes</a>,
and this proves to be integral to the transmission of conformational
change; secreted PrP lacking the anchor component is unaffected by the
infectious isoform.
</p><p>The primary sequence of PrP is 253 <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acids</a> long before <a href="https://en.wikipedia.org/wiki/Post-translational_modification" title="Post-translational modification">post-translational modification</a>. <a href="https://en.wikipedia.org/wiki/Signal_peptide" title="Signal peptide">Signal sequences</a> in the <a href="https://en.wikipedia.org/wiki/Amine" title="Amine">amino</a>- and <a href="https://en.wikipedia.org/wiki/Carboxylic_acid" title="Carboxylic acid">carboxy</a>- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and <a href="https://en.wikipedia.org/wiki/Golden_hamster" title="Golden hamster">golden hamster</a> PrP, two <a href="https://en.wikipedia.org/wiki/Glycosylation" title="Glycosylation">glycosylated</a> sites exist on helices 2 and 3 at <a href="https://en.wikipedia.org/wiki/Asparagine" title="Asparagine">Asn</a>181 and Asn197. <a href="https://en.wikipedia.org/wiki/Murinae" title="Murinae">Murine</a> PrP has glycosylation sites as Asn180 and Asn196. A <a href="https://en.wikipedia.org/wiki/Disulfide" title="Disulfide">disulfide</a> bond exists between <a href="https://en.wikipedia.org/wiki/Cysteine" title="Cysteine">Cys</a>179 of the second helix and Cys214 of the third helix (human PrP<sup>C</sup> numbering).
</p><p>PrP <a href="https://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA">messenger RNA</a> contains a <a href="https://en.wikipedia.org/wiki/Pseudoknot" title="Pseudoknot">pseudoknot</a> structure (<a href="https://en.wikipedia.org/wiki/Prion_pseudoknot" title="Prion pseudoknot">prion pseudoknot</a>), which is thought to be involved in regulation of PrP <a href="https://en.wikipedia.org/wiki/Protein_biosynthesis#Translation" title="Protein biosynthesis">protein translation</a>.
</p>
<h3><span class="mw-headline" id="Ligand-binding">Ligand-binding</span></h3><p>The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive <a href="https://en.wikipedia.org/wiki/Ligand" title="Ligand">ligand</a>-protein,
but, so far, no such compound has been identified. However, a large
body of research has developed on candidates and their interaction with
the PrP<sup>C</sup>.
</p><p><a href="https://en.wikipedia.org/wiki/Copper" title="Copper">Copper</a>, <a href="https://en.wikipedia.org/wiki/Zinc" title="Zinc">zinc</a>, <a href="https://en.wikipedia.org/wiki/Manganese" title="Manganese">manganese</a>, and <a href="https://en.wikipedia.org/wiki/Nickel" title="Nickel">nickel</a> are confirmed PrP ligands that bind to its octarepeat region. Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to <a href="https://en.wikipedia.org/wiki/Oxidative_stress" title="Oxidative stress">oxidative stress</a> arising from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Heavy_metal_toxicity" title="Heavy metal toxicity">heavy metal toxicity</a>.
</p>
<h3><span id="PrPC_.28normal_cellular.29_isoform"></span><span class="mw-headline" id="PrPC_(normal_cellular)_isoform">PrP<sup>C</sup> (normal cellular) isoform</span></h3><p>Although the precise function of PrP is not yet known, it is possibly involved in the transport of <a href="https://en.wikipedia.org/wiki/Ion" title="Ion">ionic</a>
copper to cells from the surrounding environment. Researchers have also
proposed roles for PrP in cell signaling or in the formation of <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapses</a>. PrP<sup>C</sup> attaches to the outer surface of the <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">cell membrane</a> by a <a href="https://en.wikipedia.org/wiki/Glycosylphosphatidylinositol" title="Glycosylphosphatidylinositol">glycosylphosphatidylinositol</a> anchor at its <a class="mw-redirect" href="https://en.wikipedia.org/wiki/C-terminal" title="C-terminal">C-terminal</a> <a href="https://en.wikipedia.org/wiki/Serine" title="Serine">Ser</a>231.
</p><p><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Prion_protein" title="Prion protein">Prion protein</a> contains five <a href="https://en.wikipedia.org/wiki/Peptide" title="Peptide">octapeptide</a> repeats with sequence PHGGGWGQ (though the first repeat has the slightly-modified, <a href="https://en.wikipedia.org/wiki/Histidine" title="Histidine">histidine</a>-deficient sequence PQGGGGWGQ). This is thought to generate a copper-<a href="https://en.wikipedia.org/wiki/Binding_domain" title="Binding domain">binding domain</a> via nitrogen atoms in the histidine <a href="https://en.wikipedia.org/wiki/Imidazole" title="Imidazole">imidazole</a> <a href="https://en.wikipedia.org/wiki/Side_chain" title="Side chain">side-chains</a> and deprotonated <a href="https://en.wikipedia.org/wiki/Amide" title="Amide">amide</a> nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, <a href="https://en.wikipedia.org/wiki/PH" title="PH">pH</a>-dependent. <a href="https://en.wikipedia.org/wiki/Nuclear_magnetic_resonance" title="Nuclear magnetic resonance">NMR</a> shows copper binding results in a <a href="https://en.wikipedia.org/wiki/Protein_structure" title="Protein structure">conformational</a> change at the <a href="https://en.wikipedia.org/wiki/N-terminus" title="N-terminus">N-terminus</a>.
</p>
<h3><span id="PrPSc_.28scrapie.29_isoform"></span><span class="mw-headline" id="PrPSc_(scrapie)_isoform">PrP<sup>Sc</sup> (scrapie) isoform</span></h3><p>PrP<sup>Sc</sup> is a conformational isoform of PrP<sup>C</sup>, but this orientation tends to accumulate in compact, <a href="https://en.wikipedia.org/wiki/Protease" title="Protease">protease</a>-resistant aggregates within neural tissue. The abnormal PrP<sup>Sc</sup> isoform has a different <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Secondary_structure" title="Secondary structure">secondary</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tertiary_structure" title="Tertiary structure">tertiary structure</a> from PrP<sup>C</sup>, but identical primary sequence. Whereas PrP<sup>C</sup> has largely alpha helical and disordered domains, PrP<sup>Sc</sup>
has no alpha helix and an amyloid fibril core composed of a stack of
PrP molecules glued together by parallel in-register intermolecular beta
sheets. This refolding renders the PrP<sup>Sc</sup> isoform extremely resistant to <a href="https://en.wikipedia.org/wiki/Proteolysis" title="Proteolysis">proteolysis</a>.
</p><p>The propagation of PrP<sup>Sc</sup> is a topic of great interest, as its accumulation is a pathological cause of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegeneration" title="Neurodegeneration">neurodegeneration</a>.
Based on the progressive nature of spongiform encephalopathies, the
predominant hypothesis posits that the change from normal PrP<sup>C</sup> is caused by the presence and interaction with PrP<sup>Sc</sup>. Strong support for this is taken from studies in which <i>PRNP</i>-knockout mice are resistant to the introduction of PrP<sup>Sc</sup>.
Despite widespread acceptance of the conformation conversion
hypothesis, some studies mitigate claims for a direct link between PrP<sup>Sc</sup> and <a href="https://en.wikipedia.org/wiki/Cytotoxicity" title="Cytotoxicity">cytotoxicity</a>.
</p><p><a href="https://en.wikipedia.org/wiki/Polymorphism_(biology)" title="Polymorphism (biology)">Polymorphisms</a> at sites 136, 154, and 171 are associated with varying susceptibility to ovine <a href="https://en.wikipedia.org/wiki/Scrapie" title="Scrapie">scrapie</a>.
(These ovine sites correspond to human sites 133, 151, and 168.)
Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with
increased susceptibility, whereas PrP-ARR is associated with resistance.
The National Scrapie Plan of the UK aims to breed out these scrapie
polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie, so this may prove unfruitful.
</p>
<h2><span class="mw-headline" id="Function">Function</span></h2><h3><span class="mw-headline" id="Nervous_system">Nervous system</span></h3><p>The
strong association to neurodegenerative diseases raises many questions
of the function of PrP in the brain. A common approach is using
PrP-knockout and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transgenic" title="Transgenic">transgenic</a> mice to investigate deficiencies and differences.
Initial attempts produced two strains of PrP-null mice that show no
physiological or developmental differences when subjected to an array of
tests. However, more recent strains have shown significant cognitive
abnormalities.
</p><p>As the null mice age, a marked loss of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Purkinje_cells" title="Purkinje cells">Purkinje cells</a> in the <a href="https://en.wikipedia.org/wiki/Cerebellum" title="Cerebellum">cerebellum</a>
results in decreased motor coordination. However, this effect is not a
direct result of PrP's absence, and rather arises from increased <a href="https://en.wikipedia.org/wiki/PRND" title="PRND">Doppel</a> gene expression. Other observed differences include reduced stress response and increased exploration of novel environments.
</p><p><a href="https://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm">Circadian rhythm</a> is altered in null mice. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatal_familial_insomnia" title="Fatal familial insomnia">Fatal familial insomnia</a> is thought to be the result of a point mutation in <i>PRNP</i> at codon 178, which corroborates PrP's involvement in sleep-wake cycles. In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.
</p>
<h4><span class="mw-headline" id="Memory">Memory</span></h4><p>While null mice exhibit normal learning ability and <a href="https://en.wikipedia.org/wiki/Short-term_memory" title="Short-term memory">short-term memory</a>, <a href="https://en.wikipedia.org/wiki/Long-term_memory" title="Long-term memory">long-term memory</a> consolidation deficits have been demonstrated. As with <a href="https://en.wikipedia.org/wiki/Ataxia" title="Ataxia">ataxia</a>, this is attributable to Doppel gene expression. However, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spatial_learning" title="Spatial learning">spatial learning</a>,
a predominantly hippocampal-function, is decreased in the null mice and
can be recovered with the reinstatement of PrP in neurons; this
indicates that loss of PrP function is the cause. The interaction of hippocampal PrP with <a href="https://en.wikipedia.org/wiki/Laminin" title="Laminin">laminin</a> (LN) is pivotal in memory processing and is likely modulated by the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Kinases" title="Kinases">kinases</a> PKA and ERK1/2.
</p><p>Further support for PrP's role in memory formation is derived
from several population studies. A test of healthy young humans showed
increased long-term memory ability associated with an MM or MV genotype
when compared to VV. <a href="https://en.wikipedia.org/wiki/Down_syndrome" title="Down syndrome">Down syndrome</a> patients with a single <a href="https://en.wikipedia.org/wiki/Valine" title="Valine">valine</a> substitution have been linked to earlier cognitive decline. Several <a href="https://en.wikipedia.org/wiki/Polymorphism_(biology)" title="Polymorphism (biology)">polymorphisms</a> in <i>PRNP</i> have been linked with cognitive impairment in the elderly as well as earlier cognitive decline. All of these studies investigated differences in codon 129, indicating
its importance in the overall functionality of PrP, in particular with
regard to memory.
</p>
<h4><span class="mw-headline" id="Neurons_and_synapses">Neurons and synapses</span></h4><p>PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion.
Considering this and PrP's suite of behavioral influences, the neural
cell functions and interactions are of particular interest. Based on the
copper ligand, one proposed function casts PrP as a copper buffer for
the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Synaptic_cleft" title="Synaptic cleft">synaptic cleft</a>. In this role, the protein could serve as either a copper <a href="https://en.wikipedia.org/wiki/Homeostasis" title="Homeostasis">homeostasis</a> mechanism, a calcium modulator, or a sensor for copper or oxidative stress. Loss of PrP function has been linked to <a href="https://en.wikipedia.org/wiki/Long-term_potentiation" title="Long-term potentiation">long-term potentiation</a> (LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the <a href="https://en.wikipedia.org/wiki/Hippocampus" title="Hippocampus">hippocampus</a>.
</p><p>Some research indicates PrP involvement in neuronal development, differentiation, and <a href="https://en.wikipedia.org/wiki/Neurite" title="Neurite">neurite</a>
outgrowth. The PrP-activated signal transduction pathway is associated
with axon and dendritic outgrowth with a series of kinases.
