A Medley of Potpourri

Monday, September 2, 2024

Patients' rights

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Patients%27_rights

Patient rights consist of enforceable duties that healthcare professionals and healthcare business persons owe to patients to provide them with certain services or benefits. When such services or benefits become rights instead of simply privileges, then a patient can expect to receive them and can expect the support of people who enforce organization policies or legal codes to intervene on the patient's behalf if the patient does not receive them. A patient's bill of rights is a list of guarantees for those receiving medical care. It may take the form of a law or a non-binding declaration. Typically a patient's bill of rights guarantees patients information, fair treatment, and autonomy over medical decisions, among other rights.

India

Under the direction of the Ministry of Health and Family Welfare (MOHFW), India's National Human Rights Commission drafted a Charter of Patients' Rights in 2018. Following a recommendation by the National Council of Clinical Establishments, MOHFW submitted the draft in the public domain for comments and suggestions in August 2018.

The Charter draws upon different provisions relevant to patients' rights that were previously scattered across the Constitution of India, the Drugs and Cosmetic Act of 1940, the Clinical Establishment Act of 2010, and various judgments by the Supreme Court of India, among other sources. The Charter aims to:

provide a reference for State Governments to enact or modify existing regulation.
provide a framework of healthcare standards for service providers.
And, raise awareness among patients about their rights.

Recognized patients' rights

The Charter of Patients' Rights lists seventeen rights that patients are entitled to:

Right to information: Every patient has the right to know what is the illness that they are suffering, its causes, the status of the diagnosis (provisional or confirmed), expected costs of treatment. Furthermore, service providers should communicate this in a manner that is understandable for the patient.
Right to records and reports: The patient has the right to access his/her medical records and investigation reports. Service providers should make these available upon the patients' payment of any photocopy fees as applicable.
Right to emergency care: Public and private hospitals have an obligation to provide emergency medical care regardless of the patients' capacity to pay for the services.
Right to informed consent: Patients have the right to be asked for their informed consent before submitting to potentially hazardous treatment. Physicians should clearly explain the risks from receiving the treatment and only administer the treatment after getting explicit written consent from the patient.
Right to confidentiality, human dignity and privacy: Doctors should observe strict confidentiality of a patient's condition, with the only exception of potential threats to public health. In case of a physical inspection by a male doctor on a female patient, the latter has the right to have a female person present throughout the procedure. Hospitals also have an obligation to secure patient information from any external threats.
Right to second opinion: Patients are entitled to seek a second opinion and hospitals should facilitate any information or records that the patient requires to do so.
Right to transparency in rates, and care according to prescribed rates wherever relevant: Hospitals should display the rates that they charge in a visible manner and patients should receive an itemized bill when payment is required. Essential medicines, devices and implants should comply with rates established by the National Pharmaceutical Pricing Authority (NPPA).
Right to non-discrimination: Service providers cannot deny treatment on the basis of gender, caste, religion, age, sexual orientation or social origins. Additionally, it is against the Charter to deny treatment on the basis of a patients' health condition, including HIV status.
Right to safety and quality care according to standards: Hospitals must ensure a hygienic and sanitized environment to provide their services.
Right to choose alternative treatment options if available: Patients have the right to consider treatment alternatives and even refuse treatment.
Right to choose source for obtaining medicines or tests: Any registered pharmacy and laboratory is eligible to provide patients with goods and services they require.
Right to proper referral and transfer, which is free from perverse commercial influences: In case of transfers or referrals, the patient has the right to an explanation that justifies the transfer, as well as confirmation from the hospital receiving the patient about their acceptance of the transfer.
Right to protection for patients involved in clinical trials: Clinical trials should comply with all the standards and protocols under the Directorate General of Health Services.
Right to protection of participants involved in biomedical and health research: Studies involving patients should follow the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants.
Right to take discharge of patient, or receive body of deceased from hospital: Patients have the right to be discharged and may not be detained at a health service provider facility because of procedural reasons such as payment disputes.
Right to Patient Education: In addition to information about their condition, patients have the right to know about public health services such as insurance schemes and charitable hospitals.
Right to be heard and seek redressal: feedback and comments to their health service providers and file complaints as required. They additionally have the right to redressal in cases where any of their rights are violated.

Morocco

Morocco has expressed its interest in recognizing the right to health for the entire population, a right rooted in the Islamic religion.

