<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cestoda and can you explain it in depth? [/INST] Cestoda is a class of parasitic worms in the flatworm phylum (Platyhelminthes). Most of the species—and the best-known—are those in the subclass Eucestoda; they are ribbon-like worms as adults, known as tapeworms. Their bodies consist of many similar units known as proglottids—essentially packages of eggs which are regularly shed into the environment to infect other organisms. Species of the other subclass, Cestodaria, are mainly fish infecting parasites.
All cestodes are parasitic; many have complex life histories, including a stage in a definitive (main) host in which the adults grow and reproduce, often for years, and one or two intermediate stages in which the larvae develop in other hosts. Typically the adults live in the digestive tracts of vertebrates, while the larvae often live in the bodies of other animals, either vertebrates or invertebrates. For example, Diphyllobothrium has at least two intermediate hosts, a crustacean and then one or more freshwater fish; its definitive host is a mammal.  Some cestodes are host-specific, while others are parasites of a wide variety of hosts. Some six thousand species have been described; probably all vertebrates can host at least one species.
The adult tapeworm has a scolex (head), a short neck, and a strobila (segmented body) formed of proglottids. Tapeworms anchor themselves to the inside of the intestine of their host using their scolex, which typically has hooks, suckers, or both. They have no mouth, but absorb nutrients directly from the hosts gut. The neck continually produces proglottids, each one containing a reproductive tract; mature proglottids are full of eggs, and fall off to leave the host, either passively in the feces or actively moving. All tapeworms are hermaphrodites, with each individual having both male and female reproductive organs.
Humans are subject to infection by several species of tapeworms if they eat undercooked meat such as pork (Taenia solium), beef (T. saginata), and fish (Diphyllobothrium), or if they live in, or eat food prepared in, conditions of poor hygiene (Hymenolepis or Echinococcus species). The unproven concept of using tapeworms as a slimming aid has been touted since around 1900.

Diversity and habitat
All 6,000 species of Cestoda are parasites, mainly intestinal; their definitive hosts are vertebrates, both terrestrial and marine, while their intermediate hosts include insects, crustaceans, molluscs, and annelids as well as other vertebrates.T. saginata, the beef tapeworm, can grow up to 20 m (65 ft); the largest species, the whale tapeworm Tetragonoporus calyptocephalus, can grow to over 30 m (100 ft). Species with small hosts tend to be small. For example, vole and lemming tapeworms are only 13–240 mm (0.5–9.4 in) in length, and those parasitizing shrews only 0.8–60 mm (0.03–2.36 in).

Anatomy
Cestodes have no gut or mouth and absorb nutrients from the hosts alimentary tract through their specialised neodermal cuticle, or tegument, through which gas exchange also takes place. The tegument also protects the parasite from the hosts digestive enzymes and allows it to transfer molecules back to the host.The body form of adult eucestodes is simple, with a scolex, or grasping head, adapted for attachment to the definitive host, a short neck, and a strobila, or segmented trunk formed of proglottids, which makes up the worms body. Members of the subclass Cestodaria, the Amphilinidea and Gyrocotylidea, are wormlike but not divided into proglottids. Amphilinids have a muscular proboscis at the front end; Gyrocotylids have a sucker or proboscis which they can pull inside or push outside at the front end, and a holdfast rosette at the posterior end.The Cestodaria have 10 larval hooks while Eucestoda have 6 larval hooks.

Scolex
The scolex, which attaches to the intestine of the definitive host, is often minute in comparison with the proglottids. It is typically a four-sided knob, armed with suckers or hooks or both. In some species, the scolex is dominated by bothria, or "sucking grooves" that function like suction cups. Cyclophyllid cestodes can be identified by the presence of four suckers on their scolices. Other species have ruffled or leaflike scolices, and there may be other structures to aid attachment.In the larval stage the scolex is similarly shaped and is known as the protoscoleces.

Body systems
Circular and longitudinal muscles lie under the neodermis, beneath which further longitudinal, dorso-ventral and transverse muscles surround the central parenchyma. Protonephridial cells drain into the parenchyma. There are four longitudinal collection canals, two dorso-lateral and two ventro-lateral, running along the length of the worm, with a transverse canal linking the ventral ones at the posterior of each segment. When the proglottids begin to detach, these canals open to the exterior through the terminal segment.The main nerve centre of a cestode is a cerebral ganglion in its scolex. Nerves emanate from the ganglion to supply the general body muscular and sensory endings, with two lateral nerve cords running the length of the strobila. The cirrus and vagina are innervated, and sensory endings around the genital pore are more plentiful than in other areas. Sensory function includes both tactoreception (touch) and chemoreception (smell or taste).

Proglottids
Once anchored to the hosts intestinal wall, tapeworms absorb nutrients through their surface as their food flows past them. Cestodes are unable to synthesise lipids, which they use for reproduction, and are therefore entirely dependent on their hosts.The tapeworm body is composed of a series of segments called proglottids. These are produced from the neck by mitotic growth, which is followed by transverse constriction. The segments become larger and more mature as they are displaced backwards by newer segments. Each proglottid contains an independent reproductive tract, and like some other flatworms, cestodes excrete waste through flame cells (protonephridia) located in the proglottids. The sum of the proglottids is called a strobila, which is thin and resembles a strip of tape; from this is derived the common name "tapeworm". Proglottids are continually being produced by the neck region of the scolex, as long as the scolex is attached and alive.Mature proglottids are essentially bags of eggs, each of which is infective to the proper intermediate host. They are released and leave the host in feces, or migrate outwards as independent motile proglottids. The number of proglottids forming the tapeworm ranges from three to four thousand. Their layout comes in two forms: craspedote, meaning any given proglottid is overlapped by the previous proglottid, or acraspedote, indicating the proglottids do not overlap.

Reproduction
Cestodes are exclusively hermaphrodites, with both male and female reproductive systems in each body. The reproductive system includes one or more testes, cirri, vas deferens, and seminal vesicles as male organs, and a single lobed or unlobed ovary with the connecting oviduct and uterus as female organs. The common external opening for both male and female reproductive systems is known as the genital pore, which is situated at the surface opening of the cup-shaped atrium. Though they are sexually hermaphroditic and cross-fertilization is the norm, self-fertilization sometimes occurs and makes possible the reproduction of a worm when it is the only individual in its hosts gut. During copulation, the cirri of one individual connect with those of the other through the genital pore, and then spermatozoa are exchanged.