</p>
<h3><span class="mw-headline" id="Immune_system">Immune system</span></h3><p>Though
most attention is focused on PrP's presence in the nervous system, it
is also abundant in immune system tissue. PrP immune cells include
hematopoietic stem cells, mature lymphoid and myeloid compartments, and
certain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Lymphocytes" title="Lymphocytes">lymphocytes</a>; also, it has been detected in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Natural_killer_cells" title="Natural killer cells">natural killer cells</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Platelets" title="Platelets">platelets</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Monocytes" title="Monocytes">monocytes</a>. <a href="https://en.wikipedia.org/wiki/T_cell" title="T cell">T cell</a> activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immunoresponse to <a href="https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy" title="Transmissible spongiform encephalopathy">transmissible spongiform encephalopathies</a> (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrP<sup>Sc</sup>.
</p>
<h3><span id="Muscles.2C_liver.2C_and_pituitary"></span><span class="mw-headline" id="Muscles,_liver,_and_pituitary">Muscles, liver, and pituitary</span></h3><p>PrP-null
mice provide clues to a role in muscular physiology when subjected to a
forced swimming test, which showed reduced locomotor activity. Aging
mice with an overexpression of PRNP showed significant degradation of
muscle tissue.
</p><p>Though present, very low levels of PrP exist in the liver and
could be associated with liver fibrosis. Presence in the pituitary has
been shown to affect neuroendocrine function in amphibians, but little
is known concerning mammalian pituitary PrP.
</p>
<h3><span class="mw-headline" id="Cellular">Cellular</span></h3><p>Varying expression of PrP through the <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a>
has led to speculation on involvement in development. A wide range of
studies has been conducted investigating the role in cell proliferation,
differentiation, death, and survival. Engagement of PrP has been linked to activation of <a href="https://en.wikipedia.org/wiki/Signal_transduction" title="Signal transduction">signal transduction</a>.
</p><p>Modulation of signal transduction pathways has been demonstrated
in cross-linking with antibodies and ligand-binding (hop/STI1 or
copper).
Given the diversity of interactions, effects, and distribution, PrP has
been proposed as dynamic surface protein functioning in signaling
pathways. Specific sites along the protein bind other proteins,
biomolecules, and metals. These interfaces allow specific sets of cells
to communicate based on level of expression and the surrounding
microenvironment. The anchoring on a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glycophosphatidylinositol" title="Glycophosphatidylinositol">GPI raft</a> in the <a href="https://en.wikipedia.org/wiki/Lipid_bilayer" title="Lipid bilayer">lipid bilayer</a> supports claims of an <a href="https://en.wikipedia.org/wiki/Extracellular_matrix" title="Extracellular matrix">extracellular scaffolding</a> function.
</p>
<h2><span class="mw-headline" id="Diseases_caused_by_PrP_misfolding">Diseases caused by PrP misfolding</span></h2><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy" title="Transmissible spongiform encephalopathy">Transmissible spongiform encephalopathy</a></div>
<p>More than 20 mutations in the <i>PRNP</i> gene have been identified in people with inherited <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Prion_disease" title="Prion disease">prion diseases</a>, which include the following:
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">Creutzfeldt–Jakob disease</a> – <a href="https://en.wikipedia.org/wiki/Glutamic_acid" title="Glutamic acid">glutamic acid</a>-200 is replaced by <a href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">lysine</a> while <a href="https://en.wikipedia.org/wiki/Valine" title="Valine">valine</a> is present at amino acid 129</li><li><a href="https://en.wikipedia.org/wiki/Gerstmann%E2%80%93Str%C3%A4ussler%E2%80%93Scheinker_syndrome" title="Gerstmann–Sträussler–Scheinker syndrome">Gerstmann–Sträussler–Scheinker syndrome</a> – usually a change in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codon</a> 102 from <a href="https://en.wikipedia.org/wiki/Proline" title="Proline">proline</a> to <a href="https://en.wikipedia.org/wiki/Leucine" title="Leucine">leucine</a></li><li><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fatal_familial_insomnia" title="Fatal familial insomnia">fatal familial insomnia</a> – <a href="https://en.wikipedia.org/wiki/Aspartic_acid" title="Aspartic acid">aspartic acid</a>-178 is replaced by <a href="https://en.wikipedia.org/wiki/Asparagine" title="Asparagine">asparagine</a> while <a href="https://en.wikipedia.org/wiki/Methionine" title="Methionine">methionine</a> is present at amino acid 129</li></ul>
<p>The conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> conformation is
the mechanism of transmission of fatal, neurodegenerative transmissible
spongiform encephalopathies (TSE). This can arise from genetic factors,
infection from external source, or spontaneously for reasons unknown.
Accumulation of PrP<sup>Sc</sup> corresponds with progression of neurodegeneration and is the proposed cause. Some <i>PRNP</i> mutations lead to a change in single <a href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acids</a>
(the building-blocks of proteins) in the prion protein. Others insert
additional amino acids into the protein or cause an abnormally short
protein to be made. These mutations cause the cell to make prion
proteins with an abnormal structure. The abnormal protein PrP<sup>Sc</sup> accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases.
</p><p>Several other changes in the <i>PRNP</i> gene (called
polymorphisms) do not cause prion diseases but may affect a person's
risk of developing these diseases or alter the course of the disorders.
An <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">allele</a> that codes for a PRNP variant, G127V, provides resistance to <a href="https://en.wikipedia.org/wiki/Kuru_(disease)" title="Kuru (disease)">kuru</a>.
</p><p>In addition, some prion diseases can be transmitted from external sources of PrP<sup>Sc</sup>.
</p>
<ul><li><a href="https://en.wikipedia.org/wiki/Scrapie" title="Scrapie">Scrapie</a> – fatal neurodegenerative disease in sheep, not transmissible to humans</li><li><a href="https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy" title="Bovine spongiform encephalopathy">Bovine spongiform encephalopathy</a>
(mad-cow disease) – fatal neurodegenerative disease in cows, which can
be transmitted to humans by ingestion of brain, spinal, or digestive
tract tissue of an infected cow</li><li><a href="https://en.wikipedia.org/wiki/Kuru_(disease)" title="Kuru (disease)">Kuru</a>
– TSE in humans, transmitted via funerary cannibalism. Generally,
affected family members were given, by tradition, parts of the central
nervous system according to ritual when consuming deceased family
members.</li></ul>
<h3><span id="Alzheimer.27s_disease"></span><span class="mw-headline" id="Alzheimer's_disease">Alzheimer's disease</span></h3><p>PrP<sup>C</sup> protein is one of several cellular receptors of soluble <a href="https://en.wikipedia.org/wiki/Amyloid_beta" title="Amyloid beta">amyloid beta</a> (Aβ) oligomers, which are canonically implicated in causing <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a>. These <a href="https://en.wikipedia.org/wiki/Oligomer" title="Oligomer">oligomers</a> are composed of smaller Aβ plaques, and are the most damaging to the integrity of a <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuron</a>. The precise mechanism of soluble Aβ oligomers directly inducing <a href="https://en.wikipedia.org/wiki/Neurotoxicity" title="Neurotoxicity">neurotoxicity</a> is unknown, and experimental deletion of <i>PRNP</i> in animals has yielded several conflicting findings. When Aβ oligomers were injected into the <a href="https://en.wikipedia.org/wiki/Ventricular_system" title="Ventricular system">cerebral ventricles</a> of a mouse model of Alzheimer's, <i>PRNP</i> deletion did not offer protection, only anti-PrP<sup>C</sup> antibodies prevented long-term memory and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Spatial_learning" title="Spatial learning">spatial learning</a> deficits. This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegeneration" title="Neurodegeneration">neurodegeneration</a> or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the <a href="https://en.wikipedia.org/wiki/Hippocampus" title="Hippocampus">hippocampus</a>, <i>PRNP</i>-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of <a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" title="Synaptic plasticity">synaptic plasticity</a>. It was further found that Aβ-oligomers bind to PrP<sup>C</sup> at the <a href="https://en.wikipedia.org/wiki/Postsynaptic_density" title="Postsynaptic density">postsynaptic density</a>, indirectly overactivating the <a href="https://en.wikipedia.org/wiki/NMDA_receptor" title="NMDA receptor">NMDA receptor</a> via the <a href="https://en.wikipedia.org/wiki/FYN" title="FYN">Fyn</a> enzyme, resulting in <a href="https://en.wikipedia.org/wiki/Excitotoxicity" title="Excitotoxicity">excitotoxicity</a>. Soluble Aβ oligomers also bind to PrP<sup>C</sup> at the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dendritic_spines" title="Dendritic spines">dendritic spines</a>, forming a complex with Fyn and excessively activating <a href="https://en.wikipedia.org/wiki/Tau_protein" title="Tau protein">tau</a>, another protein implicated in Alzheimer's. As the gene <a href="https://en.wikipedia.org/wiki/FYN" title="FYN">FYN</a> codes for the enzyme Fyn, FYN-knockout mice display neither <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Excitotoxic" title="Excitotoxic">excitotoxic</a> events nor <a href="https://en.wikipedia.org/wiki/Dendritic_spine" title="Dendritic spine">dendritic spine shrinkage</a> when injected with Aβ oligomers. In mammals, the full functional significance of PRNP remains unclear, as <i>PRNP</i> deletion has been prophylactically implemented by the cattle industry without apparent harm. In mice, this same deletion <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Phenotypically" title="Phenotypically">phenotypically</a> varies between Alzheimer's mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Epileptic" title="Epileptic">epileptic</a> activity, contributing to conflicting results when examining Alzheimer's survival rates. Of note, the deletion of <i>PRNP</i> in both APPswe and SEN1dE9, two other <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transgenic" title="Transgenic">transgenic</a> models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.
Taken collectively, recent evidence suggests PRNP may be important for
conducing the neurotoxic effects of soluble Aβ-oligomers and the
emergent disease state of Alzheimer's.
</p><p>In humans, the <a href="https://en.wikipedia.org/wiki/Methionine" title="Methionine">methionine</a>/<a href="https://en.wikipedia.org/wiki/Valine" title="Valine">valine</a> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Genetic_polymorphism" title="Genetic polymorphism">polymorphism</a> at <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Codon" title="Codon">codon</a> 129 of <i>PRNP</i> (rs1799990) is most closely associated with Alzheimer's disease. Variant V <a href="https://en.wikipedia.org/wiki/Allele" title="Allele">allele</a> carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer's compared to the methionine <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Homozygote" title="Homozygote">homozygote</a> (MM). However, the protective effects of variant V carriers have been found exclusively in <a href="https://en.wikipedia.org/wiki/Caucasian_race" title="Caucasian race">Caucasians</a>. The decreased risk in V allele carriers is further limited to late-onset Alzheimer's disease only (≥ 65 years). PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer's, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PSEN1" title="PSEN1">PSEN1</a> and <a href="https://en.wikipedia.org/wiki/Apolipoprotein_E" title="Apolipoprotein E">APOE</a>, to compound risk for both Alzheimer's and <a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">sporadic Creutzfeldt–Jakob disease</a>. A <a href="https://en.wikipedia.org/wiki/Point_mutation" title="Point mutation">point mutation</a> on codon 102 of <i>PRNP</i> at least in part contributed to three separate patients' atypical <a href="https://en.wikipedia.org/wiki/Frontotemporal_dementia" title="Frontotemporal dementia">frontotemporal dementia</a> within the same family, suggesting a new phenotype for <a href="https://en.wikipedia.org/wiki/Gerstmann%E2%80%93Str%C3%A4ussler%E2%80%93Scheinker_syndrome" title="Gerstmann–Sträussler–Scheinker syndrome">Gerstmann–Sträussler–Scheinker syndrome</a>. The same study proposed sequencing <i>PRNP</i> in cases of ambiguously diagnosed dementia, as the various forms of <a href="https://en.wikipedia.org/wiki/Dementia" title="Dementia">dementia</a> can prove challenging to <a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">differentially diagnose</a>.
