<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 Hereditary haemochromatosis and can you explain it in depth? [/INST] Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron.Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the liver, heart, pancreas, skin, joints, gonads, thyroid and pituitary gland; patients can present with cirrhosis, polyarthropathy, hypogonadism, heart failure, or diabetes.There are 5 types of hereditary hemochromatosis: type 1, 2 (2A, 2B), 3, 4 and 5, all caused by mutated genes. Hereditary hemochromatosis is the most frequent, and unique related to the HFE gene. It is most common among those of Northern European ancestry, in particular those of Celtic descent. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not express signs or symptoms of the condition. In this situation, the otherwise unaffected parents are referred to as carriers.

Signs and symptoms
Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy.Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.The more common clinical manifestations include:
Fatigue
Malaise
Joint pain (mainly knee and hand)
Abdominal pain
Bronze or gray skin color (for this the illness was named "bronze diabetes" when it was first described by Armand Trousseau in 1865)
Liver fibrosis or cirrhosis (with an increased risk of hepatocellular carcinoma): Liver disease is always preceded by evidence of liver dysfunction, including elevated serum enzymes specific to the liver, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema, and spider naevi. Cirrhosis can also present with jaundice (yellowing of the skin) and ascites.
Diabetes mellitus type 2: HH patients have insulin resistance for liver disease, and poor insulin secretion due to pancreatic damage from iron deposition.
Erectile dysfunction and hypogonadism, resulting in decreased libido, amenorrhea
Congestive heart failure, abnormal heart rhythms, or pericarditis
Arthritis of the hands (especially the second and third metacarpophalangeal joints), but also the knee and shoulder joints
Weight lossLess common findings including:

Memory loss
Hair loss
Splenomegaly
adrenal insufficiency
Deafness
Dyskinesias, including Parkinsonian symptoms
Dysfunction of certain endocrine organs:
Parathyroid gland (leading to hypocalcaemia)
Pituitary gland: secondary hypothyroidism, secondary hypogonadism
Adrenal gland
An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:
Vibrio vulnificus infections from eating seafood or wound infection
Listeria monocytogenes
Yersinia enterocolica
Salmonella enterica (serotype Typhymurium)
Klebsiella pneumoniae
Escherichia coli
Rhizopus arrhizus
Mucor species
Aspergillus fumigatus
Cytomegalovirus
Hepatitis B virus
Hepatitis C virusIn the hereditary hemochromatosis (HH or HHC), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause. The severity of clinical disease varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone.  Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.

End-organ damage
Iron is stored in the liver, pancreas and heart.
Long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated.Since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload.
Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy.
Together, they can increase the risk of liver cancer to one in three persons.
If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. Arrhythmia or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. This condition can often be reversed with treatment.The pancreas, which also stores iron, is very important in the bodys mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure.Haemochromatosis may lead to cirrhosis and its complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites).
Severity of periodontal disease is associated with high transferrin saturation in haemochromatosis patients.

Genetics
The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6, which codes for hepcidin, a protein that participates in the regulation of iron absorption. The HFE gene has three often observed genetic variants:
rs1799945, c.187C>G, p.His63Asp (H63D);
rs1800562, c.845G>A, p. Cys282Tyr (C282Y);
rs1800730, c.193A>T, p.Ser65Cys (S65C).The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively.The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in HFE, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid. Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body. Homozygosity for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D variants, so-called compound heterozygotes, results in clinically evident iron overload. Considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. Most males homozygous for HFE C282Y show at least one manifestation of iron-storage disease by middle age. Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.
The H63D variant is just a gene polymorphism, and if there are no other changes, it may not have clinical significance. In a 2014 study, H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload. Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high V̇O2max in male athletes.
.
Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease. Penetrance differs between populations.
Disease-causing genetic variants of the HFE gene account for 90% of the cases of non-transfusion iron overload.This gene is closely linked to the HLA-A3 locus.

Pathophysiology
Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive. Normally, HFE facilitates the binding of transferrin, which is irons carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body.  Thus, the iron stores of the body increase.  As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.  Iron is a pro-oxidant.   Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilsons disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs.   The latter also experience "bronzing".

Diagnosis
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation or elevated serum ferritin.. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.