Life cycle
Cestodes are parasites of vertebrates, with each species infecting a single definitive host or group of closely related host species. All but amphilinids and gyrocotylids (which burrow through the gut or body wall to reach the coelom) are intestinal, though some life-cycle stages rest in muscle or other tissues. The definitive host is always a vertebrate but in nearly all cases, one or more intermediate hosts are involved in the lifecycle, typically arthropods or other vertebrates. Infections can be long-lasting; in humans, tapeworm infection may last as much as 30 years. No asexual phases occur in the lifecycle, as they do in other flatworms, but the lifecycle pattern has been a crucial criterion for assessing evolution among Platyhelminthes.Cestodes produce large numbers of eggs, but each one has a low probability of finding a host. To increase their chances, different species have adopted various strategies of egg release. In the Pseudophyllidea, many eggs are released in the brief period when their aquatic intermediate hosts are abundant (semelparity). In contrast, in the terrestrial Cyclophyllidea, proglottids are released steadily over a period of years, or as long as their host lives (iteroparity). Another strategy is to have very long-lived larvae; for example, in Echinococcus, the hydatid larvae can survive for ten years or more in humans and other vertebrate hosts, giving the tapeworm an exceptionally long time window in which to find another host.Many tapeworms have a two-phase lifecycle with two types of host. The adult Taenia saginata lives in the gut of a primate such as a human, its definitive host. Proglottids leave the body through the anus and fall to the ground, where they may be eaten with grass by a grazing animal such as a cow. This animal then becomes an intermediate host, the oncosphere boring through the gut wall and migrating to another part of the body such as the muscle. Here it encysts, forming a cysticercus. The parasite completes its lifecycle when the intermediate host passes on the parasite to the definitive host, usually when the definitive host eats contaminated parts of the intermediate host, for example a human eating raw or undercooked meat.  Another two-phase lifecycle is exhibited by Anoplocephala perfoliata, the definitive host being an equine and the intermediate host an oribatid mite.Diphyllobothrium exhibits a more complex, three-phase lifecycle. If the eggs are laid in water, they develop into free-swimming oncosphere larvae. After ingestion by a suitable freshwater crustacean such as a copepod, the first intermediate host, they develop into procercoid larvae. When the copepod is eaten by a suitable second intermediate host, typically a minnow or other small freshwater fish, the procercoid larvae migrate into the fishs flesh where they develop into plerocercoid larvae. These are the infective stages for the mammalian definitive host. If the small fish is eaten by a predatory fish, its muscles too can become infected.Schistocephalus solidus is another three-phase example. The intermediate hosts are copepods and small fish, and the definitive hosts are waterbirds. This species has been used to demonstrate that cross-fertilisation produces a higher infective success rate than self-fertilisation.

Host immunity
Hosts can become immune to infection by a cestode if the lining, the mucosa, of the gut is damaged. This exposes the hosts immune system to cestode antigens, enabling the host to mount an antibody defence. Host antibodies can kill or limit cestode infection by damaging their digestive enzymes, which reduces their ability to feed and therefore to grow and to reproduce; by binding to their bodies; and by neutralising toxins that they produce. When cestodes feed passively in the gut, they do not provoke an antibody reaction.

Evolution and phylogeny
Fossil history
Parasite fossils are rare, but recognizable clusters of cestode eggs, some with an operculum (lid) indicating that they had not erupted, one with a developing larva, have been discovered in fossil shark coprolites dating to the Permian, some 270 million years ago.The fossil Rugosusivitta, which was found in China at base of the Cambrian deposits in Yunnan  just above the Ediacaran-Cambrian border, has great similarities to present day Cestodians. If correct, this would be the earliest example of a Platyzoan and also one of the earliest bilaterian body-fossils and might thus provide an insight to the living mode of Cestodians before they became specialized parasites.

External
The position of the Cestoda within the Platyhelminthes and other Spiralian phyla based on genomic analysis is shown in the phylogenetic tree. The non-parasitic flatworms, traditionally grouped as the "Turbellaria", are paraphyletic, as the parasitic Neodermata including the Cestoda arose within that grouping. The approximate times when major groups first appeared is shown in millions of years ago.

Internal
The evolutionary history of the Cestoda has been studied using ribosomal RNA, mitochondrial and other DNA, and morphological analysis and continues to be revised. "Tetraphyllidea" is seen to be paraphyletic; "Pseudophyllidea" has been broken up into two orders, Bothriocephalidea and Diphyllobothriidea. Hosts, whose phylogeny often mirrors that of the parasites (Fahrenholzs rule), are indicated in italics and parentheses, the life-cycle sequence (where known) shown by arrows as (intermediate host1 [→ intermediate host2 ] → definitive host). Alternatives, generally for different species within an order, are shown in square brackets.
The Taeniidae, including species such as the pork tapeworm and the beef tapeworm that often infect humans, may be the most basal of the 12 orders of the Cyclophyllidea.

Interactions with humans
Infection and treatment
Like other species of mammal, humans can become infected with tapeworms. There may be few or no symptoms, and the first indication of the infection may be the presence of one or more proglottids in the stools. The proglottids appear as flat, rectangular, whitish objects about the size of a grain of rice, which may change size or move about. Bodily symptoms which are sometimes present include abdominal pain, nausea, diarrhea, increased appetite and weight loss.There are several classes of anthelminthic drugs, some effective against many kinds of parasite, others more specific; these can be used both preventatively and to treat infections. For example, praziquantel is an effective treatment for tapeworm infection, and is preferred over the older niclosamide. While accidental tapeworm infections in developed countries are quite rare, such infections are more likely to occur in countries with poor sanitation facilities or where food hygiene standards are low.

History and culture
In ancient Greece, the comic playwright Aristophanes and philosopher Aristotle described the lumps that form during cysticercosis as "hailstones" </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Urethrovaginal fistula and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Contact stomatitis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Transmissible spongiform encephalopathy and can you explain it in depth? [/INST] Transmissible spongiform encephalopathies (TSEs) are a group of progressive 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, including memory changes, personality changes and problems with movement that worsen chronically.TSEs of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, 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. Misshapened 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
Features
The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronal loss, astrocytosis, 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 patients 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. It may also be involved in protecting brain cells and helping them communicate. 24 Point-Mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrPSc. 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 PrPC into PrPSc. Evidence for this hypothesis:

Infectivity titre correlates with PrPSc levels. However, this is disputed.
PrPSc is an isomer of PrPC
Denaturing PrP removes infectivity
PrP-null mice cannot be infected
PrPC 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 PrPC appears unable to convert to the infectious PrPSc 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 an as of yet undiscovered infectious viral agent is the cause of the disease.  Evidence for this hypothesis is as follows:

Incubation time is comparable to a lentivirus
Strain variation of different isolates of PrPSc
An increasing titre of PrPSc as the disease progresses suggests a replicating agent.