</p>
<h2><span class="mw-headline" id="Research">Research</span></h2><p>In 2006 the production of cattle lacking PrP<sup>C</sup>
form of the major prion protein (PrP) protein was reported which were
resistant to prion propagation with no apparent developmental
abnormalities. Besides the study of bovine products free of prion
proteins another use could be so that human pharmaceuticals can be made
in their blood without the danger that those products might get
contaminated with the infectious agent that causes mad cow.
</p>
<h2><span class="mw-headline" id="Interactions">Interactions</span></h2>A strong <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Protein-protein_interaction" title="Protein-protein interaction">interaction</a> exists between PrP and the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cochaperone" title="Cochaperone">cochaperone</a> <a href="https://en.wikipedia.org/wiki/Hop_(protein)" title="Hop (protein)">Hop</a> (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/HSP70" title="HSP70">Hsp70</a>/<a class="mw-redirect" href="https://en.wikipedia.org/wiki/HSP90" title="HSP90">Hsp90</a> organizing protein; also called STI1 (Stress-induced protein 1)).David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-49837095290958003672024-03-27T09:00:00.008-04:002024-03-27T09:00:39.582-04:00Grey matter<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia<br /><a href="https://en.wikipedia.org/wiki/Grey_matter">https://en.wikipedia.org/wiki/Grey_matter</a><br /></div>
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<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background-color: dimgrey; color: white;">Grey matter</th></tr><tr><td class="infobox-image" colspan="2"><div style="text-align: center;"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Spinal_nerve.svg"><img class="mw-file-element" data-file-height="700" data-file-width="1200" height="234" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d2/Spinal_nerve.svg/250px-Spinal_nerve.svg.png" width="400" /></a></span></div><div class="infobox-caption">The formation of the spinal nerve from the dorsal and ventral roots (with grey matter labelled at centre right).</div></td></tr><tr><td class="infobox-image" colspan="2"><div style="text-align: center;"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Grey_matter_and_white_matter_-_very_high_mag.jpg"><img class="mw-file-element" data-file-height="2848" data-file-width="4272" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d7/Grey_matter_and_white_matter_-_very_high_mag.jpg/250px-Grey_matter_and_white_matter_-_very_high_mag.jpg" width="400" /></a></span></div><div class="infobox-caption"><a href="https://en.wikipedia.org/wiki/Micrograph" title="Micrograph">Micrograph</a> showing grey matter, with the characteristic <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuronal cell bodies</a> (dark shade of pink), and <a href="https://en.wikipedia.org/wiki/White_matter" title="White matter">white matter</a> with its characteristic fine meshwork-like appearance (left of image; lighter shade of pink). <a href="https://en.wikipedia.org/wiki/HPS_stain" title="HPS stain">HPS stain</a>.</div></td></tr><tr><td class="infobox-below" colspan="2"></td></tr></tbody></table><p><b>Grey matter</b>, or <b>gray matter</b> in <a href="https://en.wikipedia.org/wiki/American_English" title="American English">American English</a>, is a major component of the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>, consisting of <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuronal</a> <a href="https://en.wikipedia.org/wiki/Soma_(biology)" title="Soma (biology)">cell bodies</a>, <a href="https://en.wikipedia.org/wiki/Neuropil" title="Neuropil">neuropil</a> (<a href="https://en.wikipedia.org/wiki/Dendrite" title="Dendrite">dendrites</a> and unmyelinated <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a>), <a href="https://en.wikipedia.org/wiki/Glia" title="Glia">glial cells</a> (<a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a> and <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocytes</a>), <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapses</a>, and <a href="https://en.wikipedia.org/wiki/Capillary" title="Capillary">capillaries</a>. Grey matter is distinguished from <a href="https://en.wikipedia.org/wiki/White_matter" title="White matter">white matter</a>
in that it contains numerous cell bodies and relatively few myelinated
axons, while white matter contains relatively few cell bodies and is
composed chiefly of long-range myelinated axons. The colour difference arises mainly from the whiteness of <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a>.
In living tissue, grey matter actually has a very light grey colour
with yellowish or pinkish hues, which come from capillary blood vessels
and neuronal cell bodies.
</p>
<h2><span class="mw-headline" id="Structure">Structure</span></h2></div></div></div><p>Grey matter refers to unmyelinated <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neurons</a> and other cells of the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>. It is present in the <a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a>, <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a> and <a href="https://en.wikipedia.org/wiki/Cerebellum" title="Cerebellum">cerebellum</a>, and present throughout the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>.
</p><p>Grey matter is distributed at the surface of the <a href="https://en.wikipedia.org/wiki/Cerebral_hemisphere" title="Cerebral hemisphere">cerebral hemispheres</a> (<a href="https://en.wikipedia.org/wiki/Cerebral_cortex" title="Cerebral cortex">cerebral cortex</a>) and of the cerebellum (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cerebellar_cortex" title="Cerebellar cortex">cerebellar cortex</a>), as well as in the depths of the cerebrum (the <a href="https://en.wikipedia.org/wiki/Thalamus" title="Thalamus">thalamus</a>; <a href="https://en.wikipedia.org/wiki/Hypothalamus" title="Hypothalamus">hypothalamus</a>; <a href="https://en.wikipedia.org/wiki/Subthalamus" title="Subthalamus">subthalamus</a>, <a href="https://en.wikipedia.org/wiki/Basal_ganglia" title="Basal ganglia">basal ganglia</a> – <a href="https://en.wikipedia.org/wiki/Putamen" title="Putamen">putamen</a>, <a href="https://en.wikipedia.org/wiki/Globus_pallidus" title="Globus pallidus">globus pallidus</a> and <a href="https://en.wikipedia.org/wiki/Nucleus_accumbens" title="Nucleus accumbens">nucleus accumbens</a>; as well as the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Septal_nuclei" title="Septal nuclei">septal nuclei</a>), cerebellum (deep cerebellar nuclei – the <a href="https://en.wikipedia.org/wiki/Dentate_nucleus" title="Dentate nucleus">dentate nuclei</a>, <a href="https://en.wikipedia.org/wiki/Globose_nucleus" title="Globose nucleus">globose nucleus</a>, <a href="https://en.wikipedia.org/wiki/Emboliform_nucleus" title="Emboliform nucleus">emboliform nucleus</a>, and <a href="https://en.wikipedia.org/wiki/Fastigial_nucleus" title="Fastigial nucleus">fastigial nucleus</a>), and <a href="https://en.wikipedia.org/wiki/Brainstem" title="Brainstem">brainstem</a> (the <a href="https://en.wikipedia.org/wiki/Substantia_nigra" title="Substantia nigra">substantia nigra</a>, <a href="https://en.wikipedia.org/wiki/Red_nucleus" title="Red nucleus">red nucleus</a>, <a href="https://en.wikipedia.org/wiki/Olivary_body" title="Olivary body">olivary nuclei</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cranial_nerve_nuclei" title="Cranial nerve nuclei">cranial nerve nuclei</a>).
</p><p>Grey matter in the spinal cord is known as the <a href="https://en.wikipedia.org/wiki/Grey_column" title="Grey column">grey column</a>
which travels down the spinal cord distributed in three grey columns
that are presented in an "H" shape. The forward-facing column is the <a href="https://en.wikipedia.org/wiki/Anterior_grey_column" title="Anterior grey column">anterior grey column</a>, the rear-facing one is the <a href="https://en.wikipedia.org/wiki/Posterior_grey_column" title="Posterior grey column">posterior grey column</a> and the interlinking one is the <a href="https://en.wikipedia.org/wiki/Lateral_grey_column" title="Lateral grey column">lateral grey column</a>. The grey matter on the left and right side is connected by the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gray_commissure" title="Gray commissure">grey commissure</a>. The grey matter in the spinal cord consists of <a href="https://en.wikipedia.org/wiki/Spinal_interneuron" title="Spinal interneuron">interneurons</a>, as well as the <a href="https://en.wikipedia.org/wiki/Soma_(biology)" title="Soma (biology)">cell bodies</a> of <a href="https://en.wikipedia.org/wiki/Projection_fiber" title="Projection fiber">projection neurons</a>.
</p>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Cervical_vertebra_english.png" title="Cross-section of a spinal vertebra with the spinal cord in the centre (and grey matter labelled)."><img alt="Cross-section of a spinal vertebra with the spinal cord in the centre (and grey matter labelled)." class="mw-file-element" data-file-height="1317" data-file-width="1883" height="280" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d9/Cervical_vertebra_english.png/120px-Cervical_vertebra_english.png" width="400" /></a></span></div>
<div class="gallerytext">Cross-section of a spinal <a href="https://en.wikipedia.org/wiki/Vertebra" title="Vertebra">vertebra</a> with the spinal cord in the centre (and grey matter labelled).</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Medulla_spinalis_-_Section_-_English.svg" title="Cross-section of spinal cord with the grey matter labelled."><img alt="Cross-section of spinal cord with the grey matter labelled." class="mw-file-element" data-file-height="615" data-file-width="716" height="343" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/dc/Medulla_spinalis_-_Section_-_English.svg/120px-Medulla_spinalis_-_Section_-_English.svg.png" width="400" /></a></span></div>
<div class="gallerytext">Cross-section of <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a> with the grey matter labelled.</div>
</li></ul>
<p>Grey matter undergoes development and growth throughout childhood and adolescence.
Recent studies using cross-sectional neuroimaging have shown that by
around the age of 8 the volume of grey matter begins to decrease. However, the density of grey matter appears to increase as a child develops into early adulthood. Males tend to exhibit grey matter of increased volume but lower density than that of females.
</p>
<h2><span class="mw-headline" id="Function">Function</span></h2><p>Grey matter contains most of the brain's neuronal cell bodies.
The grey matter includes regions of the brain involved in muscle
control, and sensory perception such as seeing and hearing, memory,
emotions, speech, decision-making, and self-control.
</p><p>The grey matter in the <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a> is split into three grey columns:
</p>
<ul><li>The <a href="https://en.wikipedia.org/wiki/Anterior_grey_column" title="Anterior grey column">anterior grey column</a> contains <a href="https://en.wikipedia.org/wiki/Motor_neuron" title="Motor neuron">motor neurons</a>. These <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapse</a> with interneurons and the <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a> of cells that have travelled down the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pyramidal_tract" title="Pyramidal tract">pyramidal tract</a>. These cells are responsible for the movement of muscles.</li><li>The <a href="https://en.wikipedia.org/wiki/Posterior_grey_column" title="Posterior grey column">posterior grey column</a> contains the points where <a href="https://en.wikipedia.org/wiki/Sensory_neuron" title="Sensory neuron">sensory neurons</a> synapse. These receive sensory information from the body, including <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Fine_touch" title="Fine touch">fine touch</a>, <a href="https://en.wikipedia.org/wiki/Proprioception" title="Proprioception">proprioception</a>, and <a href="https://en.wikipedia.org/wiki/Vibration" title="Vibration">vibration</a>.
This information is sent from receptors of the skin, bones, and joints
through sensory neurons whose cell bodies lie in the dorsal root
ganglion. This information is then transmitted in axons up the spinal
cord in spinal tracts, including the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dorsal_column-medial_lemniscus_tract" title="Dorsal column-medial lemniscus tract">dorsal column-medial lemniscus tract</a> and the <a href="https://en.wikipedia.org/wiki/Spinothalamic_tract" title="Spinothalamic tract">spinothalamic tract</a>.</li><li>The <a href="https://en.wikipedia.org/wiki/Lateral_grey_column" title="Lateral grey column">lateral grey column</a> is the third column of the spinal cord.</li></ul>
<p>The grey matter of the spinal cord can be divided into different layers, called <a href="https://en.wikipedia.org/wiki/Rexed_laminae" title="Rexed laminae">Rexed laminae</a>. These describe, in general, the purpose of the cells within the grey matter of the spinal cord at a particular location.