Blood tests
Serum ferritin and fasting transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood. Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis. Other source says that the normal values for males are 12-300 ng/mL and for female, 12-150 ng/mL. Fasting transferrin saturation is a better test to detect HH. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues.  Measuring ferritin provides a crude estimate of whole-body iron stores, though many conditions, particularly inflammatory conditions, infection, chronic alcohol consumption (mainly >20g/day), liver disease, cancer, porphyria, Hemophagocytic lymphohistiocytosis, hyperthyroidism, obesity, metabolic syndrome, diabetes, several blood transfusions, too many iron supplements, aceruloplasminemia, atransferrinemia, hyperferritinemia cataract syndrome and others, can elevate serum ferritin, which can account for up to 90% of cases where elevated levels are observed. Measuring iron in the body</ref> Serum ferritin in excess of 1000 ng/mL of blood is almost always attributable to haemochromatosis.Other blood tests routinely performed include blood count, renal function, liver enzymes, electrolytes, and glucose (and/or an oral glucose tolerance test).

Liver biopsy
Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding, and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis,  whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.

MRI
MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.

Other imaging
Clinically, the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity in MRI scans. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand.  The arthropathy can, therefore, be an early clue as to the diagnosis of haemochromatosis.

Functional testing
Based on the history, a physician might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.

Stages
The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):
Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.
Iron overload but no organ or tissue damage.
Organ or tissue damage as a result of iron deposition.Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.

Differential diagnosis
Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 is diagnosed.

Haemochromatosis type 2.
Haemochromatosis type 3.
Haemochromatosis type 4.
Haemochromatosis type 5.
African iron overload, formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa. Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin, which predisposes some people of African descent to iron overload.
Secondary haemochromatosis: its main cause is the Transfusional haemosiderosis. It is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassaemia). Other causes are: chronic hemolytic anemia, chronic liver disease (hepatitis B, hepatitis C, cirrhosis, fatty liver disease), dysmetabolic hyperferritinemia, overdose of oral iron pills or iron injections, long-time kidney dialysis, and dyserythropoeisis, also known as myelodysplastic syndrome. It is a disorder in the production of red blood cells that leads to increased iron recycling from the bone marrow and accumulation in the liver.
Aceruloplasminemia.
Atransferrinemia.
Neonatal hemochromatosis
GRACILE syndrome
Porphyria cutanea tarda

Screening
Standard diagnostic measures for haemochromatosis, transferrin saturation and ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child, or sibling with the disease.Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force, among other groups, which recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than one in 1,000.  Although strong evidence shows that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection  (phlebotomy) provides any clinical benefit. Recently,  patients are suggested to be screened for iron overload using serum ferritin as a marker. If serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.

Treatment
Phlebotomy
Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.Phlebotomy (or bloodletting) is usually done at a weekly or each two weeks interval until ferritin levels are 50 μg/L or less. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females to keep the serum ferritin between 50 and 100 ug/L

Iron chelation therapy
Where venesection is not possible, long-term administration of an iron chelator as Deferoxamine (or Desferrioxamine), Deferasirox and Deferiprone is useful. Deferoxamine is an iron-chelating compound, and excretion induced by deferoxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.

Organ damage
Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy). Hepatic transplantation in patients with liver failure.

Diet
Limiting intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron), and potential causes of food poisoning (shellfish, raw seafood)
Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (such as collard greens, which must be consumed at the same time as the iron-containing foods to be effective)

Chelating polymers
A novel experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators. These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting the uptake of these ions and their long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects in sub-chronic studies. Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.

Prognosis
Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.

Epidemiology
Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe, with a prevalence of 1:200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism. In the U.S., the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele. The prevalence of mutations in iron-metabolism genes varies in different populations.  A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload.  Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population, It is 2-3 times most common in males.Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece.

Terminology
The term "haemochromatosis" is used by different sources in many different ways.
It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, many different genetic associations with this condition are now known. The older the text, or the more general the audience, the more likely that HFE is implied. "Haemochromatosis" has also been used in contexts where a genetic cause for iron accumulation had not been known. In some cases, however, a condition that was thought to be due to diet or environment was later linked to a genetic polymorphism, as in African iron overload.