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 PrPSc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc  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 PrPSc, 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 PrPSc 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 PrPSc. After amplifying and then concentrating any PrPSc, 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 PrPSc 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 PrPSc could be detected in the blood of animals long before the symptoms appeared.

Epidemiology
Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions. 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 man. 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 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Diprosopus and can you explain it in depth? [/INST] Diprosopus (Greek: διπρόσωπος, "two-faced", from δι-, di-, "two" and πρόσωπον, prósopon [neuter], "face", "person"; with Latin ending), also known as craniofacial duplication (cranio- from Greek κρανίον, "skull", the other parts Latin), is an extremely rare congenital disorder whereby parts (accessories) or all of the face are duplicated on the head.

Development
Although classically considered conjoined twinning (which it resembles), diprosopus is not normally due to the fusion or incomplete separation of two embryos. It is the result of abnormal activity by the protein SHH (sonic hedgehog). (The name of this protein was inspired by the Sonic the Hedgehog video game character and is part of an idiosyncratic naming tradition in molecular biology research.)SHH and its corresponding genes have been found to play an important role in signaling craniofacial patterning during embryonic development. Among other things, SHH governs the width of facial features. In excess it leads to widening of facial features and to duplication of facial structures. The greater the widening, the more structures are duplicated, often in a mirror image form. This has been demonstrated in the laboratory by introducing pellets of the SHH protein into chicken embryos, resulting in chickens with duplicate beaks. Inadequate amounts of that protein lead to opposite conditions such as cyclopia where facial features are insufficiently developed.Healthy brain development is also dependent on the signaling function of SHH. During embryonic development, SHH directs embryonic cells to organize in specific areas that later become specialized neural tissues, thus controlling the size and shape of brain structures.

Occurrences
Diprosopus often occurs in combination with other congenital disorders, particularly anencephaly, neural tube defect and cardiac malformations. When present, the brain may show abnormalities ranging from partial to complete duplication of brain structures, and/or underdevelopment of brain tissues.

Humans
Most human infants with diprosopus are stillborn. Known instances of humans with diprosopus surviving for longer than minutes to hours past birth are very rare; only a few are recorded. In 2002 and 2003, two living male infants with partial diprosopus were described in the medical literature in separate case reports. One infant was born with duplication of the nose and the cerebral frontal lobes, two widely spaced eyes, a small, underdeveloped central eye socket, and a large, asymmetric mouth. The other infant was born with duplication of the upper and lower jaw, two tongues arising from the same base, cleft palate, a slightly divided tip of the nose, and two widely spaced eyes, as well as absence of the corpus callosum, duplication of the pituitary gland and stalk, and abnormalities in the midbrain. Because they were born with a milder, partial form of diprosopus, both infants were considered candidates for surgical correction of their abnormal facial features.

Spanish case
In January 1775, a Spanish family gave birth to a girl with diprosopus. She had 3 eyes (one a combination of 2), 2 noses, 2 mouths, and 3 chins. The child was taken on tour from village to village, and gained much attention in Spain and neighboring countries. Her case is mentioned in Nicolas-François and Geneviève Regnaults Les écarts de la nature, published that year.  Her full lifespan is unknown, but is mentioned to still be alive in French publications as late as 1777.

Lali Singh
Lali Singh (10 March – 10 May 2008) was born to Sushma and Vinod Singh in Saini, Sunpura Sohanpur village, near Delhi; the birth was delayed by dystocia caused by her large head, and her birth in a hospital was facilitated by her mothers receiving an episiotomy. She was one of the very few infants with diprosopus to survive well past birth, and may have been the only known living individual with complete facial duplication. Her facial features included two pairs of eyes, two noses, and two mouths (but only one pair of ears). She was seen as the reincarnation of the goddess Durga, who is sometimes depicted with many limbs and eyes.
Sushma and Vinod Singh declined an offer from local doctors to evaluate their daughter through CT or MRI scanning. Without diagnostic imaging, it was not possible to know the full extent to which the childs condition might have affected her brain and other vital structures in her head and neck. Thus, any estimation of her ability to thrive or even survive could be only speculative, though Lalis family described her as functioning normally. It is also unknown whether neurosurgeons or craniofacial surgeons, if consulted, would have had feasible solutions to offer with respect to corrective surgery. A local doctor told reporters that the baby should be considered a healthy child who currently was living a normal life, a previously unknown occurrence among sufferers of the disorder.Lalis two middle eyes suffered from corneal opacity due to abnormal anatomy of the facial muscles, which prevented her from properly closing those eyes; initially, this was wrongly blamed on camera flashes.
A cleft palate caused difficulty in her feeding under village conditions. A poor diet of bottle-fed sugar solution and diluted milk, allowed to drip down her throat, as she could not suck properly due to her cleft palate, weakened her condition, and vomiting and infection ensued. Admission to hospital was delayed by discussion (including taking her back home from hospital) among her extended family and her villages headman. Finally, her parents, alarmed at her illness and dehydration, defied her other relatives and took her back to hospital, where under proper medical treatment including antibiotic and a saline drip she started to improve, stopped vomiting, started drinking milk and defecating normally. However, six hours later, at two months old to the day, she died of a heart attack. She was buried in her village, as is usual in Hinduism with children who die very young. Later a temple was built at the village in her memory.

Faith and Hope Howie
Faith Daisy and Hope Alice Howie (8 May – 27 May 2014) were born in Sydney, Australia, to parents Simon Howie and Renee Young. Faith and Hope shared one body and skull, but had complete duplication of the facial features, as well as duplication of the brain; both brains joined to one brain stem. Young and Howie had learned at nineteen weeks gestation of their childrens condition, but opted not to terminate the pregnancy. The children were born six weeks prematurely and appeared to be doing well, able to breathe unaided several days after their birth, and they were observed to sleep and cry at different times. They died nineteen days following their birth due to unknown causes, although some sources indicated that the girls died following an operation for unknown reasons.