</p>
<ul class="gallery mw-gallery-traditional"><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Anatomy_and_physiology_of_animals_A_reflex_arc.jpg" title="Interneurons present in the grey matter of the spinal cord"><img alt="Interneurons present in the grey matter of the spinal cord" class="mw-file-element" data-file-height="272" data-file-width="549" height="197" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/2f/Anatomy_and_physiology_of_animals_A_reflex_arc.jpg/120px-Anatomy_and_physiology_of_animals_A_reflex_arc.jpg" width="400" /></a></span></div>
<div class="gallerytext"><a href="https://en.wikipedia.org/wiki/Interneuron" title="Interneuron">Interneurons</a> present in the grey matter of the spinal cord</div><div class="gallerytext"> </div>
</li><li class="gallerybox">
<div class="thumb"><span><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Medulla_spinalis_-_Substantia_grisea_-_English.svg" title="Rexed laminae groups the grey matter in the spinal cord according to its function."><img alt="Rexed laminae groups the grey matter in the spinal cord according to its function." class="mw-file-element" data-file-height="514" data-file-width="700" height="293" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Medulla_spinalis_-_Substantia_grisea_-_English.svg/120px-Medulla_spinalis_-_Substantia_grisea_-_English.svg.png" width="400" /></a></span></div>
<div class="gallerytext"><a href="https://en.wikipedia.org/wiki/Rexed_laminae" title="Rexed laminae">Rexed laminae</a> groups the grey matter in the spinal cord according to its function.</div>
</li></ul>
<h2><span class="mw-headline" id="Clinical_significance">Clinical significance</span></h2><p>High <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Alcohol_consumption" title="Alcohol consumption">alcohol consumption</a> has been correlated with significant reductions in grey matter volume.<sup> </sup>Short-term <a href="https://en.wikipedia.org/wiki/Cannabis" title="Cannabis">cannabis</a> use (30 days) is not correlated with changes in <a href="https://en.wikipedia.org/wiki/White_matter" title="White matter">white</a> or grey matter.
However, several cross-sectional studies have shown that repeated
long-term cannabis use is associated with smaller grey matter volumes in
the <a href="https://en.wikipedia.org/wiki/Hippocampus" title="Hippocampus">hippocampus</a>, <a href="https://en.wikipedia.org/wiki/Amygdala" title="Amygdala">amygdala</a>, medial <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Temporal_cortex" title="Temporal cortex">temporal cortex</a>, and <a href="https://en.wikipedia.org/wiki/Prefrontal_cortex" title="Prefrontal cortex">prefrontal cortex</a>, with increased grey matter volume in the cerebellum. Long-term cannabis use is also associated with alterations in white matter integrity in an age-dependent manner, with heavy cannabis use during adolescence and early adulthood associated with the greatest amount of change.
</p><p>Meditation has been shown to change grey matter structure.
</p><p>Habitual playing of action video games has been reported to
promote a reduction of grey matter in the hippocampus while 3D
platformer games have been reported to increase grey matter in the
hippocampus.
</p><p>Women and men with equivalent IQ scores have differing
proportions of grey to white matter in cortical brain regions associated
with intelligence.
</p><p>Pregnancy renders substantial changes in brain structure,
primarily reductions in grey matter volume in regions subserving social
cognition. The grey matter reductions endured for at least 2 years
post-pregnancy.
The profile of brain changes is comparable to that taking place during
adolescence, a hormonally similar transitional period of life.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><h3><span class="mw-headline" id="Etymology">Etymology</span></h3>In the current edition of the official Latin nomenclature, <i><a href="https://en.wikipedia.org/wiki/Terminologia_Anatomica" title="Terminologia Anatomica">Terminologia Anatomica</a></i>, <i>substantia grisea</i> is used for English <i>grey matter</i>. The adjective <i>grisea</i> for <i>grey</i> is however not attested in <a href="https://en.wikipedia.org/wiki/Classical_Latin" title="Classical Latin">classical Latin</a>. The adjective <i>grisea</i> is derived from the <a href="https://en.wikipedia.org/wiki/French_language" title="French language">French</a> word for grey, <i>gris</i>. Alternative designations like <i>substantia cana</i> and <i>substantia cinerea</i> are being used alternatively. The adjective <i>cana</i>, attested in classical Latin, can mean <i>grey</i>, or <i>greyish white</i>. The classical Latin <i>cinerea</i> means <i>ash-coloured</i>.David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-74698514072886202862024-03-27T08:49:00.004-04:002024-03-27T08:49:23.224-04:00Kuru (disease)<p></p><div><div class="vector-column-end">
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<div class="hatnote navigation-not-searchable" role="note"><a href="https://en.wikipedia.org/wiki/Kuru_(disease)">https://en.wikipedia.org/wiki/Kuru_(disease)</a></div><div class="hatnote navigation-not-searchable" role="note"> <br /></div>
<table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background: #ccc;">Kuru</th></tr><tr align="center"><td class="infobox-full-data" colspan="2"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:PMC4235695_pathogens-02-00472-g009.png"><img class="mw-file-element" data-file-height="733" data-file-width="512" height="400" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fa/PMC4235695_pathogens-02-00472-g009.png/220px-PMC4235695_pathogens-02-00472-g009.png" width="279" /></a></span></td></tr><tr><td class="infobox-full-data" colspan="2">A <a href="https://en.wikipedia.org/wiki/Fore_people" title="Fore people">Fore</a> child with advanced kuru. He is unable to walk or sit upright without assistance and is severely <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Malnourished" title="Malnourished">malnourished</a>.</td></tr><tr><th class="infobox-label" scope="row">Pronunciation</th><td class="infobox-data"><div class="plainlist"><ul><li>IPA: <span class="IPA nowrap" lang="und-Latn-fonipa" title="Representation in the International Phonetic Alphabet (IPA)">kuru</span> </li></ul></div></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_specialty" title="Medical specialty">Specialty</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Neuropathology" title="Neuropathology">Neuropathology</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Infectious_disease" title="Infectious disease">infectious disease</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Signs_and_symptoms" title="Signs and symptoms">Symptoms</a></th><td class="infobox-data">Body tremors, random outbursts of laughter, gradual loss of <a href="https://en.wikipedia.org/wiki/Motor_coordination" title="Motor coordination">coordination</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Complication_(medicine)" title="Complication (medicine)">Complications</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Infection" title="Infection">Infection</a> and <a href="https://en.wikipedia.org/wiki/Pneumonia" title="Pneumonia">pneumonia</a> during the terminal stage.</td></tr><tr><th class="infobox-label" scope="row">Usual onset</th><td class="infobox-data">Often takes years or even decades for symptoms to appear after exposure</td></tr><tr><th class="infobox-label" scope="row">Duration</th><td class="infobox-data">11–14 month life expectancy after onset of symptoms</td></tr><tr><th class="infobox-label" scope="row">Causes</th><td class="infobox-data">Transmission of infected <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Prion_proteins" title="Prion proteins">prion proteins</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Risk_factor" title="Risk factor">Risk factors</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Human_cannibalism" title="Human cannibalism">Cannibalism</a></td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Medical_diagnosis" title="Medical diagnosis">Diagnostic method</a></th><td class="infobox-data">Autopsy</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Differential_diagnosis" title="Differential diagnosis">Differential diagnosis</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">Creutzfeldt–Jakob disease</a></td></tr><tr><th class="infobox-label" scope="row">Prevention</th><td class="infobox-data">Avoiding practices of <a href="https://en.wikipedia.org/wiki/Human_cannibalism" title="Human cannibalism">cannibalism</a></td></tr><tr><th class="infobox-label" scope="row">Treatment</th><td class="infobox-data">Supportive care</td></tr><tr><th class="infobox-label" scope="row"><a href="https://en.wikipedia.org/wiki/Prognosis" title="Prognosis">Prognosis</a></th><td class="infobox-data">Fatal</td></tr><tr><th class="infobox-label" scope="row">Frequency</th><td class="infobox-data">Rare</td></tr><tr><th class="infobox-label" scope="row">Deaths</th><td class="infobox-data">Approximately 2,700 as of 2005</td></tr></tbody></table>
<p><b>Kuru</b> is a rare, incurable, and fatal <a href="https://en.wikipedia.org/wiki/Neurological_disorder" title="Neurological disorder">neurodegenerative disorder</a> that was formerly common among the <a href="https://en.wikipedia.org/wiki/Fore_people" title="Fore people">Fore people</a> of <a href="https://en.wikipedia.org/wiki/Papua_New_Guinea" title="Papua New Guinea">Papua New Guinea</a>. Kuru is a form of <a href="https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy" title="Transmissible spongiform encephalopathy">transmissible spongiform encephalopathy</a> (TSE) caused by the transmission of abnormally folded proteins (<a href="https://en.wikipedia.org/wiki/Prion" title="Prion">prions</a>), which leads to symptoms such as tremors and loss of coordination from <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neurodegeneration" title="Neurodegeneration">neurodegeneration</a>.
</p><p>The term kuru derives from the <a href="https://en.wikipedia.org/wiki/Fore_language" title="Fore language">Fore</a> word <i>kuria</i> or <i>guria</i> ("to shake"), due to the body <a href="https://en.wikipedia.org/wiki/Tremor" title="Tremor">tremors</a> that are a classic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Symptom" title="Symptom">symptom</a> of the disease. <i>Kúru</i> itself means "trembling". It is also known as the "laughing sickness" due to the pathologic
bursts of laughter which are a symptom of the disease. It is now widely
accepted that kuru was transmitted among members of the Fore tribe of
Papua New Guinea via <a href="https://en.wikipedia.org/wiki/Endocannibalism" title="Endocannibalism">funerary cannibalism</a>. Deceased family members were traditionally cooked and eaten, which was thought to help free the spirit of the dead.
Women and children usually consumed the brain, the organ in which
infectious prions were most concentrated, thus allowing for transmission
of kuru. The disease was therefore more prevalent among women and
children.
</p><p>The epidemic likely started when a villager developed sporadic <a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">Creutzfeldt–Jakob disease</a>
and died. When villagers ate the brain, they contracted the disease and
then spread it to other villagers who ate their infected brains.
</p><p>While the Fore people stopped consuming human meat in the early 1960s, when it was first speculated to be transmitted via <a href="https://en.wikipedia.org/wiki/Endocannibalism" title="Endocannibalism">endocannibalism</a>, the disease lingered due to kuru's long <a href="https://en.wikipedia.org/wiki/Incubation_period" title="Incubation period">incubation period</a> of anywhere from 10 to over 50 years.
The epidemic finally declined sharply after half a century, from 200
deaths per year in 1957 to no deaths from at least 2010 onwards, with
sources disagreeing on whether the last known kuru victim died in 2005
or 2009.
</p>
<h2><span class="mw-headline" id="Signs_and_symptoms">Signs and symptoms</span></h2></div></div></div><p>Kuru,
a transmissible spongiform encephalopathy, is a disease of the nervous
system that causes physiological and neurological effects which
ultimately lead to death. It is characterized by progressive <a href="https://en.wikipedia.org/wiki/Cerebellar_ataxia" title="Cerebellar ataxia">cerebellar ataxia</a>, or loss of <a href="https://en.wikipedia.org/wiki/Motor_coordination" title="Motor coordination">coordination</a> and control over muscle movements.
</p><p>The preclinical or <a href="https://en.wikipedia.org/wiki/Asymptomatic" title="Asymptomatic">asymptomatic</a>
phase, also called the incubation period, averages 10–13 years, but can
be as short as five and has been estimated to last as long as 50 years
or more after initial exposure.
</p><p>The clinical stage, which begins at the first onset of symptoms,
lasts an average of 12 months. The clinical progression of kuru is
divided into three specific stages: the ambulant, sedentary and terminal
stages. While there is some variation in these stages from individual
to individual, they are highly conserved among the affected population. Before the onset of clinical symptoms, an individual can also present with <a href="https://en.wikipedia.org/wiki/Prodrome" title="Prodrome">prodromal</a> symptoms including headache and joint pain in the legs.
</p><h3><span class="mw-headline" id="Ambulant_stage">Ambulant stage</span></h3><p>In
the ambulant stage, the infected individual may exhibit unsteady stance
and gait, decreased muscle control, difficulty pronouncing words (<a href="https://en.wikipedia.org/wiki/Dysarthria" title="Dysarthria">dysarthria</a>), and tremors (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Titubation" title="Titubation">titubation</a>). This stage is named the ambulant because the individual is still able to walk around despite symptoms.