History
In 1847, Virchow described a golden brown granular pigment that was soluble in sulfuric acid and produced red ash on ignition. The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin. Two years later, Perls developed the first practical method for the analysis of iron in tissue. Despite Trousseau did not associate diabetes with iron accumulation, the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890. In 1935, English gerontologist Joseph Sheldon described the cases of haemochromatosis. He established this as the name of the disorder and his detailed monograph. Despite lacking the modern molecular techniques accessible today, he came to accurate conclusions that describe haemochromatosis disease as an inborn error of metabolism where this inherited disorder can increase the absorption of iron and thus cause tissue damage due to iron deposition. Moreover, he rejected theories that alcohol, drug, and other factors contribute to the disorder.The clinical case series from 1935 to 1955 indicated that haemochromatosis was more common than had been acknowledged </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 Brodie abscess 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 POEMS syndrome and can you explain it in depth? [/INST] POEMS syndrome (also termed osteosclerotic myeloma, Crow–Fukase syndrome, Takatsuki disease, or PEP syndrome) is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the diseases major signs and symptoms (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes), as is PEP (polyneuropathy, endocrinopathy, plasma cell dyscrasia).
The signs and symptoms of most neoplasms are due to their mass effects caused by the invasion and destruction of tissues by the neoplasms cells. Signs and symptoms of a cancer causing a paraneoplastic syndrome result from the release of humoral factors such as hormones, cytokines, or immunoglobulins by the syndromes neoplastic cells and/or the response of the immune system to the neoplasm. Many of the signs and symptoms in POEMS syndrome are due at least in part to the release of an aberrant immunoglobulin, i.e. a myeloma protein, as well as certain cytokines by the malignant plasma cells.POEMS syndrome typically begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women.

Signs and symptoms
The signs and symptoms of POEMS syndrome are highly variable. This often leads to long delays (e.g. 13–18 months) between the onset of initial symptoms and diagnosis. In addition to the signs and symptoms indicated by the POEMS acronym, the PEST acronym is used to describe some of the other signs and symptoms of the disease. PEST stands for Papilledema, evidence of Extravascular volume overload (ascites, pleural effusion, pericardial effusion, and lower extremity edema), Sclerotic bone lesions, and Thrombocytosis/erythrocytosis (i.e. increased in blood platelets and red blood cells). Other features of the disease include a tendency toward leukocytosis, blood clot formation, abnormal lung function (restrictive lung disease, pulmonary hypertension, and impaired lung diffusion capacity), very high blood levels of the cytokine vascular endothelial growth factor (VEGF), and an overlap with the signs and symptoms of multicentric Castleman disease.

Common features
The more common features of the disease are summarized in the acronym POEMS:
Papilledema (swelling of the optic disc) often but not always due to increased intracranial pressure) is the most common ocular sign of POEMS syndrome, occurring in ≥29% of cases. Less frequent ocular findings include cystoid macular edema, serous macular detachment, infiltrative orbitopathy, and venous sinus thrombosis.Pulmonary disease/ Polyneuropathy: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.Organomegaly: The liver may be enlarged, and less often the spleen or lymph nodes, though these organs usually function normally.Edema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral edema, pulmonary edema, effusions such as pleural effusion or ascites, or generalized capillary leakage (anasarca).Endocrinopathy: In women, amenorrhea, and in men, gynecomastia, erectile dysfunction and testicular atrophy, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism, and adrenal insufficiency.Monoclonal paraprotein: In most cases a serum myeloma protein can be detected, although this is not universal. This may represent IgG or IgA, but the light chain type is almost always lambda. This is in contrast to most paraproteinemic neuropathies, in which the paraprotein is usually an IgM antibody.Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation. The fingernails may be clubbed or white. There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis), skin angiomas or hemangiomas, or changes reminiscent of scleroderma.

Possible features
Some features have been observed in patients with POEMS syndrome but are not yet certain to form part of the syndrome itself. These include a predisposition to forming blood clots, joint pain, cardiomyopathy (systolic dysfunction), fever, low vitamin B12 levels, and diarrhea.

Pathogenesis
While the main features of this paraneoplastic disease have been described, the exact mechanism behind its development, progression, and manifestations remain elusive. Overproduction of the myeloma protein and VEGF may underlie some, but are insufficient to explain all, of the multi-organ features of the disease. It is suggested that various other cytokines produced by the clonal plasma cells, perhaps working in concert with each other as well as with VEGF and the myeloma proteins, mediate many of the features of POEMS syndrome. The other cytokines detected in, and suspected of contributing to, POEMS syndrome include interleukin 1β, interleukin 6, and TNFα. Nonetheless, it seems likely that some of these paraneoplastic factors, operating individually, make a major contribution to certain features of the disease. For example, VEGF, given its ability to stimulate blood vessel formation, would seem likely to be the major contributor to the pathologic hyper-vascularization changes seem in many tissues, such as lymph nodes, affected by POEMS syndrome.