Other animals
Janus, a goat with two faces on one body, survived from April 5 to May 5, 2020 in Wittenberg, Wisconsin.
Few two-faced animals have survived due to associated internal organ abnormalities and brain abnormalities. One of the most famous was Ditto, a pig. Ditto was raised to adulthood, but died of pneumonia caused by food inhalation when breathing through one muzzle while eating with the other.
Cats with the condition are known as Janus cats, after the Roman god. In July 2006, a six-year-old male Janus cat called "Frank and Louie" from Millbury, Massachusetts, USA, received publicity. In their case, only one esophagus (and possibly only one trachea) were functional; this aided survival. In September 2011, when Frank and Louie were twelve years old, it was announced that they would appear in the 2012 Guinness Book of World Records as the longest-surviving Janus cat on record. In 2014, Frank and Louie died at the age of fifteen.

See also
Conjoined twins
Craniopagus parasiticus
Cyclopia
Durga, a three-eyed Hindu goddess
Edward Mordake, a disputed story of a 19th-century man with a face on the back of his head
Futakuchi-onna, a female Japanese yōkai with mouth on back of her head/hair
Janus, a Roman god with two faces
Kara Mia, a Philippine TV series that tells the story of a young woman with two faces divided in one body.
Polycephaly

References
External links

Armand Marie, Leroi (2005). Mutants: On Genetic Variety and the Human Body. New York, NY: Penguin Books. ISBN 9780142004821. Retrieved March 13, 2014.
Howie, Sarah; Fisher, Carolyn Elaine, eds. (2010). Shh and Gli Signalling in Development. Molecular Biology Intelligence Unit. New York, NY: Springer Science+Business Media, Inc. doi:10.1007/978-0-387-39957-7. ISBN 978-0-387-39957-7. Retrieved March 13, 2014.
Tapadia MD, Cordero DR, Helms JA (November 2005) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Trinucleotide repeat disorder and can you explain it in depth? [/INST] Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.Trinucleotide repeats are a subset of a larger class of unstable microsatellite repeats that occur throughout all genomes.
The first trinucleotide repeat disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome.  Patients carry from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome, while unaffected individuals have up to 50 repeats and carriers of the disease have 60 to 230 repeats. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring.There are several known categories of trinucleotide repeat disorder.  Category I includes Huntingtons disease (HD) and the spinocerebellar ataxias. These are caused by a CAG repeat expansion in protein-coding portions, or exons, of specific genes. Category II expansions are also found in exons, and tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude.  Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreichs ataxia.  These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located in introns rather than exons.

Types
Some of the problems in trinucleotide repeat syndromes result from causing alterations in the coding region of the gene, while others are caused by altered gene regulation. In over half of these disorders, the repeated trinucleotide, or codon, is CAG. In a coding region, CAG codes for glutamine (Q), so CAG repeats result in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or polyQ) diseases. The repeated codons in the remaining disorders do not code for glutamine, and these are classified as non-polyglutamine diseases.

Polyglutamine (PolyQ) diseases
Non-polyglutamine diseases
Symptoms and signs
A common symptom of polyQ diseases is the progressive degeneration of nerve cells, usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats are found in different, unrelated genes. In all cases, the expanded CAG repeats are translated into an uninterrupted sequence of glutamine residues, forming a polyQ tract, and the accumulation of polyQ proteins damages key cellular functions such as the ubiquitin-proteasome system. However different polyQ-containing proteins damage different subsets of neurons, leading to different symptoms. As of 2017, ten neurological and neuromuscular disorders were known to be caused by an increased number of CAG repeats.The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases.  In some of these diseases, such as Fragile X syndrome, the pathology is caused by lack of the normal function of the protein encoded by the affected gene. In others, such as Myotonic Dystrophy Type 1, the pathology is caused by a change in protein expression or function mediated through changes in the messenger RNA produced by the expression of the affected gene. In yet others, the pathology is caused by toxic assemblies of RNA in the nuclei of cells.

Genetics
Trinucleotide repeat disorders generally show genetic anticipation: their severity increases with each successive generation that inherits them. This is likely explained by the addition of CAG repeats in the affected gene as the gene is transmitted from parent to child.  For example, Huntingtons disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered normal and would not exhibit any symptoms of the disease </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Leydig cell hypoplasia and can you explain it in depth? [/INST] Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism (partially or fully underdeveloped genitalia), hypergonadotropic hypogonadism (decreased or lack of production of sex steroids by the gonads despite high circulating levels of gonadotropins), reduced or absent puberty (lack of development of secondary sexual characteristics, resulting in sexual infantilism if left untreated), and infertility.Leydig cell hypoplasia does not occur in biological females as they do not have either Leydig cells or testicles. However, the cause of the condition in males, luteinizing hormone insensitivity, does affect females, and because LH plays a role in the female reproductive system, it can result in primary amenorrhea or oligomenorrhea (absent or reduced menstruation), infertility due to anovulation, and ovarian cysts.A related condition is follicle-stimulating hormone (FSH) insensitivity, which presents with similar symptoms to those of Leydig cell hypoplasia but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in females and merely problems with fertility in males). Despite their similar causes, FSH insensitivity is considerably less common in comparison to LH insensitivity.

Symptoms and signs
The symptoms of Leydig cell hypoplasia include pseudohermaphroditism, i.e., feminized, ambiguous, or relatively mildly underdeveloped (e.g., micropenis, severe hypospadias, and/or cryptorchidism [undescended testes]) external genitalia, a female gender identity or gender variance, hypergonadotropic hypogonadism (hypogonadism despite high levels of gonadotropins), delayed, impaired, or fully absent puberty with an associated reduction in or complete lack of development of secondary sexual characteristics (sexual infantilism), impaired fertility or complete sterility, tall stature (due to delayed epiphyseal closure), eunuchoid skeletal proportions, delayed or absent bone maturation, and osteoporosis.