United Kingdom

In the UK, the Patient's Charter was introduced and revised in the 1990s. It was replaced by the NHS Constitution for England in 2013.

United States

In the United States there have been a number of attempts to enshrine a patient's bill of rights in law, including a bill rejected by Congress in 2001.

Bill of 2001

The United States Congress considered a bill designed to safeguard patients' rights in 2001. The "Bipartisan Patient Protection Act" (S.1052), sponsored by Senators Edward Kennedy and John McCain, contained new rules for what health maintenance organizations had to cover and granted new rights for patients to sue in state or federal courts, if they are denied needed care.

The House of Representatives and Senate passed differing versions of the proposed law. Although both bills would have provided patients key rights, such as prompt access to emergency care and medical specialists, only the Senate-passed measure would provide patients with adequate means to enforce their rights. The Senate's proposal would have conferred a broad array of rights on patients. It would have ensured that patients with health care plans had the right to:

have their medical decisions made by a doctor;
see a medical specialist;
go to the closest emergency room;

The bill was passed by the US Senate by a vote of 59–36 in 2001, it was then amended by the House of Representatives and returned to the Senate. Reportedly, president Bush threatened to veto the bill if it included the Senate's provision to allow patients to sue managed care organizations in the state and federal courts.

Industry resistance

Wendell Potter, former senior executive at Cigna-turned-whistleblower, has written that the insurance industry worked to kill "any reform that might interfere with insurers' ability to increase profits" by engaging in extensive and well-funded anti-reform campaigns. The industry, he says, "goes to great lengths to keep its involvement in these campaigns hidden from public view," including the use of "front groups".

The ethical responsibility of health professionals to respect patients' rights

By highlighting the ethical responsibility of health care professionals towards their patients, basic principles are mentioned, such as self-esteem, prevention of harm, promotion of well-being and justice. These principles play an essential role in guiding medical decisions, helping healthcare providers care for the well-being of patients while maintaining their decision-making capacity, thus achieving a fundamental balance between medical ethics and the commitment of health professionals to patients

Just-world fallacy

From Wikipedia, the free encyclopedia

The just-world fallacy, or just-world hypothesis, is the cognitive bias that assumes that "people get what they deserve" – that actions will necessarily have morally fair and fitting consequences for the actor. For example, the assumptions that noble actions will eventually be rewarded and evil actions will eventually be punished fall under this fallacy. In other words, the just-world fallacy is the tendency to attribute consequences to—or expect consequences as the result of— either a universal force that restores moral balance or a universal connection between the nature of actions and their results. This belief generally implies the existence of cosmic justice, destiny, divine providence, desert, stability, order, or the anglophone colloquial use of "karma". It is often associated with a variety of fundamental fallacies, especially in regard to rationalizing suffering on the grounds that the sufferers "deserve" it. This is called victim blaming.

This fallacy popularly appears in the English language in various figures of speech that imply guaranteed punishment for wrongdoing, such as: "you got what was coming to you", "what goes around comes around", "chickens come home to roost", "everything happens for a reason", and "you reap what you sow". This hypothesis has been widely studied by social psychologists since Melvin J. Lerner conducted seminal work on the belief in a just world in the early 1960s. Research has continued since then, examining the predictive capacity of the fallacy in various situations and across cultures, and clarifying and expanding the theoretical understandings of just-world beliefs.

Emergence

Many philosophers and social theorists have observed and considered the phenomenon of belief in a just world, going back to at least as early as the Pyrrhonist philosopher Sextus Empiricus, writing circa 180 CE, who argued against this belief. Lerner's work made the just-world hypothesis a focus of research in the field of social psychology. Aristotelian ethics views "justice" as the chief of the virtues, moral sense being deeply rooted in the nature of humans as social and rational animals.

Melvin Lerner

Lerner was prompted to study justice beliefs and the just-world fallacy in the context of social psychological inquiry into negative social and societal interactions. Lerner saw his work as extending Stanley Milgram's work on obedience. He sought to answer the questions of how regimes that cause cruelty and suffering maintain popular support, and how people come to accept social norms and laws that produce misery and suffering.