Diagnosis
The diagnosis of POEMS syndrome is based on meeting its two mandatory criteria, meeting at least one of its 3 other major criteria, and meeting at least one of its 6 minor criteria. These criteria are:
Mandatory major criteria
Plasma cell dyscrasia: This is evidenced by 1) the presence of a serum myeloma protein, typically an IgG or IgA isotype (occurs in nearly 100% of cases; in >95% of instances the myeloma proteins contain a λ chain that is restricted to either of two V lambda 1 subfamily members viz., IGLV1-40*01 and IGLV1-44*01 (see V lambda family); 2)   any, but often a small, increase above the normal value of <1.5% in the percentage of nucleated bone marrow cells that are clonal plasma cells (occurs ~67% of cases); and/or 3) presence of a plasma cell tumor (i.e. plasmacytoma) usually in bone (occurs in ~33% of cases).
Polyneuropathy: The nerve damage is usually symmetrical, located in distal extremities, and due to the nerve losing its fatty myelin coating and axonal damage. Neurons of the Sensory, motor and autonomic nervous systems are all affected. The typical symptoms are therefore numbness, tingling, and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.
Other major criteria
Castleman disease: The lymphoproliferative disorder Castleman disease associated with POEMS syndrome is multicentric and occurs in ~15 of cases. It is characterized by a morphology in lymph nodes termed angiofollicular lymph node hyperplasia; an overly activate immune system; excessive production of cytokines including particularly IL-6 and to lesser extents, proliferation of immune B cells and T cells, enlarged lymph nodes, enlarged liver and spleen, capillary leak syndrome, anasarca, evidence of extravascular fluid overload, and organ failure. Patients with Castleman disease without a plasma cell dyscrasia and peripheral neuropathy but having other signs and symptoms of POEMS syndrome can be classified as a Castleman disease variant of POEMS syndrome.
Sclerotic bone lesions: These lesions consist of plasma cell tumors encased within or associated with abnormally dense bone structures; in different studies, they have been observed to occur in 27% to 97% of cases.
Elevated VEGF: VEGF is a cytokine that stimulates angiogenesis (i.e. capillary formation), increases capillary permeability, and contributes to polyneuropathy. It is elevated in almost all cases of POEMS syndrome and has become a clinically useful marker for the syndromes presence, severity, and response to treatment. However, its role in mediating the symptoms of this disease are unclear.  A second cytokine, IL-12, is similar to VEGF in being highly correlated with the disease activity level in POEMS syndrome.
Minor criteria
Organomegaly: Enlargement spleen, liver, and/or lymph nodes occurs in 45% to 85% of cases.
Extravascular volume overload: Ascites, pleural effusions, pericardial effusions, and/or lower extremity edema occur in 27% to 89% of cases.
Endocrinopathy: Gynecomastia occurs in 12% to 18% of cases; endocrine abnormalities involving the regulation of gonadotrophins, adrenal gland corticosteroids, and prolactin occur in 55% to 89%, 16% to 33%, and 55 to 20% of cases, respectively.  Diabetes and hypothyroidism also occur in 3% to 36% and 9% to 67%, respectively, of cases but are not considered to be criteria for the presence of POEMS syndrome because of their frequent occurrence in the general population.
Skin changes: Skin changes occur in 68% to 89% of POEMS syndrome patients. These changes most commonly are hyperpigmentation and/or hypertrichosis (abnormal amount of hair growth over the body) but less commonly include glomeruloid hemangioma, signs or symptoms of Hypervolemia (e.g. edema and ascites), acrocyanosis (blue discoloration of the extremities due to blood flow abnormalities), flushing, and/or white nails.
Papilledema: Papilledema (swelling of retinal optical discs) occurs in 29% to 64% of cases. Papilledema in POEMS syndrome patients may occur with or without visual disturbances, increased intracranial pressure, or changes in cerebral spinal fluid protein levels.
Thrombocytosis/polycythemia: Thrombocytosis (increase in blood platelet count) and polycythemia (increase in red blood cells) occurs 54% to 88% and 12% to 19%, respectively, of POEMS syndrome patients and may be may underlying causes of these patients to experience thrombosis events.