Cause
Leydig cell hypoplasia is caused by genetic mutations in LHCGR, a gene which encodes the LH/hCG receptor. LH normally acts through the LH/hCG receptor to stimulate the growth of Leydig cells in the testicles and the production of androgens such as testosterone and dihydrotestosterone (DHT) by these cells. In Leydig cell hypoplasia however, there is a reduced capacity for the LH/hCG receptor to respond to LH </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Xerotic eczema and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Papillary fibroelastoma and can you explain it in depth? [/INST] A papillary fibroelastoma is a primary tumor of the heart that typically involves one of the valves of the heart. Papillary fibroelastomas, while considered generally rare, make up about 10 percent of all primary tumors of the heart </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Retina and can you explain it in depth? [/INST] The retina (from Latin: rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.
The neural retina consists of several layers of neurons interconnected by synapses and is supported by an outer layer of pigmented epithelial cells. The primary light-sensing cells in the retina are the photoreceptor cells, which are of two types: rods and cones. Rods function mainly in dim light and provide monochromatic vision. Cones function in well-lit conditions and are responsible for the perception of colour through the use of a range of opsins, as well as high-acuity vision used for tasks such as reading. A third type of light-sensing cell, the photosensitive ganglion cell, is important for entrainment of circadian rhythms and reflexive responses such as the pupillary light reflex.
Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses that are sent to various visual centres of the brain through the fibres of the optic nerve. Neural signals from the rods and cones undergo processing by other neurons, whose output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve. Several important features of visual perception can be traced to the retinal encoding and processing of light.
In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, specifically the embryonic diencephalon; thus, the retina is considered part of the central nervous system (CNS) and is actually brain tissue. It is the only part of the CNS that can be visualized non-invasively. Much like the rest of the brain is isolated from the vasular system via the Blood-brain barrier, the retina is similarly protected by the Blood-retinal barrier.

Structure
Inverted versus non-inverted retina
The vertebrate retina is inverted in the sense that the light sensing cells are in the back of the retina, so that light has to pass through layers of neurons and capillaries before it reaches the photosensitive sections of the rods and cones. The ganglion cells, whose axons form the optic nerve, are at the front of the retina; therefore the optic nerve must cross through the retina en route to the brain. In this region there are no photoreceptors, giving rise to the blind spot. In contrast, in the cephalopod retina the photoreceptors are in front, with processing neurons and capillaries behind them. Because of this, cephalopods do not have a blind spot.
Although the overlying neural tissue is partly transparent, and the accompanying glial cells have been shown to act as fibre-optic channels to transport photons directly to the photoreceptors, light scattering does occur. Some vertebrates, including humans, have an area of the central retina adapted for high-acuity vision. This area, termed the fovea centralis, is avascular (does not have blood vessels), and has minimal neural tissue in front of the photoreceptors, thereby minimizing light scattering.The cephalopods have a non-inverted retina which is comparable in resolving power to the eyes of many vertebrates. Squid eyes do not have an analog of the vertebrate retinal pigment epithelium (RPE). Although their photoreceptors contain a protein, retinochrome, that recycles retinal and replicates one of the functions of the vertebrate RPE, one could argue that cephalopod photoreceptors are not maintained as well as in vertebrates and that, as a result, the useful lifetime of photoreceptors in invertebrates is much shorter than in vertebrates. Having easily replaced stalk-eyes (some lobsters) or retinae (some spiders, such as Deinopis) rarely occurs.
The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. It is arguable that this difference shows that vertebrate and cephalopod eyes are not homologous but have evolved separately. From an evolutionary perspective, a more complex structure such as the inverted retina can generally come about as a consequence of two alternate processes: (a) an advantageous "good" compromise between competing functional limitations, or (b) as a historical maladaptive relic of the convoluted path of organ evolution and transformation. Vision is an important adaptation in higher vertebrates.
A third view of the "inverted" vertebrate eye is that it combines two benefits: the maintenance of the photoreceptors mentioned above, and the reduction in light intensity necessary to avoid blinding the photoreceptors, which are based on the extremely sensitive eyes of the ancestors of modern hagfishes (a fish that lives in very deep, dark water).

Retinal layers
The vertebrate retina has ten distinct layers. From closest to farthest from the vitreous body:

Inner limiting membrane – basement membrane elaborated by Müller cells.
Nerve fibre layer – axons of the ganglion cell bodies (note that a thin layer of Müller cell footplates exists between this layer and the inner limiting membrane).
Ganglion cell layer – contains nuclei of ganglion cells, the axons of which become the optic nerve fibres, and some displaced amacrine cells.
Inner plexiform layer – contains the synapse between the bipolar cell axons and the dendrites of the ganglion and amacrine cells.
Inner nuclear layer – contains the nuclei and surrounding cell bodies (perikarya) of the amacrine cells, bipolar cells, and horizontal cells.
Outer plexiform layer – projections of rods and cones ending in the rod spherule and cone pedicle, respectively. These make synapses with dendrites of bipolar cells and horizontal cells. In the macular region, this is known as the Fiber layer of Henle.
Outer nuclear layer – cell bodies of rods and cones.
External limiting membrane – layer that separates the inner segment portions of the photoreceptors from their cell nuclei.
Inner segment / outer segment layer – inner segments and outer segments of rods and cones. The outer segments contain a highly specialized light-sensing apparatus.
Retinal pigment epithelium – single layer of cuboidal epithelial cells (with extrusions not shown in diagram). This layer is closest to the choroid, and provides nourishment and supportive functions to the neural retina, The black pigment melanin in the pigment layer prevents light reflection throughout the globe of the eyeball; this is extremely important for clear vision.These layers can be grouped into 4 main processing stages: photoreception; transmission to bipolar cells; transmission to ganglion cells, which also contain photoreceptors, the photosensitive ganglion cells; and transmission along the optic nerve. At each synaptic stage there are also laterally connecting horizontal and amacrine cells.
The optic nerve is a central tract of many axons of ganglion cells connecting primarily to the lateral geniculate body, a visual relay station in the diencephalon (the rear of the forebrain). It also projects to the superior colliculus, the suprachiasmatic nucleus, and the nucleus of the optic tract. It passes through the other layers, creating the optic disc in primates.Additional structures, not directly associated with vision, are found as outgrowths of the retina in some vertebrate groups. In birds, the pecten is a vascular structure of complex shape that projects from the retina into the vitreous humour; it supplies oxygen and nutrients to the eye, and may also aid in vision. Reptiles have a similar, but much simpler, structure.In adult humans, the entire retina is approximately 72% of a sphere about 22 mm in diameter. The entire retina contains about 7 million cones and 75 to 150 million rods. The optic disc, a part of the retina sometimes called "the blind spot" because it lacks photoreceptors, is located at the optic papilla, where the optic-nerve fibres leave the eye. It appears as an oval white area of 3 mm². Temporal (in the direction of the temples) to this disc is the macula, at whose centre is the fovea, a pit that is responsible for our sharp central vision but is actually less sensitive to light because of its lack of rods. Human and non-human primates possess one fovea, as opposed to certain bird species, such as hawks, who are bifoviate, and dogs and cats, who possess no fovea but a central band known as the visual streak. Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The farthest edge of the retina is defined by the ora serrata. The distance from one ora to the other (or macula), the most sensitive area along the horizontal meridian is about 32 mm.In section, the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses, including the unique ribbon synapse. The optic nerve carries the ganglion cell axons to the brain, and the blood vessels that supply the retina. The ganglion cells lie innermost in the eye while the photoreceptive cells lie beyond. Because of this counter-intuitive arrangement, light must first pass through and around the ganglion cells and through the thickness of the retina, (including its capillary vessels, not shown) before reaching the rods and cones. Light is absorbed by the retinal pigment epithelium or the choroid (both of which are opaque).
The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerers phenomenon).
Between the ganglion cell layer and the rods and cones there are two layers of neuropils where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer neuropil layer, the rods and cones connect to the vertically running bipolar cells, and the horizontally oriented horizontal cells connect to ganglion cells.
The central retina predominantly contains cones, while the peripheral retina predominantly contains rods. In total, there are about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are narrow and long, and, arranged in a hexagonal mosaic, the most dense, in contradistinction to the much fatter cones located more peripherally in the retina. At the foveal pit the other retinal layers are displaced, before building up along the foveal slope until the rim of the fovea, or parafovea, is reached, which is the thickest portion of the retina. The macula has a yellow pigmentation, from screening pigments, and is known as the macula lutea. The area directly surrounding the fovea has the highest density of rods converging on single bipolar cells. Since its cones have a much lesser convergence of signals, the fovea allows for the sharpest vision the eye can attain.Though the rod and cones are a mosaic of sorts, transmission from receptors, to bipolars, to ganglion cells is not direct. Since there are about 150 million receptors and only 1 million optic nerve fibres, there must be convergence and thus mixing of signals. Moreover, the horizontal action of the horizontal and amacrine cells can allow one area of the retina to control another (e.g. one stimulus inhibiting another). This inhibition is key to lessening the sum of messages sent to the higher regions of the brain. In some lower vertebrates (e.g. the pigeon), there is a "centrifugal" control of messages – that is, one layer can control another, or higher regions of the brain can drive the retinal nerve cells, but in primates this does not occur.

Layers imagable with optical coherence tomography
Using optical coherence tomography (OCT) there are 18 layers that can be identified in the retina. The layers and anatomical correlation are as follows:

From innermost to outermost, the layers identifiable by OCT are as follows:

Development
Retinal development begins with the establishment of the eye fields mediated by the SHH and SIX3 proteins, with subsequent development of the optic vesicles regulated by the PAX6 and LHX2 proteins. The role of Pax6 in eye development was elegantly demonstrated by Walter Gehring and colleagues, who showed that ectopic expression of Pax6 can lead to eye formation on Drosophila antennae, wings, and legs. The optic vesicle gives rise to three structures: the neural retina, the retinal pigmented epithelium, and the optic stalk. The neural retina contains the retinal progenitor cells (RPCs) that give rise to the seven cell types of the retina. Differentiation begins with the retinal ganglion cells and concludes with production of the Muller glia. Although each cell type differentiates from the RPCs in a sequential order, there is considerable overlap in the timing of when individual cell types differentiate. The cues that determine a RPC daughter cell fate are coded by multiple transcription factor families including the bHLH and homeodomain factors.In addition to guiding cell fate determination, cues exist in the retina to determine the dorsal-ventral (D-V) and nasal-temporal (N-T) axes. The D-V axis is established by a ventral to dorsal gradient of VAX2, whereas the N-T axis is coordinated by expression of the forkhead transcription factors FOXD1 and FOXG1. Additional gradients are formed within the retina. This spatial distribution may aid in proper targeting of RGC axons that function to establish the retinotopic map.

Blood supply
The retina is stratified into distinct layers, each containing specific cell types or cellular compartments that have metabolisms with different nutritional requirements. To satisfy these requirements, the ophthalmic artery bifurcates and supplies the retina via two distinct vascular networks: the choroidal network, which supplies the choroid and the outer retina, and the retinal network, which supplies the retinas inner layer.

Circulatory mechanisms
At first glance, one may think that the vertebrate retina is "wired wrongly" or "badly designed"; but in fact, the retina could not function if it were not inverted. The photoreceptor layer must be embedded in the retinal pigment epithelium (RPE), which performs at least seven vital functions, one of the most obvious being to supply oxygen and other necessary nutrients needed for the photoreceptors to function. These nutrients include glucose, fatty acids, and retinal. The mammalian photoreceptor amplification process uses large quantities energy for vision in photopic conditions (requiring less under scotopic conditions) and, thus, requires the large supply nutrients supplied by the blood vessels in the choroid, which lies beyond the RPE. The choroid supplies about 75% of these nutrients to the retina and the retinal vasculature only 25%.When light strikes 11-cis-retinal (in the disks in the rods and cones), 11-cis-retinal changes to all-trans-retinal which then triggers changes in the opsins. Now, the outer segments do not regenerate the retinal back into the cis- form once it has been changed by light. Instead the retinal is pumped out to the surrounding RPE where it is regenerated and transported back into the outer segments of the photoreceptors. This recycling function of the RPE protects the photoreceptors against photo-oxidative damage and allows the photoreceptor cells to have decades-long useful lives.

In birds
The bird retina is devoid of blood vessels, perhaps to give unobscured passage of light for forming images, thus giving better resolution. It is, therefore, a considered view that the bird retina depends for nutrition and oxygen supply on a specialized organ, called the "pecten" or pecten oculi, located on the blind spot or optic disk. This organ is extremely rich in blood vessels and is thought to supply nutrition and oxygen to the bird retina by diffusion through the vitreous body. The pecten is highly rich in alkaline phosphatase activity and polarized cells in its bridge portion – both befitting its secretory role. Pecten cells are packed with dark melanin granules, which have been theorized to keep this organ warm with the absorption of stray light falling on the pecten. This is considered to enhance metabolic rate of the pecten, thereby exporting more nutritive molecules to meet the stringent energy requirements of the retina during long periods of exposure to light.