Lerner's inquiry was influenced by repeatedly witnessing the tendency of observers to blame victims for their suffering. During his clinical training as a psychologist, he observed treatment of mentally ill persons by the health care practitioners with whom he worked. Although Lerner knew them to be kindhearted, educated people, they often blamed patients for the patients' own suffering. Lerner also describes his surprise at hearing his students derogate (disparage, belittle) the poor, seemingly oblivious to the structural forces that contribute to poverty. The desire to understand the processes that caused these phenomena led Lerner to conduct his first experiments on what is now called the just-world fallacy.

Early evidence

In 1966, Lerner and his colleagues began a series of experiments that used shock paradigms to investigate observer responses to victimization. In the first of these experiments conducted at the University of Kansas, 72 female participants watched what appeared to be a confederate receiving electrical shocks for her errors during a learning task (learning pairs of nonsense syllables). Initially, these observing participants were upset by the victim's apparent suffering. But as the suffering continued and observers remained unable to intervene, the observers began to reject and devalue the victim. Rejection and devaluation of the victim was greater when the observed suffering was greater. But when participants were told the victim would receive compensation for her suffering, the participants did not derogate the victim. Lerner and colleagues replicated these findings in subsequent studies, as did other researchers.

Theory

To explain these studies' findings, it was theorized that there was a prevalent belief in a just world. A just world is one in which actions and conditions have predictable, appropriate consequences. These actions and conditions are typically individuals' behaviors or attributes. The specific conditions that correspond to certain consequences are socially determined by a society's norms and ideologies. Lerner presents the belief in a just world as functional: it maintains the idea that one can influence the world in a predictable way. Belief in a just world functions as a sort of "contract" with the world regarding the consequences of behavior. This allows people to plan for the future and engage in effective, goal-driven behavior. Lerner summarized his findings and his theoretical work in his 1980 monograph The Belief in a Just World: A Fundamental Delusion.

Lerner hypothesized that the belief in a just world is crucially important for people to maintain for their own well-being. But people are confronted daily with evidence that the world is not just: people suffer without apparent cause. Lerner explained that people use strategies to eliminate threats to their belief in a just world. These strategies can be rational or irrational. Rational strategies include accepting the reality of injustice, trying to prevent injustice or provide restitution, and accepting one's own limitations. Non-rational strategies include denial, withdrawal, and reinterpretation of the event.

There are a few modes of reinterpretation that could make an event fit the belief in a just world. One can reinterpret the outcome, the cause, and/or the character of the victim. In the case of observing the injustice of the suffering of innocent people, one major way to rearrange the cognition of an event is to interpret the victim of suffering as deserving. Specifically, observers can blame victims for their suffering on the basis of their behaviors and/or their characteristics. Much psychological research on the belief in a just world has focused on these negative social phenomena of victim blaming and victim derogation in different contexts.

An additional effect of this thinking is that individuals experience less personal vulnerability because they do not believe they have done anything to deserve or cause negative outcomes. This is related to the self-serving bias observed by social psychologists.

Many researchers have interpreted just-world beliefs as an example of causal attribution. In victim blaming, the causes of victimization are attributed to an individual rather than to a situation. Thus, the consequences of belief in a just world may be related to or explained in terms of particular patterns of causal attribution.

Alternatives

Veridical judgment

Others have suggested alternative explanations for the derogation of victims. One suggestion is that derogation effects are based on accurate judgments of a victim's character. In particular, in relation to Lerner's first studies, some have hypothesized that it would be logical for observers to derogate an individual who would allow himself to be shocked without reason. A subsequent study by Lerner challenged this alternative hypothesis by showing that individuals are only derogated when they actually suffer; individuals who agreed to undergo suffering but did not were viewed positively.

Guilt reduction

Another alternative explanation offered for the derogation of victims early in the development of the just-world fallacy was that observers derogate victims to reduce their own feelings of guilt. Observers may feel responsible, or guilty, for a victim's suffering if they themselves are involved in the situation or experiment. In order to reduce the guilt, they may devalue the victim. Lerner and colleagues claim that there has not been adequate evidence to support this interpretation. They conducted one study that found derogation of victims occurred even by observers who were not implicated in the process of the experiment and thus had no reason to feel guilty.