</p><h3><span class="mw-headline" id="Sedentary_stage">Sedentary stage</span></h3><p>In the sedentary stage, the infected individual is incapable of walking without support and experiences <a href="https://en.wikipedia.org/wiki/Ataxia" title="Ataxia">ataxia</a>
and severe tremors. Furthermore, the individual shows signs of
emotional instability and depression, yet exhibits uncontrolled and
sporadic laughter. Despite the other neurological symptoms, tendon
reflexes are still intact at this stage of the disease.
</p><h3><span class="mw-headline" id="Terminal_stage">Terminal stage</span></h3><p>In
the terminal stage, the infected individual's existing symptoms, like
ataxia, progress to the point where it is no longer possible to sit up
without support. New symptoms also emerge: the individual develops <a href="https://en.wikipedia.org/wiki/Dysphagia" title="Dysphagia">dysphagia</a>,
which can lead to severe malnutrition, and may also become incontinent,
lose the ability or will to speak, and become unresponsive to their
surroundings despite maintaining consciousness.
Towards the end of the terminal stage, patients often develop chronic
decubitus ulcerated wounds that can be easily infected. An infected
person usually dies within three months to two years after the first
terminal stage symptoms, often because of aspiration pneumonia or other <a href="https://en.wikipedia.org/wiki/Opportunistic_infection" title="Opportunistic infection">secondary infections</a>.
</p><h2><span class="mw-headline" id="Causes">Causes</span></h2><p>Kuru is largely localized to the Fore people and people with whom they intermarried.
The Fore people ritualistically cooked and consumed body parts of their
family members following their death to incorporate "the body of the
dead person into the bodies of living relatives, thus helping to free
the spirit of the dead".
Because the brain is the organ enriched in the infectious prion, women
and children, who consumed brain, had a much higher likelihood of being
infected than men, who preferentially consumed muscles.
</p><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Prion_subdomain-colored_sec_structure.png"><img class="mw-file-element" data-file-height="480" data-file-width="640" height="300" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f2/Prion_subdomain-colored_sec_structure.png/220px-Prion_subdomain-colored_sec_structure.png" width="400" /></a><figcaption>Normally folded prion protein PrP<sup>c</sup> subdomain-Residues 125–228. Note the presence of alpha helices (blue).</figcaption></figure><h3><span class="mw-headline" id="Prion">Prion</span></h3><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Model_of_a_three_dimensional_structure_for_PrPSc.jpg"><img class="mw-file-element" data-file-height="456" data-file-width="754" height="242" src="https://upload.wikimedia.org/wikipedia/commons/thumb/3/37/Model_of_a_three_dimensional_structure_for_PrPSc.jpg/220px-Model_of_a_three_dimensional_structure_for_PrPSc.jpg" width="400" /></a><figcaption>Cryoelectron microscopy model of the misfolded PrP<sup>sc</sup> protein, enriched in beta sheets (center)</figcaption></figure><p>The infectious agent is a misfolded form of a host-encoded protein called prion (PrP). <a href="https://en.wikipedia.org/wiki/Prion" title="Prion">Prion</a> proteins are encoded by the Prion Protein Gene (<a class="mw-redirect" href="https://en.wikipedia.org/wiki/PRNP" title="PRNP">PRNP</a>). The two forms of prion are designated as PrP<sup>c</sup>, which is a normally folded protein, and PrP<sup>sc</sup>,
a misfolded form which gives rise to the disease. The two forms do not
differ in their amino acid sequence; however, the pathogenic PrP<sup>sc</sup> isoform differs from the normal PrP<sup>c</sup> form in its secondary and tertiary structure. The PrP<sup>sc</sup> isoform is more enriched in <a href="https://en.wikipedia.org/wiki/Beta_sheet" title="Beta sheet">beta sheets</a>, while the normal PrP<sup>c</sup> form is enriched in <a href="https://en.wikipedia.org/wiki/Alpha_helix" title="Alpha helix">alpha helices</a>. The differences in conformation allow PrP<sup>sc</sup>
to aggregate and be extremely resistant to protein degradation by
enzymes or by other chemical and physical means. The normal form, on the
other hand, is susceptible to complete <a href="https://en.wikipedia.org/wiki/Proteolysis" title="Proteolysis">proteolysis</a> and soluble in non-denaturing detergents.
</p><p>It has been suggested that pre-existing or acquired PrP<sup>sc</sup> can promote the conversion of PrP<sup>c</sup> into PrP<sup>sc</sup>, which goes on to convert other PrP<sup>c</sup>. This initiates a chain reaction that allows for its rapid propagation, resulting in the pathogenesis of prion diseases.
</p><h3><span class="mw-headline" id="Transmission">Transmission</span></h3><p>In 1961, Australian medical researcher <a href="https://en.wikipedia.org/wiki/Michael_Alpers" title="Michael Alpers">Michael Alpers</a> conducted extensive field studies among the Fore accompanied by anthropologist <a href="https://en.wikipedia.org/wiki/Shirley_Lindenbaum" title="Shirley Lindenbaum">Shirley Lindenbaum</a>.
Their historical research suggested the epidemic may have originated
around 1900 from a single individual who lived on the edge of Fore
territory and who is thought to have spontaneously developed some form
of Creutzfeldt–Jakob disease.
Alpers and Lindenbaum's research conclusively demonstrated that kuru
spread easily and rapidly in the Fore people due to their
endocannibalistic funeral practices, in which relatives consumed the
bodies of the dead to return the person's "life force" to the hamlet, a
Fore social subunit.
Corpses of family members were often buried for days, then exhumed once
the corpses were colonized by insect larvae, at which point the corpse
would be dismembered and served with the larvae as a side dish.
</p><p>The demographic distribution evident in the infection rates –
kuru was eight to nine times more prevalent in women and children than
in men at its peak – is because Fore men considered consuming human
flesh to weaken them in times of conflict or battle, while the women and
children were more likely to eat the bodies of the deceased, including
the brain, where the prion particles were particularly concentrated.
Also, the strong possibility exists that it was passed on to women and
children more easily because they took on the task of cleaning relatives
after death and might have had open sores and cuts on their hands.
</p><p>Although ingestion of the prion particles can lead to the disease, a high degree of transmission occurred if the prion particles could reach the subcutaneous tissue. With elimination of <a href="https://en.wikipedia.org/wiki/Human_cannibalism" title="Human cannibalism">cannibalism</a> because of Australian colonial law enforcement and the local <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Christian_missionaries" title="Christian missionaries">Christian missionaries</a>'
efforts, Alpers' research showed that kuru was already declining among
the Fore by the mid‑1960s. However, the mean incubation period of the
disease is 14 years, and seven cases were reported with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Clinical_latency" title="Clinical latency">latencies</a>
of 40 years or more for those who were most genetically resilient,
continuing to appear for several more decades. Sources disagree on
whether the last person with kuru died in 2005 or 2009.
</p><h2><span class="mw-headline" id="Diagnosis">Diagnosis</span></h2><p>Kuru
is diagnosed by reviewing the patient's history of cerebellar signs and
symptoms, performing neurological exams, and excluding other
neurological diseases during exams.
The symptoms evaluated are typically coordination issues and
involuntary muscle movements, but these markers can be confused with
other diseases that affect the nervous and muscle system; physical
scans are often required to differentiate Kuru from other disorders.
There is no laboratory test to determine the presence of Kuru, except
for postmortem evaluation of central nervous system (CNS) tissues, so
diagnoses are achieved by eliminating other possible disorders.
</p><p>Electroencephalogram (EEG) is used to discern kuru from
Creutzfeldt–Jakob disease, a similar encephalopathy (any disease that
affects the structure of the brain).
EEGs search for electrical activity in the patient's brain and measure
the frequency of each wave to determine if there is an issue with the
brain's activity.
Periodic complexes (PC), reoccurring patterns with spike wave-complexes
occurring at intervals, are recorded frequently in some diseases but
are not presented in the kuru readings.
Exams and testing, like EEG, MRIs, blood test, and scans, can be used
to determine if the infected person is dealing with Kuru disease or
another encephalopathy. However, testing over periods of time can be
difficult.
</p><h2><span class="mw-headline" id="Immunity">Immunity</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Cerebellum_of_kuru_victim.png"><img class="mw-file-element" data-file-height="378" data-file-width="512" height="295" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e6/Cerebellum_of_kuru_victim.png/220px-Cerebellum_of_kuru_victim.png" width="400" /></a><figcaption>Cerebellum of a kuru patient</figcaption></figure><p>In 2009, researchers at the <a href="https://en.wikipedia.org/wiki/Medical_Research_Council_(United_Kingdom)" title="Medical Research Council (United Kingdom)">Medical Research Council</a> discovered a naturally occurring variant of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PRNP" title="PRNP">prion protein</a> in a population from Papua New Guinea that confers strong resistance to kuru. In the study, which began in 1996,
researchers assessed over 3,000 people from the affected and
surrounding Eastern Highland populations, and identified a variation in
the prion protein G127. G127 <a href="https://en.wikipedia.org/wiki/Polymorphism_(biology)" title="Polymorphism (biology)">polymorphism</a> is the result of a <a href="https://en.wikipedia.org/wiki/Missense_mutation" title="Missense mutation">missense mutation</a>,
and is highly geographically restricted to regions where the kuru
epidemic was the most widespread. Researchers believe that the PrnP
variant occurred very recently, estimating that the most recent common
ancestor lived 10 generations ago.
</p><p>The findings of the study could help researchers better
understand and develop treatments for other related prion diseases, such
as <a href="https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease" title="Creutzfeldt–Jakob disease">Creutzfeldt–Jakob disease</a> and other neurodegenerate diseases like <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a>.
</p><h2><span class="mw-headline" id="History">History</span></h2><p>Kuru
was first described in official reports by Australian officers
patrolling the Eastern Highlands of Papua New Guinea in the early 1950s. Some unofficial accounts place kuru in the region as early as 1910. In 1951, Arthur Carey was the first to use the term <i>kuru</i>
in a report to describe a new disease afflicting the Fore tribes of
Papua New Guinea (PNG). In his report, Carey noted that kuru mostly
affected Fore women, eventually killing them. Kuru was noted in the
Fore, <a class="new" href="https://en.wikipedia.org/w/index.php?title=Yate_people&action=edit&redlink=1" title="Yate people (page does not exist)">Yate</a> and <a class="new" href="https://en.wikipedia.org/w/index.php?title=Usurufa_people&action=edit&redlink=1" title="Usurufa people (page does not exist)">Usurufa</a> people in 1952–1953 by anthropologists <a href="https://en.wikipedia.org/wiki/Ronald_Berndt" title="Ronald Berndt">Ronald Berndt</a> and <a href="https://en.wikipedia.org/wiki/Catherine_Berndt" title="Catherine Berndt">Catherine Berndt</a>.
In 1953, kuru was observed by patrol officer John McArthur, who
provided a description of the disease in his report. McArthur believed
that kuru was merely a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Psychosomatic" title="Psychosomatic">psychosomatic</a> episode resulting from the sorcery practices of the tribal people in the region.
After the disease had progressed into a larger epidemic, the tribal
people asked Charles Pfarr, a Lutheran medical officer, to come to the
area to report the disease to Australian authorities.
</p><p>Initially, the Fore people believed the causes of kuru to be sorcery or witchcraft.
They also thought that the magic causing kuru was contagious. It was
also called negi-nagi, which meant foolish person as the victims laughed
at spontaneous intervals.
This disease, the Fore people believed, was caused by ghosts, because
of the shaking and strange behaviour that comes with kuru. Attempting to
cure this, they would feed victims <a href="https://en.wikipedia.org/wiki/Casuarina" title="Casuarina">casuarina</a> bark.
</p><p>When kuru disease had become an epidemic, <a href="https://en.wikipedia.org/wiki/Daniel_Carleton_Gajdusek" title="Daniel Carleton Gajdusek">Daniel Carleton Gajdusek</a>, a virologist, and <a href="https://en.wikipedia.org/wiki/Vincent_Zigas" title="Vincent Zigas">Vincent Zigas</a>, a medical doctor, started research on the disease. In 1957, Zigas and Gajdusek published a report in the <i>Medical Journal of Australia</i>
that suggested that kuru had a genetic origin, and that "any
ethnic-environmental variables that are operating in kuru pathogenesis
have not yet been determined."