Biometric identification and diagnosis of disease
The bifurcations and other physical characteristics of the inner retinal vascular network are known to vary among individuals, and these individual variances have been used for biometric identification and for early detection of the onset of disease. The mapping of vascular bifurcations is one of the basic steps in biometric identification. Results of such analyses of retinal blood vessel structure can be evaluated against the ground truth data of vascular bifurcations of retinal fundus images that are obtained from the DRIVE dataset. In addition, the classes of vessels of the DRIVE dataset have also been identified, and an automated method for accurate extraction of these bifurcations is also available. Changes in retinal blood circulation are seen with aging and exposure to air pollution, and may indicate cardiovascular diseases such as hypertension and atherosclerosis. Determining the equivalent width of arterioles and venules near the optic disc is also a widely used technique to identify cardiovascular risks.

Function
The retina translates an optical image into neural impulses starting with the patterned excitation of the colour-sensitive pigments of its rods and cones, the retinas photoreceptor cells. The excitation is processed by the neural system and various parts of the brain working in parallel to form a representation of the external environment in the brain.
The cones respond to bright light and mediate high-resolution colour vision during daylight illumination (also called photopic vision). The rod responses are saturated at daylight levels and dont contribute to pattern vision. However, rods do respond to dim light and mediate lower-resolution, monochromatic vision under very low levels of illumination (called scotopic vision). The illumination in most office settings falls between these two levels and is called mesopic vision. At mesopic light levels, both the rods and cones are actively contributing pattern information. What contribution the rod information makes to pattern vision under these circumstances is unclear.
The response of cones to various wavelengths of light is called their spectral sensitivity. In normal human vision, the spectral sensitivity of a cone falls into one of three subtypes, often called blue, green, and red, but more accurately known as short, medium, and long wavelength-sensitive cone subtypes. It is a lack of one or more of the cone subtypes that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. These individuals are not blind to objects of a particular colour, but are unable to distinguish between colours that can be distinguished by people with normal vision. Humans have this trichromatic vision, while most other mammals lack cones with red sensitive pigment and therefore have poorer dichromatic colour vision. However, some animals have four spectral subtypes, e.g. the trout adds an ultraviolet subgroup to short, medium, and long subtypes that are similar to humans. Some fish are sensitive to the polarization of light as well.
In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cyclic guanosine monophosphate (cGMP) keep the Na+ channel open, and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes the receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to activate a phosphodiesterase (PDE6), which degrades cGMP, resulting in the closing of Na+ cyclic nucleotide-gated ion channels (CNGs). Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity.
When thus excited by light, the photoceptor sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The photoreceptors are also cross-linked by horizontal cells and amacrine cells, which modify the synaptic signal before it reaches the ganglion cells, the neural signals being intermixed and combined. Of the retinas nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials.
In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central, approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. In a linear model, this response profile is well described by a difference of Gaussians and is the basis for edge detection algorithms. Beyond this simple difference, ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called parvocellular, P, or midget ganglion cells), and those showing non-linear summation are Y cells (also called magnocellular, M, or parasol retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.
In the transfer of visual signals to the brain, the visual pathway, the retina is vertically divided in two, a temporal (nearer to the temple) half and a nasal (nearer to the nose) half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.
Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve. So, a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined to be around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour.

Spatial encoding
When the retina sends neural impulses representing an image to the brain, it spatially encodes (compresses) those impulses to fit the limited capacity of the optic nerve. Compression is necessary because there are 100 times more photoreceptor cells than ganglion cells. This is done by "decorrelation", which is carried out by the "centre–surround structures", which are implemented by the bipolar and ganglion cells.
There are two types of centre–surround structures in the retina – on-centres and off-centres. On-centres have a positively weighted centre and a negatively weighted surround. Off-centres are just the opposite. Positive weighting is more commonly known as excitatory, and negative weighting as inhibitory.
These centre–surround structures are not physical apparent, in the sense that one cannot see them by staining samples of tissue and examining the retinas anatomy. The centre–surround structures are logical (i.e., mathematically abstract) in the sense that they depend on the connection strengths between bipolar and ganglion cells. It is believed that the connection strength between cells is caused by the number and types of ion channels embedded in the synapses between the bipolar and ganglion cells.
The centre–surround structures are mathematically equivalent to the edge detection algorithms used by computer programmers to extract or enhance the edges in a digital photograph. Thus, the retina performs operations on the image-representing impulses to enhance the edges of objects within its visual field. For example, in a picture of a dog, a cat and a car, it is the edges of these objects that contain the most information. In order for higher functions in the brain (or in a computer for that matter) to extract and classify objects such as a dog and a cat, the retina is the first step to separating out the various objects within the scene.
As an example, the following matrix is at the heart of a computer algorithm that implements edge detection. This matrix is the computer equivalent to the centre–surround structure. In this example, each box (element) within this matrix would be connected to one photoreceptor. The photoreceptor in the centre is the current receptor being processed. The centre photoreceptor is multiplied by the +1 weight factor. The surrounding photoreceptors are the "nearest neighbors" to the centre and are multiplied by the −1/8 value. The sum of all nine of these elements is finally calculated. This summation is repeated for every photoreceptor in the image by shifting left to the end of a row and then down to the next line.

The total sum of this matrix is zero, if all the inputs from the nine photoreceptors are of the same value. The zero result indicates the image was uniform (non-changing) within this small patch. Negative or positive sums mean the image was varying (changing) within this small patch of nine photoreceptors.
The above matrix is only an approximation to what really happens inside the retina. The differences are:

The above example is called "balanced". The term balanced means that the sum of the negative weights is equal to the sum of the positive weights so that they cancel out perfectly. Retinal ganglion cells are almost never perfectly balanced.
The table is square while the centre–surround structures in the retina are circular.
Neurons operate on spike trains traveling down nerve cell axons. Computers operate on a single floating-point number that is essentially constant from each input pixel. (The computer pixel is basically the equivalent of a biological photoreceptor.)
The retina performs all these calculations in parallel while the computer operates on each pixel one at a time. The retina performs no repeated summations and shifting as would a computer.
Finally, the horizontal and amacrine cells play a significant role in this process, but that is not represented here.Here is an example of an input image and how edge detection would modify it.