Discomfort reduction

Alternatively, victim derogation and other strategies may only be ways to alleviate discomfort after viewing suffering. This would mean that the primary motivation is not to restore a belief in a just world, but to reduce discomfort caused by empathizing. Studies have shown that victim derogation does not suppress subsequent helping activity and that empathizing with the victim plays a large role when assigning blame. According to Ervin Staub, devaluing the victim should lead to lesser compensation if restoring belief in a just world was the primary motive; instead, there is virtually no difference in compensation amounts whether the compensation precedes or follows devaluation. Psychopathy has been linked to the lack of just-world maintaining strategies, possibly due to dampened emotional reactions and lack of empathy.

Additional evidence

After Lerner's first studies, other researchers replicated these findings in other settings in which individuals are victimized. This work, which began in the 1970s and continues today, has investigated how observers react to victims of random calamities like traffic accidents, as well as rape and domestic violence, illnesses, and poverty. Generally, researchers have found that observers of the suffering of innocent victims tend to both derogate and blame victims for their suffering. Observers thus maintain their belief in a just world by changing their cognitions about the victims' character.

In the early 1970s, social psychologists Zick Rubin and Letitia Anne Peplau developed a measure of belief in a just world. This measure and its revised form published in 1975 allowed for the study of individual differences in just-world beliefs. Much of the subsequent research on the just-world hypothesis used these measurement scales.

These studies on victims of violence, illness, and poverty and others like them have provided consistent support for the link between observers' just-world beliefs and their tendency to blame victims for their suffering. As a result, the existence of the just-world hypothesis as a psychological phenomenon has become widely accepted.

Violence

Researchers have looked at how observers react to victims of rape and other violence. In a formative experiment on rape and belief in a just world by Linda Carli and colleagues, researchers gave two groups of subjects a narrative about interactions between a man and a woman. The description of the interaction was the same until the end; one group received a narrative that had a neutral ending and the other group received a narrative that ended with the man raping the woman. Subjects judged the rape ending as inevitable and blamed the woman in the narrative for the rape on the basis of her behavior, but not her characteristics. These findings have been replicated repeatedly, including using a rape ending and a "happy ending" (a marriage proposal).

Other researchers have found a similar phenomenon for judgments of battered partners. One study found that observers' labels of blame of female victims of relationship violence increase with the intimacy of the relationship. Observers blamed the perpetrator only in the least intimate case of violence, in which a male struck an acquaintance.

Bullying

Researchers have employed the just-world fallacy to understand bullying. Given other research on beliefs in a just world, it would be expected that observers would derogate and blame bullying victims, but the opposite has been found: individuals high in just-world belief have stronger anti-bullying attitudes. Other researchers have found that strong belief in a just world is associated with lower levels of bullying behavior. This finding is in keeping with Lerner's understanding of belief in a just world as functioning as a "contract" that governs behavior. There is additional evidence that belief in a just world is protective of the well-being of children and adolescents in the school environment, as has been shown for the general population.

Illness

Other researchers have found that observers judge sick people as responsible for their illnesses. One experiment showed that persons suffering from a variety of illnesses were derogated on a measure of attractiveness more than healthy individuals were. In comparison to healthy people, victim derogation was found for persons presenting with indigestion, pneumonia, and stomach cancer. Moreover, derogation was found to be higher for those suffering from more severe illnesses, except for those presenting with cancer. Stronger belief in a just world has also been found to correlate with greater derogation of AIDS victims.

Poverty

More recently, researchers have explored how people react to poverty through the lens of the just-world fallacy. Strong belief in a just world is associated with blaming the poor, with weak belief in a just world associated with identifying external causes of poverty including world economic systems, war, and exploitation.

The self as victim

Some research on belief in a just world has examined how people react when they themselves are victimized. An early paper by Dr. Ronnie Janoff-Bulman found that rape victims often blame their own behavior, but not their own characteristics, for their victimization. It was hypothesized that this may be because blaming one's own behavior makes an event more controllable.

Theoretical refinement

Subsequent work on measuring belief in a just world has focused on identifying multiple dimensions of the belief. This work has resulted in the development of new measures of just-world belief and additional research. Hypothesized dimensions of just-world beliefs include belief in an unjust world, beliefs in immanent justice and ultimate justice, hope for justice, and belief in one's ability to reduce injustice. Other work has focused on looking at the different domains in which the belief may function; individuals may have different just-world beliefs for the personal domain, the sociopolitical domain, the social domain, etc. An especially fruitful distinction is between the belief in a just world for the self (personal) and the belief in a just world for others (general). These distinct beliefs are differentially associated with positive mental health.