Laboratory findings
In addition to tests corresponding to the above findings, such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of POEMS syndrome. These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters.

Differential diagnosis
Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of POEMS syndrome but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having POEMS syndrome. They are better classified as having Castleman disease variant of POEMS syndrome. These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to POEMS syndrome patients. Treatment of patients with this POEMS syndrome variant who have evidence of bone lesions and/or myeloma proteins are the same as those for POEMS syndrome patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.

Treatment
As reported by Dispenzieri et al. Mayo Clinic treatment regimens are tailored to treat the clinical manifestations and prognosis for the rate of progression of the POEMS syndrome in each patient. In rare cases, patients may have minimal or no symptoms at presentation or after successful treatment of their disorder. These patients may be monitored every 2–3 months for symptoms and disease progression. Otherwise, treatment is divided based on the local versus systemic spread of its clonal plasma cells. Patients with one or two plasmacytoma bone lesions and no clonal plasma cells in their bone marrow biopsy specimens are treated by surgical removal or radiotherapy of their tumors. These treatments can relieve many of the syndromes clinical manifestations including neuropathies, have a 10-year overall survival of 70% and a 6-year progression-free survival of 62%. Patients with >2 plasmacytoma bone lesions and/or increases in bone marrow clonal plasma cells are treated with a low-dose or high-dose chemotherapy regimen, i.e. a corticosteroid such as dexamethasone plus an alkylating agents such as melphalan. Dosage regimens are selected on the basis of patient tolerance </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 Saddle sore and can you explain it in depth? [/INST] A saddle sore in humans is a skin ailment on the buttocks due to, or exacerbated by, horse riding or cycling on a bicycle saddle. It often develops in three stages:  skin abrasion, folliculitis (which looks like a small, reddish acne), and finally abscess.
Because it most commonly starts with skin abrasion, it is desirable to reduce the factors which lead to skin abrasion.  Some of these factors include:

Reducing the friction. In equestrian activities, friction is reduced with a proper riding position and using properly fitting clothing and equipment </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 Polymelia and can you explain it in depth? [/INST] Polymelia is a birth defect in which an affected individual has more than the usual number of limbs. It is a type of dysmelia. In humans and most land-dwelling vertebrates, this means having five or more limbs. The extra limb is most commonly shrunken and/or deformed. The term is from Greek πολυ- "many", μέλεα "limbs".
Sometimes an embryo started as conjoined twins, but one twin degenerated completely except for one or more limbs, which end up attached to the other twin.
Sometimes small extra legs between the normal legs are caused by the body axis forking in the dipygus condition.
Notomelia (from Greek for "back-limb-condition") is polymelia where the extra limb is rooted along or near the midline of the back. Notomelia has been reported in Angus cattle often enough to be of concern to farmers.Cephalomelia (from Greek for "head-limb-condition") is polymelia where the extra limb is rooted on the head.

Origin
Tetrapod legs evolved in the Devonian or Carboniferous geological period from the pectoral fins and pelvic fins of their crossopterygian fish ancestors.
Fish fins develop along a "fin line", which runs from the back of the head along the midline of the back, round the end of the tail, and forwards along the underside of the tail, and at the cloaca splits into left and right fin lines which run forwards to the gills. In the paired ventral part of the fin line, normally only the pectoral and pelvic fins survive (but the Devonian acanthodian fish Mesacanthus developed a third pair of paired fins); but along the non-paired parts of the fin line, other fins develop.
In tetrapods, only the four paired fins normally persisted, and became the four legs. Notomelia and cephalomelia are atavistic reappearances of dorsal fins. Some other cases of polymelia are extra development along the paired part of the fin lines, or along the ventral posterior non-paired part of the fin line.