Once the image is spatially encoded by the centre–surround structures, the signal is sent out along the optic nerve (via the axons of the ganglion cells) through the optic chiasm to the LGN (lateral geniculate nucleus). The exact function of the LGN is unknown at this time. The output of the LGN is then sent to the back of the brain. Specifically, the output of the LGN "radiates" out to the V1 primary visual cortex.
Simplified signal flow: Photoreceptors → Bipolar → Ganglion → Chiasm → LGN → V1 cortex

Clinical significance
There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:

Retinitis pigmentosa is a group of genetic diseases that affect the retina and cause the loss of night vision and peripheral vision.
Macular degeneration describes a group of diseases characterized by loss of central vision because of death or impairment of the cells in the macula.
Cone-rod dystrophy (CORD) describes a number of diseases where vision loss is caused by deterioration of the cones and/or rods in the retina.
In retinal separation, the retina detaches from the back of the eyeball. Ignipuncture is an outdated treatment method. The term retinal detachment is used to describe a separation of the neurosensory retina from the retinal pigment epithelium. There are several modern treatment methods for fixing a retinal detachment: pneumatic retinopexy, scleral buckle, cryotherapy, laser photocoagulation and pars plana vitrectomy.
Both hypertension and diabetes mellitus can cause damage to the tiny blood vessels that supply the retina, leading to hypertensive retinopathy and diabetic retinopathy.
Retinoblastoma is a cancer of the retina.
Retinal diseases in dogs include retinal dysplasia, progressive retinal atrophy, and sudden acquired retinal degeneration.
Lipaemia retinalis is a white appearance of the retina, and can occur by lipid deposition in lipoprotein lipase deficiency.
Retinal Detachment. The neural retina occasionally detaches from the pigment epithelium. In some instances, the cause of such detachment is injury to the eyeball that allows fluid or blood to collect between the neural retina and the pigment epithelium. Detachment is occasionally caused by contracture of fine collagenous fibrils in the vitreous humor, which pull areas of the retina toward the interior of the globe.
Night blindness: Night blindness occurs in any person with severe vitamin A deficiency. The reason for this is that without vitamin A, the amounts of retinal and rhodopsin that can be formed are severely depressed. This condition is called night blindness because the amount of light available at night is too little to permit adequate vision in vitamin A–deficient persons.In addition, the retina has been described as a "window" into the brain and body, given that abnormalities detected through an examination of the retina can discover both neurological and systemic diseases.

Diagnosis
A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. Ophthalmoscopy and fundus photography have long been used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina, and a company based in Scotland has engineered technology that allows physicians to observe the complete retina without any discomfort to patients.The electroretinogram is used to non-invasively measure the retinas electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the fine structures of the retina, with histologic quality. Retinal vessel analysis is a non-invasive method to examine the small arteries and veins in the retina which allows to draw conclusions about the morphology and the function of small vessels elsewhere in the human body. It has been established as a predictor of cardiovascular disease and seems to have, according to a study published in 2019, potential in the early detection of Alzheimers disease.

Treatment
Treatment depends upon the nature of the disease or disorder.

Common treatment modalities
The following are commonly modalities of management for retinal disease:

Intravitreal medication, such as anti-VEGF or corticosteroid agents
Vitreoretinal surgery
Use of nutritional supplements
Modification of systemic risk factors for retinal disease

Uncommon treatment modalities
History
Around 300 BCE, Herophilos identified the retina from dissections of cadaver eyes. He called it the arachnoid layer, from its resemblance to a spider web, and retiform, from its resemblance to a casting net. The term arachnoid came to refer to a layer around the brain; the term retiform came to refer to the retina.Between 1011 and 1021 CE, Ibn Al-Haytham published numerous experiments demonstrating that sight occurs from light reflecting from objects into the eye. This is consistent with intromission theory and against emission theory, the theory that sight occurs from rays emitted by the eyes. However, Ibn Al-Haytham decided that the retina could not be responsible for the beginnings of vision because the image formed on it was inverted. Instead he decided it must begin at the surface of the lens.In 1604, Johannes Kepler worked out the optics of the eye and decided that the retina must be where sight begins. He left it up to other scientists to reconcile the inverted retinal image with our perception of the world as upright.In 1894, Santiago Ramón y Cajal published the first major characterization of retinal neurons in Retina der Wirbelthiere (The Retina of Vertebrates).George Wald, Haldan Keffer Hartline, and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina.A recent University of Pennsylvania study calculated that the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pigs retinal transfer rate is 875 kilobits per second.MacLaren & Pearson and colleagues at University College London and Moorfields Eye Hospital in London, in 2006, showed that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. Recently Ader and colleagues in Dublin showed, using the electron microscope, that transplanted photoreceptors formed synaptic connections.In 2012, Sebastian Seung and his laboratory at MIT launched EyeWire, an online Citizen science game where players trace neurons in the retina. The goals of the EyeWire project are to identify specific cell types within the known broad classes of retinal cells, and to map the connections between neurons in the retina, which will help to determine how vision works.

Additional images
See also
Adeno associated virus and gene therapy of the human retina
Charles Schepens – "the father of modern retinal surgery"
Evolution of the eye
Duplex retina
Retinal scan
Retinal vein occlusion
List of xanthoma variants associated with hyperlipoproteinemia subtypes
Rhodopsin
Persistence of vision

References
Further reading
S. Ramón y Cajal, Histologie du Système Nerveux de lHomme et des Vertébrés, Maloine, Paris, 1911.
Rodieck RW (1965). "Quantitative analysis of cat retinal ganglion cell response to visual stimuli". Vision Res. 5 (11): 583–601. doi:10.1016/0042-6989(65)90033-7. PMID 5862581.
Wandell, Brian A. (1995). Foundations of vision. Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-853-7.
Wässle H, Boycott BB (1991). "Functional architecture of the mammalian retina". Physiol. Rev. 71 (2): 447–480. doi:10.1152/physrev.1991.71.2.447. PMID 2006220.
Schulz HL, Goetz T, Kaschkoetoe J, Weber BH (2004). "The Retinome – Defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium". BMC Genomics (about a transcriptome for eye colour). 5 (1): 50. doi:10.1186/1471-2164-5-50. PMC 512282. PMID 15283859.
Dowling, John (2007). "Retina". Scholarpedia. 2 (12): 3487 </s>


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