</p><p><a href="https://en.wikipedia.org/wiki/Human_cannibalism" title="Human cannibalism">Cannibalism</a>
was suspected as a possible cause from the very beginning but was not
formally put forth as a hypothesis until 1967 by Glasse and more
formally in 1968 by Mathews, Glasse, and Lindenbaum.
</p><p>Even before <a href="https://en.wikipedia.org/wiki/Human_cannibalism" title="Human cannibalism">anthropophagy</a>
had been linked to kuru, cannibalism was banned by the Australian
administration of Papua New Guinea, and the practice was nearly
eliminated by 1960. While the number of cases of kuru was decreasing,
medical researchers were finally able to properly investigate kuru,
which eventually led to the modern understanding of prions as its cause.
</p><p>In an effort to understand the pathology of kuru disease, Gajdusek established the first experimental tests on <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Common_chimpanzee" title="Common chimpanzee">chimpanzees</a> for kuru at the <a href="https://en.wikipedia.org/wiki/National_Institutes_of_Health" title="National Institutes of Health">National Institutes of Health</a> (NIH).
Michael Alpers, an Australian doctor, collaborated with Gajdusek by
providing samples of brain tissues he had taken from an 11-year-old Fore
girl who had died of kuru. In his work, Gajdusek was also the first to compile a bibliography of kuru disease.
Joe Gibbs joined Gajdusek to monitor and record the behavior of the
apes at the NIH and conduct their autopsies. Within two years, one of
the chimps, Daisy, had developed kuru, demonstrating that an unknown
disease factor was transmitted through infected biomaterial and that it
was capable of crossing the species barrier to other primates. After
Elisabeth Beck confirmed that this experiment had brought about the
first experimental transmission of kuru, the finding was deemed a very
important advance in human medicine, leading to the award of the <a href="https://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine" title="Nobel Prize in Physiology or Medicine">Nobel Prize in Physiology or Medicine</a> to Gajdusek in 1976.
</p><p>Subsequently, <a href="https://en.wikipedia.org/wiki/E._J._Field" title="E. J. Field">E. J. Field</a> spent large parts of the late 1960s and early 1970s in New Guinea investigating the disease, connecting it to <a href="https://en.wikipedia.org/wiki/Scrapie" title="Scrapie">scrapie</a> and <a href="https://en.wikipedia.org/wiki/Multiple_sclerosis" title="Multiple sclerosis">multiple sclerosis</a>. He noted the disease's interactions with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glial_cell" title="Glial cell">glial cells</a>,
including the critical observation that the infectious process may
depend on the structural rearrangement of the host's molecules. This was an early observation of what was to later become the prion hypothesis.
</p><h2><span class="mw-headline" id="In_popular_culture">In popular culture</span></h2><li>The Czech immunologist-poet <a href="https://en.wikipedia.org/wiki/Miroslav_Holub" title="Miroslav Holub">Miroslav Holub</a> wrote "Kuru, or the Smiling Death Syndrome" about the disease.</li><li><i>The X-Files</i> season 7 episode <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Theef_(The_X-Files)" title="Theef (The X-Files)">"Theef"</a> features a character diagnosed with advanced kuru after his sudden death.</li><li>The video game <i><a href="https://en.wikipedia.org/wiki/Dead_Island" title="Dead Island">Dead Island</a></i>, as well as <i>Dead Island: Riptide</i>, cite kuru as the disease that has swept the fictional islands of Banoi and Palanai.</li><li>In the film <i><a href="https://en.wikipedia.org/wiki/We_Are_What_We_Are_(2013_film)" title="We Are What We Are (2013 film)">We Are What We Are</a></i>, the medical examiner is able to identify the family as cannibals after he realises that the family is suffering from kuru.</li><li>In the post-apocalyptic book and film <a href="https://en.wikipedia.org/wiki/The_Road" title="The Road"><i>The Road</i></a> by <a href="https://en.wikipedia.org/wiki/Cormac_McCarthy" title="Cormac McCarthy">Cormac McCarthy</a>, two characters practicing cannibalism demonstrate symptoms of kuru.</li></div>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.comtag:blogger.com,1999:blog-3207547956289570927.post-15193377433983588932024-03-26T16:35:00.005-04:002024-03-26T16:35:32.167-04:00Glia<div class="vector-column-end">
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<div class="noprint" id="siteSub">From Wikipedia, the free encyclopedia</div>
</div><div class="mw-body-content" id="mw-content-text"><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"><a href="https://en.wikipedia.org/wiki/Glia">https://en.wikipedia.org/wiki/Glia</a></div><div class="mw-content-ltr mw-parser-output" dir="ltr" lang="en"> <br /><table class="infobox"><tbody><tr><th class="infobox-above" colspan="2" style="background-color: beige;">Glia</th></tr><tr><td class="infobox-image" colspan="2"><div style="text-align: center;"><span class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Glial_Cell_Types.png"><img class="mw-file-element" data-file-height="1123" data-file-width="750" height="640" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/ca/Glial_Cell_Types.png/250px-Glial_Cell_Types.png" width="428" /></a></span></div><div class="infobox-caption">Illustration
of the four different types of glial cells found in the central nervous
system: ependymal cells (light pink), astrocytes (green), microglial
cells (dark red) and oligodendrocytes (light blue)</div></td></tr><tr><th class="infobox-header" colspan="2" style="background-color: #efefef;">Details</th></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Embryology" title="Embryology">Precursor</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Neuroectoderm" title="Neuroectoderm">Neuroectoderm</a> for macroglia, and <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell" title="Hematopoietic stem cell">hematopoietic stem cells</a> for microglia</td></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Organ_system" title="Organ system">System</a></th><td class="infobox-data"><a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">Nervous system</a></td></tr><tr><th class="infobox-header" colspan="2" style="background-color: #efefef;">Identifiers</th></tr><tr><th class="infobox-label" scope="row" style="padding-right: 0.25em;"><a href="https://en.wikipedia.org/wiki/Medical_Subject_Headings" title="Medical Subject Headings">MeSH</a></th><td class="infobox-data"><a class="external text" href="https://meshb.nlm.nih.gov/record/ui?ui=D009457" rel="nofollow">D009457</a></td></tr></tbody></table><p><b>Glia</b>, also called <b>glial cells</b> (<b>gliocytes</b>) or <b>neuroglia</b>, are non-<a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neuronal</a> <a href="https://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)">cells</a> in the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> (<a href="https://en.wikipedia.org/wiki/Brain" title="Brain">brain</a> and <a href="https://en.wikipedia.org/wiki/Spinal_cord" title="Spinal cord">spinal cord</a>) and the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a> that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain <a href="https://en.wikipedia.org/wiki/Homeostasis" title="Homeostasis">homeostasis</a>, form <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a> in the peripheral nervous system, and provide support and protection for <a href="https://en.wikipedia.org/wiki/Neuron" title="Neuron">neurons</a>. In the central nervous system, glial cells include <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocytes</a>, <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ependymal_cell" title="Ependymal cell">ependymal cells</a> and <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">microglia</a>, and in the peripheral nervous system they include <a href="https://en.wikipedia.org/wiki/Schwann_cell" title="Schwann cell">Schwann cells</a> and <a href="https://en.wikipedia.org/wiki/Satellite_glial_cell" title="Satellite glial cell">satellite cells</a>.
</p>
<h2><span class="mw-headline" id="Function">Function</span></h2></div></div></div><p>They have four main functions:
</p>
<ul><li>to surround neurons and hold them in place</li><li>to supply <a href="https://en.wikipedia.org/wiki/Nutrient" title="Nutrient">nutrients</a> and <a href="https://en.wikipedia.org/wiki/Oxygen" title="Oxygen">oxygen</a> to neurons</li><li>to insulate one neuron from another</li><li>to destroy <a href="https://en.wikipedia.org/wiki/Pathogen" title="Pathogen">pathogens</a> and remove dead neurons.</li></ul>
<p>They also play a role in <a href="https://en.wikipedia.org/wiki/Neurotransmission" title="Neurotransmission">neurotransmission</a> and <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synaptic connections</a>, and in physiological processes such as <a href="https://en.wikipedia.org/wiki/Breathing" title="Breathing">breathing</a>.
While glia were thought to outnumber neurons by a ratio of 10:1, recent
studies using newer methods and reappraisal of historical quantitative
evidence suggests an overall ratio of less than 1:1, with substantial
variation between different brain tissues.
</p><p>Glial cells have far more cellular diversity and functions than
neurons, and glial cells can respond to and manipulate neurotransmission
in many ways. Additionally, they can affect both the preservation and <a href="https://en.wikipedia.org/wiki/Memory_consolidation" title="Memory consolidation">consolidation of memories</a>. Glia were discovered in 1856, by the pathologist <a href="https://en.wikipedia.org/wiki/Rudolf_Virchow" title="Rudolf Virchow">Rudolf Virchow</a> in his search for a "connective tissue" in the brain. The term derives from <a href="https://en.wikipedia.org/wiki/Koine_Greek" title="Koine Greek">Greek</a> γλία and γλοία "glue" (<span class="rt-commentedText nowrap"><small>English: </small><span class="IPA nopopups noexcerpt" lang="en-fonipa"><a href="https://en.wikipedia.org/wiki/Help:IPA/English" title="Help:IPA/English">/<span style="border-bottom: 1px dotted;"><span title="/ˈ/: primary stress follows">ˈ</span><span title="/ɡ/: 'g' in 'guy'">ɡ</span><span title="'l' in 'lie'">l</span><span title="/iː/: 'ee' in 'fleece'">iː</span><span title="/ə/: 'a' in 'about'">ə</span></span>/</a></span></span> or <span class="rt-commentedText nowrap"><span class="IPA nopopups noexcerpt" lang="en-fonipa"><a href="https://en.wikipedia.org/wiki/Help:IPA/English" title="Help:IPA/English">/<span style="border-bottom: 1px dotted;"><span title="/ˈ/: primary stress follows">ˈ</span><span title="/ɡ/: 'g' in 'guy'">ɡ</span><span title="'l' in 'lie'">l</span><span title="/aɪ/: 'i' in 'tide'">aɪ</span><span title="/ə/: 'a' in 'about'">ə</span></span>/</a></span></span>), and suggests the original impression that they were the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glue" title="Glue">glue</a> of the <a href="https://en.wikipedia.org/wiki/Nervous_system" title="Nervous system">nervous system</a>.
</p>
<h2><span class="mw-headline" id="Types">Types</span></h2><figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Neuroglia.png"><img class="mw-file-element" data-file-height="301" data-file-width="500" height="242" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c3/Neuroglia.png/250px-Neuroglia.png" width="400" /></a><figcaption>Neuroglia of the brain shown by <a href="https://en.wikipedia.org/wiki/Golgi%27s_method" title="Golgi's method">Golgi's method</a></figcaption></figure>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Gfapastr5.jpg"><img class="mw-file-element" data-file-height="270" data-file-width="390" height="277" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/cd/Gfapastr5.jpg/250px-Gfapastr5.jpg" width="400" /></a><figcaption><a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">Astrocytes</a> can be identified in culture because, unlike other mature glia, they express <a href="https://en.wikipedia.org/wiki/Glial_fibrillary_acidic_protein" title="Glial fibrillary acidic protein">glial fibrillary acidic protein</a> (GFAP)</figcaption></figure>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:2010-3-15_rGFAP_1-4000_1-200_Hip_20x(4).jpg"><img class="mw-file-element" data-file-height="1536" data-file-width="2040" height="301" src="https://upload.wikimedia.org/wikipedia/commons/thumb/8/81/2010-3-15_rGFAP_1-4000_1-200_Hip_20x%284%29.jpg/250px-2010-3-15_rGFAP_1-4000_1-200_Hip_20x%284%29.jpg" width="400" /></a><figcaption>Glial cells in a rat brain stained with an antibody against GFAP</figcaption></figure>
<figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Blausen_0870_TypesofNeuroglia.png"><img class="mw-file-element" data-file-height="2000" data-file-width="2500" height="320" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a6/Blausen_0870_TypesofNeuroglia.png/220px-Blausen_0870_TypesofNeuroglia.png" width="400" /></a><figcaption>Different types of neuroglia</figcaption></figure>
<h3><span class="mw-headline" id="Macroglia">Macroglia</span></h3><p>Derived from <a href="https://en.wikipedia.org/wiki/Germ_layer" title="Germ layer">ectodermal</a> tissue.