Correlates

Researchers have used measures of belief in a just world to look at correlates of high and low levels of belief in a just world.

Limited studies have examined ideological correlates of the belief in a just world. These studies have found sociopolitical correlates of just-world beliefs, including right-wing authoritarianism and the Protestant work ethic. Studies have also found belief in a just world to be correlated with aspects of religiosity.

Studies of demographic differences, including gender and racial differences, have not shown systemic differences, but do suggest racial differences, with black people and African Americans having the lowest levels of belief in a just world.

The development of measures of just-world beliefs has also allowed researchers to assess cross-cultural differences in just-world beliefs. Much research conducted shows that beliefs in a just world are evident cross-culturally. One study tested beliefs in a just world of students in 12 countries. This study found that in countries where the majority of inhabitants are powerless, belief in a just world tends to be weaker than in other countries. This supports the theory of the just-world fallacy because the powerless have had more personal and societal experiences that provided evidence that the world is not just and predictable.

Belief in unjust world has been linked to increased self-handicapping, criminality, defensive coping, anger and perceived future risk. It may also serve as ego-protective belief for certain individuals by justifying maladaptive behavior.

Current research

Although much of the initial work on belief in a just world focused on its negative social effects, other research suggests that belief in a just world is good, and even necessary, for mental health. Belief in a just world is associated with greater life satisfaction and well-being and less depressive affect.Researchers are actively exploring the reasons why the belief in a just world might have this relationship to mental health; it has been suggested that such beliefs could be a personal resource or coping strategy that buffers stress associated with daily life and with traumatic events. This hypothesis suggests that belief in a just world can be understood as a positive illusion. In line with this perspective, recent research also suggests that belief in a just world may explain the known statistical association between religiosity/spirituality and psychological well-being. Some belief in a just world research has been conducted within the framework of primal world beliefs, and has found strong correlations between just world belief and beliefs that the world is safe, abundant and cooperative (among other qualities).

Some studies also show that beliefs in a just world are correlated with internal locus of control. Strong belief in a just world is associated with greater acceptance of and less dissatisfaction with negative events in one's life. This may be one way in which belief in a just world affects mental health. Others have suggested that this relationship holds only for beliefs in a just world for oneself. Beliefs in a just world for others are related instead to the negative social phenomena of victim blaming and victim derogation observed in other studies.

Belief in a just world has also been found to negatively predict the perceived likelihood of kin favoritism. The perspective of the individual plays an important role in this relationship, such that when people imagine themselves as mere observers of injustice, general belief in a just world will be the stronger predictor, and when they imagine themselves as victims of injustice, personal belief in a just world will be the stronger predictor. This further supports the distinction between general and personal belief in a just world.

International research

More than 40 years after Lerner's seminal work on belief in a just world, researchers continue to study the phenomenon. Belief in a just world scales have been validated in several countries such as Iran, Russia, Brazil, and France. Work continues primarily in the United States, Europe, Australia, and Asia. Researchers in Germany have contributed disproportionately to recent research. Their work resulted in a volume edited by Lerner and German researcher Leo Montada titled Responses to Victimizations and Belief in a Just World.

The Hallmarks of Cancer

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/The_Hallmarks_of_Cancer

The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.

These hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. In addition to cancer cells, tumors exhibit another dimension of complexity: they incorporate a community of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways and (2) evasion of the immune system, and two enabling characteristics: (1) genome instability, and (2) inflammation.

List of hallmarks

Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis).

Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit programmed cell death (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.

All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical protein must malfunction in each of those mechanisms. These proteins become non-functional or malfunctioning when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, which Hanahan and Weinberg refer to as hallmarks.

Summary
Capability	Simple analogy
Self-sufficiency in growth signals	"accelerator pedal stuck on"
Insensitivity to anti-growth signals	"brakes don't work"
Evading apoptosis	won't die when the body normally would kill the defective cell
Limitless replicative potential	infinite generations of descendants
Sustained angiogenesis	telling the body to give it a blood supply
Tissue invasion and metastasis	migrating and spreading to other organs and tissues

Self-sufficiency in growth signals

Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply.

Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signalling; by permanently activating the signalling pathways that respond to these signals; or by destroying 'off switches' that prevents excessive growth from these signals (negative feedback). In addition, cell division in normal, non-cancerous cells is tightly controlled. In cancer cells, these processes are deregulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor.

Insensitivity to anti-growth signals

Cancer cells are generally resistant to growth-preventing signals from their neighbours.

To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are orchestrated by proteins encoded by tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not (when the DNA is damaged, for example). In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division, even when the cell has severe abnormalities. Another way cells prevent over-division is that normal cells will also stop dividing when the cells fill up the space they are in and touch other cells; known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings.

Evading programmed cell death

Apoptosis is a form of programmed cell death (cell suicide), the mechanism by which cells are programmed to die in the event they become damaged. Cancer cells are characteristically able to bypass this mechanism.

Cells have the ability to 'self-destruct'; a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability; even though cells may become grossly abnormal, they do not undergo apoptosis. The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. This means that proper signaling cannot occur, thus apoptosis cannot activate. They may also have defects in the downstream signaling itself, or the proteins involved in apoptosis, each of which will also prevent proper apoptosis.

Limitless replicative potential

Non-cancer cells die after a certain number of divisions. Cancer cells escape this limit and are apparently capable of indefinite growth and division (immortality). But those immortal cells have damaged chromosomes, which can become cancerous.

Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide (senescence), or die (crisis). The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes (telomerase) to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence.

Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60–70 doublings, at which point they reach a stage of senescence.

This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10⁻⁷) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.

The counting device for cell doublings is the telomere, which decreases in size (loses nucleotides at the ends of chromosomes) during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres.

Sustained angiogenesis

Angiogenesis is the process by which new blood vessels are formed. Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients.

Normal tissues of the body have blood vessels running through them that deliver oxygen from the lungs. Cells must be close to the blood vessels to get enough oxygen for them to survive. New blood vessels are formed during the development of embryos, during wound repair and during the female reproductive cycle. An expanding tumour requires new blood vessels to deliver adequate oxygen to the cancer cells, and thus exploits these normal physiological processes for its benefit. To do this, the cancer cells acquire the ability to orchestrate production of new vasculature by activating the 'angiogenic switch'. In doing so, they control non-cancerous cells that are present in the tumor that can form blood vessels by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote blood vessel formation.

Tissue invasion and metastasis

Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) to distant body parts.

One of the most well known properties of cancer cells is their ability to invade neighboring tissues. It is what dictates whether the tumor is benign or malignant, and is the property which enables their dissemination around the body. The cancer cells have to undergo a multitude of changes in order for them to acquire the ability to metastasize, in a multistep process that starts with local invasion of the cells into the surrounding tissues. They then have to invade blood vessels, survive in the harsh environment of the circulatory system, exit this system and then start dividing in the new tissue.

Updates

In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation."

Emerging Hallmarks

Deregulated metabolism

Most cancer cells use alternative metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, but only now gaining renewed research interest. Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration (oxidation of pyruvate, the citric acid cycle, and the electron transport chain). Instead of completely oxidizing glucose to produce as much ATP as possible, cancer cells would rather convert pyruvate into the building blocks for more cells. In fact, the low ATP:ADP ratio caused by this effect likely contributes to the deactivation of mitochondria. Mitochondrial membrane potential is hyperpolarized to prevent voltage-sensitive permeability transition pores (PTP) from triggering of apoptosis.

The ketogenic diet is being investigated as an adjuvant therapy for some cancers, including glioma, because of cancer's inefficiency in metabolizing ketone bodies.

Evading the immune system

Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33. (See cancer immunology)

Enabling Characteristics

The updated paper also identified two enabling characteristics. These are labeled as such since their acquisition leads to the development of the hypothesized "hallmarks."

Genome instability

Cancer cells generally have severe chromosomal abnormalities which worsen as the disease progresses. HeLa cells, for example, are extremely prolific and have tetraploidy 12, trisomy 6, 8, and 17, and a modal chromosome number of 82 (rather than the normal diploid number of 46). Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates. (See genome instability)

Inflammation

Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer. Inflammation leads to angiogenesis and more of an immune response. The degradation of extracellular matrix necessary to form new blood vessels increases the odds of metastasis. (See inflammation in cancer)

Criticisms

An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. The only hallmark of malignant disease was its ability to invade and metastasize.

An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading.