</p>
<table class="wikitable">
<tbody><tr>
<th scope="col">Location
</th>
<th scope="col">Name
</th>
<th scope="col">Description
</th></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">CNS</a></td>
<td><a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">Astrocytes</a></td>
<td>
<p>The most abundant type of macroglial cell in the CNS, <i>astrocytes</i> (also called <i>astroglia</i>) have numerous projections that link neurons to their blood supply while forming the <a href="https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier" title="Blood–brain barrier">blood–brain barrier</a>. They regulate the external <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Chemical" title="Chemical">chemical</a> environment of neurons by removing excess <a href="https://en.wikipedia.org/wiki/Potassium" title="Potassium">potassium</a> <a href="https://en.wikipedia.org/wiki/Ion" title="Ion">ions</a>, and recycling <a href="https://en.wikipedia.org/wiki/Neurotransmitter" title="Neurotransmitter">neurotransmitters</a> released during <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Synaptic_transmission" title="Synaptic transmission">synaptic transmission</a>. Astrocytes may regulate vasoconstriction and vasodilation by producing substances such as <a href="https://en.wikipedia.org/wiki/Arachidonic_acid" title="Arachidonic acid">arachidonic acid</a>, whose <a href="https://en.wikipedia.org/wiki/Metabolite" title="Metabolite">metabolites</a> are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Vasoactive" title="Vasoactive">vasoactive</a>.
</p><p>Astrocytes signal each other using <a href="https://en.wikipedia.org/wiki/Adenosine_triphosphate" title="Adenosine triphosphate">ATP</a>. The <a href="https://en.wikipedia.org/wiki/Gap_junction" title="Gap junction">gap junctions</a> (also known as <a href="https://en.wikipedia.org/wiki/Electrical_synapse" title="Electrical synapse">electrical synapses</a>) between astrocytes allow the messenger molecule <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Inositol_triphosphate" title="Inositol triphosphate">IP3</a> to diffuse from one astrocyte to another. IP3 activates <a href="https://en.wikipedia.org/wiki/Calcium_channel" title="Calcium channel">calcium channels</a> on <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cellular_organelles" title="Cellular organelles">cellular organelles</a>, releasing <a href="https://en.wikipedia.org/wiki/Calcium" title="Calcium">calcium</a> into the <a href="https://en.wikipedia.org/wiki/Cytoplasm" title="Cytoplasm">cytoplasm</a>. This calcium may stimulate the production of more IP3 and cause release of ATP through channels in the membrane made of <a href="https://en.wikipedia.org/wiki/Pannexin" title="Pannexin">pannexins</a>.
The net effect is a calcium wave that propagates from cell to cell.
Extracellular release of ATP, and consequent activation of <a href="https://en.wikipedia.org/wiki/Purinergic_receptor" title="Purinergic receptor">purinergic receptors</a> on other astrocytes, may also mediate calcium waves in some cases.
</p><p>In general, there are two types of astrocytes, protoplasmic and
fibrous, similar in function but distinct in morphology and
distribution. Protoplasmic astrocytes have short, thick, highly branched
processes and are typically found in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gray_matter" title="Gray matter">gray matter</a>. Fibrous astrocytes have long, thin, less-branched processes and are more commonly found in <a href="https://en.wikipedia.org/wiki/White_matter" title="White matter">white matter</a>.
</p><p>It has recently been shown that astrocyte activity is linked to
blood flow in the brain, and that this is what is actually being
measured in <a class="mw-redirect" href="https://en.wikipedia.org/wiki/FMRI" title="FMRI">fMRI</a>. They also have been involved in neuronal circuits playing an inhibitory role after sensing changes in extracellular calcium.
</p>
</td></tr>
<tr>
<td>CNS</td>
<td><a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">Oligodendrocytes</a></td>
<td>
<p><i>Oligodendrocytes</i> are cells that coat axons in the CNS with their cell membrane, forming a specialized membrane differentiation called <a href="https://en.wikipedia.org/wiki/Myelin" title="Myelin">myelin</a>, producing the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Myelin_sheath" title="Myelin sheath">myelin sheath</a>. The myelin sheath provides <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Electrical_insulation" title="Electrical insulation">insulation</a> to the axon that allows <a href="https://en.wikipedia.org/wiki/Action_potential" title="Action potential">electrical signals</a> to propagate more efficiently.
</p>
</td></tr>
<tr>
<td>CNS</td>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ependymal_cells" title="Ependymal cells">Ependymal cells</a></td>
<td>
<p><i>Ependymal cells</i>, also named <i>ependymocytes</i>, line the spinal cord and the <a href="https://en.wikipedia.org/wiki/Ventricular_system" title="Ventricular system">ventricular system</a> of the brain. These cells are involved in the creation and secretion of <a href="https://en.wikipedia.org/wiki/Cerebrospinal_fluid" title="Cerebrospinal fluid">cerebrospinal fluid</a> (CSF) and beat their <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cilia" title="Cilia">cilia</a> to help circulate the CSF and make up the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Blood-CSF_barrier" title="Blood-CSF barrier">blood-CSF barrier</a>. They are also thought to act as neural stem cells.
</p>
</td></tr>
<tr>
<td>CNS</td>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Radial_glia" title="Radial glia">Radial glia</a></td>
<td>
<p><i>Radial glia cells</i> arise from <a href="https://en.wikipedia.org/wiki/Neuroepithelial_cell" title="Neuroepithelial cell">neuroepithelial cells</a> after the onset of <a href="https://en.wikipedia.org/wiki/Neurogenesis" title="Neurogenesis">neurogenesis</a>.
Their differentiation abilities are more restricted than those of
neuroepithelial cells. In the developing nervous system, radial glia
function both as neuronal progenitors and as a scaffold upon which
newborn neurons migrate. In the mature brain, the <a href="https://en.wikipedia.org/wiki/Cerebellum" title="Cerebellum">cerebellum</a> and <a href="https://en.wikipedia.org/wiki/Retina" title="Retina">retina</a> retain characteristic radial glial cells. In the cerebellum, these are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Bergmann_glia" title="Bergmann glia">Bergmann glia</a>, which regulate <a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" title="Synaptic plasticity">synaptic plasticity</a>. In the retina, the radial <a class="mw-redirect" href="https://en.wikipedia.org/wiki/M%C3%BCller_cell" title="Müller cell">Müller cell</a> is the glial cell that spans the thickness of the retina and, in addition to astroglial cells, participates in a bidirectional communication with neurons.
</p>
</td></tr>
<tr>
<td><a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">PNS</a></td>
<td><a href="https://en.wikipedia.org/wiki/Schwann_cell" title="Schwann cell">Schwann cells</a></td>
<td>
<p>Similar in function to oligodendrocytes, <i>Schwann cells</i> provide myelination to axons in the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a> (PNS). They also have <a href="https://en.wikipedia.org/wiki/Phagocytosis" title="Phagocytosis">phagocytotic</a> activity and clear cellular debris that allows for regrowth of PNS neurons.
</p>
</td></tr>
<tr>
<td>PNS</td>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Satellite_cells_(glial)" title="Satellite cells (glial)">Satellite cells</a></td>
<td>
<p><i>Satellite glial cells</i> are small cells that surround neurons in sensory, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Sympathetic_ganglion" title="Sympathetic ganglion">sympathetic</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Parasympathetic_ganglion" title="Parasympathetic ganglion">parasympathetic</a> ganglia. These cells help regulate the external chemical environment. Like astrocytes, they are interconnected by <a href="https://en.wikipedia.org/wiki/Gap_junction" title="Gap junction">gap junctions</a> and respond to ATP by elevating the intracellular concentration of calcium ions. They are highly sensitive to <a href="https://en.wikipedia.org/wiki/Injury" title="Injury">injury</a> and <a href="https://en.wikipedia.org/wiki/Inflammation" title="Inflammation">inflammation</a> and appear to contribute to pathological states, such as <a href="https://en.wikipedia.org/wiki/Chronic_pain" title="Chronic pain">chronic pain</a>.
</p>
</td></tr>
<tr>
<td>PNS</td>
<td><a href="https://en.wikipedia.org/wiki/Nervous_tissue#Components" title="Nervous tissue">Enteric glial cells</a></td>
<td>
<p>Are found in the intrinsic ganglia of the <a href="https://en.wikipedia.org/wiki/Human_digestive_system" title="Human digestive system">digestive system</a>. Glia cells are thought to have many roles in the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Enteric" title="Enteric">enteric</a> system, some related to <a href="https://en.wikipedia.org/wiki/Homeostasis" title="Homeostasis">homeostasis</a> and muscular digestive processes.
</p>
</td></tr></tbody></table>
<h3><span class="mw-headline" id="Microglia">Microglia</span></h3><div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">Microglia</a></div>
<p><a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">Microglia</a> are specialized <a href="https://en.wikipedia.org/wiki/Macrophage" title="Macrophage">macrophages</a> capable of <a href="https://en.wikipedia.org/wiki/Phagocytosis" title="Phagocytosis">phagocytosis</a> that protect neurons of the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>. They are derived from the earliest wave of mononuclear cells that originate in <a href="https://en.wikipedia.org/wiki/Yolk_sac" title="Yolk sac">yolk sac</a> blood islands early in development, and colonize the brain shortly after the neural precursors begin to differentiate.
</p><p>These cells are found in all regions of the brain and spinal
cord. Microglial cells are small relative to macroglial cells, with
changing shapes and oblong nuclei. They are mobile within the brain and
multiply when the brain is damaged. In the healthy central nervous
system, microglia processes constantly sample all aspects of their
environment (neurons, macroglia and blood vessels). In a healthy brain,
microglia direct the immune response to brain damage and play an
important role in the inflammation that accompanies the damage. Many
diseases and disorders are associated with deficient microglia, such as <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a>, <a href="https://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease">Parkinson's disease</a> and <a href="https://en.wikipedia.org/wiki/ALS" title="ALS">ALS</a>.
</p>
<h3><span class="mw-headline" id="Other">Other</span></h3><p><a href="https://en.wikipedia.org/wiki/Pituicyte" title="Pituicyte">Pituicytes</a> from the <a href="https://en.wikipedia.org/wiki/Posterior_pituitary" title="Posterior pituitary">posterior pituitary</a> are glial cells with characteristics in common to astrocytes. <a href="https://en.wikipedia.org/wiki/Tanycyte" title="Tanycyte">Tanycytes</a> in the <a href="https://en.wikipedia.org/wiki/Median_eminence" title="Median eminence">median eminence</a> of the <a href="https://en.wikipedia.org/wiki/Hypothalamus" title="Hypothalamus">hypothalamus</a> are a type of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ependymal_cell" title="Ependymal cell">ependymal cell</a> that descend from radial glia and line the base of the <a href="https://en.wikipedia.org/wiki/Third_ventricle" title="Third ventricle">third ventricle</a>. <i><a href="https://en.wikipedia.org/wiki/Drosophila_melanogaster" title="Drosophila melanogaster">Drosophila melanogaster</a>,</i>
the fruit fly, contains numerous glial types that are functionally
similar to mammalian glia but are nonetheless classified differently.
</p>
<h3><span class="mw-headline" id="Total_number">Total number</span></h3><p>In general, neuroglial cells are smaller than neurons. There are approximately 85 billion glia cells in the human brain, about the same number as neurons. Glial cells make up about half the total volume of the brain and spinal cord.
The glia to neuron-ratio varies from one part of the brain to another.
The glia to neuron-ratio in the cerebral cortex is 3.72 (60.84 billion
glia (72%); 16.34 billion neurons), while that of the cerebellum is only
0.23 (16.04 billion glia; 69.03 billion neurons). The ratio in the
cerebral cortex gray matter is 1.48, with 3.76 for the gray and white
matter combined. The ratio of the basal ganglia, diencephalon and brainstem combined is 11.35.
</p><p>The total number of glia cells in the human brain is distributed into the different types with <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocytes</a> being the most frequent (45–75%), followed by <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a> (19–40%) and <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">microglia</a> (about 10% or less).
</p>
<h2><span class="mw-headline" id="Development">Development</span></h2><figure class="mw-default-size"><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Human_astrocyte.png"><img class="mw-file-element" data-file-height="1145" data-file-width="1577" height="291" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/56/Human_astrocyte.png/220px-Human_astrocyte.png" width="400" /></a><figcaption>23-week fetal brain culture astrocyte</figcaption></figure>
<div class="hatnote navigation-not-searchable" role="note">Main article: <a href="https://en.wikipedia.org/wiki/Gliogenesis" title="Gliogenesis">Gliogenesis</a></div>
<p>Most glia are derived from <a href="https://en.wikipedia.org/wiki/Germ_layer" title="Germ layer">ectodermal</a> tissue of the developing <a href="https://en.wikipedia.org/wiki/Embryo" title="Embryo">embryo</a>, in particular the <a href="https://en.wikipedia.org/wiki/Neural_tube" title="Neural tube">neural tube</a> and <a href="https://en.wikipedia.org/wiki/Neural_crest" title="Neural crest">crest</a>. The exception is <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">microglia</a>, which are derived from <a href="https://en.wikipedia.org/wiki/Hematopoietic_stem_cell" title="Hematopoietic stem cell">hematopoietic stem cells</a>.
In the adult, microglia are largely a self-renewing population and are
distinct from macrophages and monocytes, which infiltrate an injured and
diseased CNS.
</p><p>In the central nervous system, glia develop from the ventricular
zone of the neural tube. These glia include the oligodendrocytes,
ependymal cells, and astrocytes. In the peripheral nervous system, glia
derive from the neural crest. These PNS glia include Schwann cells in
nerves and satellite glial cells in ganglia.
</p>
<h3><span class="mw-headline" id="Capacity_to_divide">Capacity to divide</span></h3><p>Glia
retain the ability to undergo cell divisions in adulthood, whereas most
neurons cannot. The view is based on the general inability of the
mature nervous system to replace neurons after an injury, such as a <a href="https://en.wikipedia.org/wiki/Stroke" title="Stroke">stroke</a> or trauma, where very often there is a substantial proliferation of glia, or <a href="https://en.wikipedia.org/wiki/Gliosis" title="Gliosis">gliosis</a>, near or at the site of damage. However, detailed studies have found no evidence that 'mature' glia, such as astrocytes or <a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">oligodendrocytes</a>, retain mitotic capacity. Only the resident <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Oligodendrocyte_precursor_cell" title="Oligodendrocyte precursor cell">oligodendrocyte precursor cells</a> seem to keep this ability once the nervous system matures.
</p><p>Glial cells are known to be capable of <a href="https://en.wikipedia.org/wiki/Mitosis" title="Mitosis">mitosis</a>. By contrast, scientific understanding of whether neurons are permanently <a href="https://en.wikipedia.org/wiki/Mitosis" title="Mitosis">post-mitotic</a>, or capable of mitosis, is still developing. In the past, glia had been considered to lack certain features of neurons. For example, glial cells were not believed to have <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">chemical synapses</a> or to release <a href="https://en.wikipedia.org/wiki/Neurotransmitter" title="Neurotransmitter">transmitters</a>.
They were considered to be the passive bystanders of neural
transmission. However, recent studies have shown this to not be entirely
true.
</p>
<h2><span class="mw-headline" id="Functions">Functions</span></h2><p>Some glial cells function primarily as the physical support for neurons. Others provide nutrients to neurons and regulate the <a href="https://en.wikipedia.org/wiki/Extracellular_fluid" title="Extracellular fluid">extracellular fluid</a> of the brain, especially surrounding neurons and their <a href="https://en.wikipedia.org/wiki/Synapse" title="Synapse">synapses</a>. During early <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Embryogenesis" title="Embryogenesis">embryogenesis</a>, glial cells direct the migration of neurons and produce molecules that modify the growth of <a href="https://en.wikipedia.org/wiki/Axon" title="Axon">axons</a> and <a href="https://en.wikipedia.org/wiki/Dendrite" title="Dendrite">dendrites</a>. Some glial cells display regional diversity in the CNS and their functions may vary between the CNS regions.
</p>
<h3><span class="mw-headline" id="Neuron_repair_and_development">Neuron repair and development</span></h3><p>Glia are crucial in the development of the nervous system and in processes such as <a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" title="Synaptic plasticity">synaptic plasticity</a> and <a href="https://en.wikipedia.org/wiki/Synaptogenesis" title="Synaptogenesis">synaptogenesis</a>. Glia have a role in the regulation of repair of neurons after injury. In the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a> (CNS), glia suppress repair. Glial cells known as <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a>
enlarge and proliferate to form a scar and produce inhibitory molecules
that inhibit regrowth of a damaged or severed axon. In the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">peripheral nervous system</a> (PNS), glial cells known as <a href="https://en.wikipedia.org/wiki/Schwann_cell" title="Schwann cell">Schwann cells</a>
(or also as neuri-lemmocytes) promote repair. After axonal injury,
Schwann cells regress to an earlier developmental state to encourage
regrowth of the axon. This difference between the CNS and the PNS,
raises hopes for the regeneration of nervous tissue in the CNS. For
example, a spinal cord may be able to be repaired following injury or
severance.
</p>
<h3><span class="mw-headline" id="Myelin_sheath_creation">Myelin sheath creation</span></h3><p><a href="https://en.wikipedia.org/wiki/Oligodendrocyte" title="Oligodendrocyte">Oligodendrocytes</a>
are found in the CNS and resemble an octopus: they have bulbous cell
bodies with up to fifteen arm-like processes. Each process reaches out
to an axon and spirals around it, creating a myelin sheath. The myelin
sheath insulates the nerve fiber from the extracellular fluid and speeds
up signal conduction along the nerve fiber.
In the peripheral nervous system, Schwann cells are responsible for
myelin production. These cells envelop nerve fibers of the PNS by
winding repeatedly around them. This process creates a myelin sheath,
which not only aids in conductivity but also assists in the regeneration
of damaged fibers.
</p>
<h3><span class="mw-headline" id="Neurotransmission">Neurotransmission</span></h3><p><a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">Astrocytes</a> are crucial participants in the <a href="https://en.wikipedia.org/wiki/Tripartite_synapse" title="Tripartite synapse">tripartite synapse</a>. They have several crucial functions, including clearance of <a href="https://en.wikipedia.org/wiki/Neurotransmitter" title="Neurotransmitter">neurotransmitters</a> from within the <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Synaptic_cleft" title="Synaptic cleft">synaptic cleft</a>,
which aids in distinguishing between separate action potentials and
prevents toxic build-up of certain neurotransmitters such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Glutamate" title="Glutamate">glutamate</a>, which would otherwise lead to <a href="https://en.wikipedia.org/wiki/Excitotoxicity" title="Excitotoxicity">excitotoxicity</a>. Furthermore, <a href="https://en.wikipedia.org/wiki/Astrocyte" title="Astrocyte">astrocytes</a> release <a href="https://en.wikipedia.org/wiki/Gliotransmitter" title="Gliotransmitter">gliotransmitters</a> such as glutamate, ATP, and D-serine in response to stimulation.
</p>
<h2><span class="mw-headline" id="Clinical_significance">Clinical significance</span></h2><div class="hatnote navigation-not-searchable" role="note">See also: <a href="https://en.wikipedia.org/wiki/Glioma" title="Glioma">Glioma</a></div>
<figure><a class="mw-file-description" href="https://en.wikipedia.org/wiki/File:Anaplastic_astrocytoma_-_gfap_-_very_high_mag.jpg"><img class="mw-file-element" data-file-height="2848" data-file-width="4272" height="267" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1e/Anaplastic_astrocytoma_-_gfap_-_very_high_mag.jpg/250px-Anaplastic_astrocytoma_-_gfap_-_very_high_mag.jpg" width="400" /></a><figcaption><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Neoplastic" title="Neoplastic">Neoplastic</a> glial cells stained with an antibody against GFAP (brown), from a <a href="https://en.wikipedia.org/wiki/Brain_biopsy" title="Brain biopsy">brain biopsy</a></figcaption></figure>
<p>While glial cells in the <a href="https://en.wikipedia.org/wiki/Peripheral_nervous_system" title="Peripheral nervous system">PNS</a> frequently assist in regeneration of lost neural functioning, loss of neurons in the <a href="https://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system">CNS</a> does not result in a similar reaction from neuroglia. In the CNS, regrowth will only happen if the trauma was mild, and not severe.
When severe trauma presents itself, the survival of the remaining
neurons becomes the optimal solution. However, some studies
investigating the role of glial cells in <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a> are beginning to contradict the usefulness of this feature, and even claim it can "exacerbate" the disease.
In addition to affecting the potential repair of neurons in Alzheimer's
disease, scarring and inflammation from glial cells have been further
implicated in the degeneration of neurons caused by <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis" title="Amyotrophic lateral sclerosis">amyotrophic lateral sclerosis</a>.
</p><p>In addition to neurodegenerative diseases, a wide range of harmful exposure, such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Hypoxia_(medical)" title="Hypoxia (medical)">hypoxia</a>, or physical trauma, can lead to the end result of physical damage to the CNS. Generally, when damage occurs to the CNS, glial cells cause <a href="https://en.wikipedia.org/wiki/Apoptosis" title="Apoptosis">apoptosis</a> among the surrounding cellular bodies. Then, there is a large amount of <a href="https://en.wikipedia.org/wiki/Microglia" title="Microglia">microglial</a> activity, which results in inflammation, and, finally, there is a heavy release of growth inhibiting molecules.
</p>
<h2><span class="mw-headline" id="History">History</span></h2><p>Although
glial cells and neurons were probably first observed at the same time
in the early 19th century, unlike neurons whose morphological and
physiological properties were directly observable for the first
investigators of the nervous system, glial cells had been considered to
be merely "glue" that held neurons together until the mid-20th century.
</p><p>Glia were first described in 1856 by the pathologist <a href="https://en.wikipedia.org/wiki/Rudolf_Virchow" title="Rudolf Virchow">Rudolf Virchow</a>
in a comment to his 1846 publication on connective tissue. A more
detailed description of glial cells was provided in the 1858 book
'Cellular Pathology' by the same author.
</p><p>When markers for different types of cells were analyzed, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Albert_Einstein%27s_brain" title="Albert Einstein's brain">Albert Einstein's brain</a> was discovered to contain significantly more glia than normal brains in the left angular <a href="https://en.wikipedia.org/wiki/Gyrus" title="Gyrus">gyrus</a>, an area thought to be responsible for mathematical processing and language.
However, out of the total of 28 statistical comparisons between
Einstein's brain and the control brains, finding one statistically
significant result is not surprising, and the claim that Einstein's
brain is different is not scientific (c.f. <a href="https://en.wikipedia.org/wiki/Multiple_comparisons_problem" title="Multiple comparisons problem">Multiple comparisons problem</a>).
</p><p>Not only does the ratio of glia to neurons increase through
evolution, but so does the size of the glia. Astroglial cells in human
brains have a volume 27 times greater than in mouse brains.
</p><p>These important scientific findings may begin to shift the
neurocentric perspective into a more holistic view of the brain which
encompasses the glial cells as well. For the majority of the twentieth
century, scientists had disregarded glial cells as mere physical
scaffolds for neurons. Recent publications have proposed that the number
of glial cells in the brain is correlated with the intelligence of a
species.
Moreover, evidences are demonstrating the active role of glia, in
particular astroglia, in cognitive processes like learning and memory
and, for these reasons, it has been proposed the foundation of a
specific field to study these functions because investigations in this
area are still limited due to the dominance of the neurocentric
perspective.</p>David J Strumfelshttp://www.blogger.com/profile/09219454080416178949noreply@blogger.com