Transmissible spongiform encephalopathy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy

Transmissible spongiform encephalopathy (TSE)
Other names	Prion disease

Micrograph showing spongiform degeneration (vacuoles that appear as holes in tissue sections) in the cerebral cortex of a patient who had died of Creutzfeldt–Jakob disease. H&E stain, scale bar = 30 microns (0.03 mm).
Specialty	Infectious diseases
Symptoms	Dementia, seizures, tremors, insomnia, psychosis, delirium, confusion
Usual onset	Months to decades
Types	Bovine spongiform encephalopathy, Fatal familial insomnia, Creutzfeldt-Jakob disease, kuru, Huntington's disease-like 1, scrapie, variably protease-sensitive prionopathy, chronic wasting disease, Gerstmann-Sträussler-Scheinker syndrome, feline spongiform encephalopathy, transmissible mink encephalopathy, exotic ungulate encephalopathy, camel spongiform encephalopathy
Causes	Prion
Risk factors	Contact with infected fluids, ingestion of infected flesh, having one or two parents that have the disease (in case of fatal familial insomnia)
Diagnostic method	Currently there is no way to reliably detect prions except at post-mortem
Prevention	Varies
Treatment	Palliative care
Prognosis	Invariably fatal
Frequency	Rare

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive, incurable, and fatal conditions that are associated with prions and affect the brain and nervous system of many animals, including humans, cattle, and sheep. According to the most widespread hypothesis, they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection. Mental and physical abilities deteriorate and many tiny holes appear in the cortex causing it to appear like a sponge when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function which may result in memory loss, personality changes, and abnormal or impaired movement which worsen over time.

TSEs of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, and kuru, as well as the recently discovered variably protease-sensitive prionopathy and familial spongiform encephalopathy. Creutzfeldt-Jakob disease itself has four main forms, the sporadic (sCJD), the hereditary/familial (fCJD), the iatrogenic (iCJD) and the variant form (vCJD). These conditions form a spectrum of diseases with overlapping signs and symptoms.

TSEs in non-human mammals include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle – popularly known as "mad cow disease" – and chronic wasting disease (CWD) in deer and elk. The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to bovine spongiform encephalopathy prions.

Unlike other kinds of infectious disease, which are spread by agents with a DNA or RNA genome (such as virus or bacteria), the infectious agent in TSEs is believed to be a prion, thus being composed solely of protein material. Misfolded prion proteins carry the disease between individuals and cause deterioration of the brain. TSEs are unique diseases in that their aetiology may be genetic, sporadic, or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g., blood transfusion). Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant prion allele, which expresses prion proteins that contort by themselves into the disease-causing conformation. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In the 1980s and 1990s, bovine spongiform encephalopathy spread in cattle in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. In turn, consumption (by humans) of bovine-derived foodstuff which contained prion-contaminated tissues resulted in an outbreak of the variant form of Creutzfeldt–Jakob disease in the 1990s and 2000s.

Prions cannot be transmitted through the air, through touching, or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials fail to render prions non-infective. However, treatment with strong, almost undiluted bleach and/or sodium hydroxide, or heating to a minimum of 134 °C, does destroy prions.

Classification

Differences in shape between the different prion protein forms are poorly understood.

Known spongiform encephalopathies
ICTVdb Code	Disease name	Natural host	Prion name	PrP isoform	Ruminant
Non-human mammals
90.001.0.01.001.	Scrapie	Sheep and goats	Scrapie prion	PrP^Sc	Yes
90.001.0.01.002.	Transmissible mink encephalopathy (TME)	Mink	TME prion	PrP^TME	No
90.001.0.01.003.	Chronic wasting disease (CWD)	Elk, white-tailed deer, mule deer and red deer	CWD prion	PrP^CWD	Yes
90.001.0.01.004.	Bovine spongiform encephalopathy (BSE) commonly known as "mad cow disease"	Cattle	BSE prion	PrP^BSE	Yes
90.001.0.01.005.	Feline spongiform encephalopathy (FSE)	Cats	FSE prion	PrP^FSE	No
90.001.0.01.006.	Exotic ungulate encephalopathy (EUE)	Nyala and greater kudu	EUE prion	PrP^EUE	Yes
	Camel spongiform encephalopathy (CSE)	Camel	PrP^CSE		Yes
Human diseases
90.001.0.01.007.	Kuru	Humans	Kuru prion	PrP^Kuru	No
90.001.0.01.008.	Creutzfeldt–Jakob disease (CJD)		CJD prion	PrP^sCJD	No
	Variant Creutzfeldt–Jakob disease (vCJD, nvCJD)		vCJD prion	PrP^vCJD
90.001.0.01.009.	Gerstmann-Sträussler-Scheinker syndrome (GSS)		GSS prion	PrP^GSS	No
90.001.0.01.010.	Fatal familial insomnia (FFI)		FFI prion	PrP^FFI	No
	Familial spongiform encephalopathy

Signs and symptoms

The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change (the presence of many small holes), the death of neurons, astrocytosis (abnormal increase in the number of astrocytes due to the destruction of nearby neurons), and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system in individual cases.

The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait (ataxia). Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia) and lose the ability to move or speak.

Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.

Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt–Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. An example is kuru, which reached epidemic proportions in the mid-20th century in the Fore people of Papua New Guinea, who used to consume their dead as a funerary ritual. Laws in developed countries now ban the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.

There exists evidence that prion diseases may be transmissible by the airborne route.

Note that not all encephalopathies are caused by prions, as in the cases of PML (caused by the JC virus), CADASIL (caused by abnormal NOTCH3 protein activity), and Krabbe disease (caused by a deficiency of the enzyme galactosylceramidase). Progressive Spongiform Leukoencephalopathy (PSL)—which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant that causes it among heroin smokers has not yet been identified. This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.

Cause

Genetics

Mutations in the PRNP gene cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. In rare circumstances, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.

The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Under normal circumstances, this protein may be involved in transporting copper into cells. The protein may also be involved in protecting brain cells and helping them communicate. Point mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrP^Sc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.

Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.

In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.

Protein-only hypothesis

Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrP^C into PrP^Sc. Evidence for this hypothesis:

Infectivity titre correlates with PrP^Sc levels. However, this is disputed.
PrP^Sc is an isomer of PrP^C
Denaturing PrP removes infectivity
PrP-null mice cannot be infected
PrP^C depletion in the neural system of mice with established neuroinvasive prion infection reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span

Multi-component hypothesis

While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrP^C appears unable to convert to the infectious PrP^Sc form, unless other components are added, such as RNA and lipids. These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.

Viral hypothesis

This hypothesis postulates that a yet undiscovered infectious viral agent is the cause of the disease. Although this was once the leading hypothesis, it is now a minority view. Evidence for this hypothesis is as follows:

Incubation time is comparable to a lentivirus.
Strain variation of different isolates of PrP^sc.

Diagnosis

There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP^Sc form has started. At present, there is virtually no way to detect PrP^Sc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP^Sc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrP^Sc, but there are still no fully accepted methods for use in materials such as blood.

In 2010, a team from New York described detection of PrP^Sc even when initially present at only one part in a hundred billion (10⁻¹¹) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP^Sc. After amplifying and then concentrating any PrP^Sc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP^Sc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals' brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals' lives, and from uninfected animals. The results showed very clearly that PrP^Sc could be detected in the blood of animals long before the symptoms appeared.

Treatment

There are currently no known ways to cure or prevent prion disease. Certain medications can slow down the progression of the disease. But ultimately, supportive care is the only option for humans right now.

Epidemiology

Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions.^{[clarification needed]} It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that, if animals at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.

Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment). This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment. The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information.

Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed the endemic of CWD in free-ranging deer and elk spread in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. Many apparent cases of CJD were suspected transmission of CWD, however the evidence was lacking and not convincing.

In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996. This occurred because the cattle were fed processed remains of other cattle. Then human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America. The source could not be clearly identified, but researchers suspect it came from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans.

Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy. A total of 231 cases of vCJD have been reported since it was first discovered. These cases have been found in a total of 12 countries with 178 in the United Kingdom, 27 in France, five in Spain, four in Ireland, four in the United States, three in the Netherlands, three in Italy, two in Portugal, two in Canada, and one each in Japan, Saudi Arabia, and Taiwan.

History

In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in humans. Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD. In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that. Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and human disease was suspected then or has been found since. TSE was first described in humans by Alfons Maria Jakob in 1921. Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE. A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy. Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows. The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE. Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission, the search for a viral agent was, as of 2007, being continued in some laboratories.

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