Notable cases
Humans
1995: Somali baby girl born with three right arms.
In the summer of 2005, a baby girl named Destiny was born with a fully formed extra leg in Detroit. This was the result of a conjoined twin scenario.
In March 2006, a baby boy identified only as Jie-jie was born in Shanghai with a fully formed third arm: he had two full-sized left arms, one ventral to the other. This is the only documented case of a child born with a fully formed supernumerary arm. It is an example of an extra limb on a normal body axis.
In July 2007 a child was born with four legs at the Lebowakgomo hospital outside Polokwane (South Africa)
On November 6, 2007, doctors at Bangalores Sparsh Hospital in Bangalore, India successfully completed surgery on a two-year-old girl named Lakshmi Tatma who was born with four arms and four legs; this was not true polymelia but a case of ischiopagus Siamese twinning where one twins head had disappeared during development.
Frank Lentini had a third leg, as well as a fourth foot and two sets of genitals.
A boy named Gaurav, born in Tanahun district in Nepal with an extra arm growing out of his upper back between his shoulder blades, two years ago was published on 2016.

Other animals
A four-legged chicken was born at Brendle Farms in Somerset, Pennsylvania, in 2005. The story was carried on the major TV network news programs and USA Today. The bird was found living normally among the rest of the chickens after 18 months.  She was adopted and named Henrietta by the farm owners 13-year-old daughter, Ashley, who refuses to sell the chicken.  The second (hind) legs are fully formed but non-functional.
Four-legged ducks are occasionally hatched, such as Stumpy, an individual born in February 2007 on a farm in Hampshire, England.
Frogs in the US sometimes are affected by polymelia when attacked in the tadpole stage by the Ribeiroia parasite.
A puppy, known as Lilly, was born in the United States with a fully formed fifth leg jutting out between her hind legs.  She was initially set to be sold to a freak show, but was instead bought by a dog lover who had the extra leg removed.

An eight-legged lamb has been reported on at least two occasions including in 1898 and 2018.

In mythology
Many mythological creatures like dragons, winged horses, and griffins have six limbs: four legs and two wings. The dragons science is discussed in Dragons: A Fantasy Made Real.
In Greek Mythology:

The Hekatonkheires were said to each have one hundred hands.
The Gegenees were a race of giants with six arms.
The centaurs had six limbs: four horse legs and two human arms.Sleipnir, Odins horse in Norse mythology, has eight normal horse legs, and is usually depicted with limbs twinned at the shoulder or hip.
Several Hindu deities are depicted with multiple arms and sometimes also multiple legs.

In popular culture
Edward Albees stage play The Man Who Had Three Arms tells the story of a fictional individual who was normal at birth but eventually sprouted a third functional arm, protruding from between his shoulder blades. After several years of living with three arms, the extra limb was reabsorbed into his body and the man became physically normal again. In Albees play, the title character is extremely angry that we (the audience) seem to be much more interested in the period of his life when he had three arms, rather than his normal life before and after that interval.
Monty Pythons Flying Circus performed a skit about a man with three buttocks. He believes that he has been invited to be interviewed on television because he is a nice person, and is dismayed to learn that he has only been invited because the interviewer is curious about his unusual condition.
The Dark Backward is a 1991 comedy film directed and written by Adam Rifkin, which features Judd Nelson as an unfunny garbage man who pursues a stand-up comedy career.  When the "comedian" grows a third arm out of his back, he becomes an overnight hit.
Justice, the main antagonist in the cartoon Afro Samurai, has a fully formed extra arm protruding from his right shoulder.

Paco, a playable character in Brawlout, is a four-armed frog- and shark-like creature.
Spiral, character in the X-Men stories of Marvel Comics, has six arms.
A 6-armed Spider-Man frequently appears as an alternate reality incarnation of the character, and is sometimes referred to as "Polymelian".
In the Mortal Kombat series, the Shokan is a race of humanoids known to have four arms.
Ibid: A Life is a fictional biography of Jonathan Blashette, a man with three legs.
Zaphod Beeblebrox, a character in Douglas Adams Hitchhikers Guide to the Galaxy, has a third arm as well as a second head.

See also
Dipygus
Dysmelia
Polydactyly
Polysyndactyly
Supernumerary body parts

References
Sources
Avian Diseases, 1985 Jan-Mar; 29(1): pp. 244-5. Polymelia in a broiler chicken., Anderson WI, Langheinrich KA, McCaskey PC.: "A polymelus monster was observed in a 7-week-old slaughterhouse chicken. The supernumerary limbs were smaller than the normal appendages but contained an equal number of digits.".
Kim C, Yeo S, Cho G, Lee J, Choi M, Won C, Kim J, Lee S (2001) </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 Transient neonatal pustular melanosis and can you explain it in depth? [/INST] Transient neonatal pustular melanosis (TNPM), also known as pustular melanosis, is a transient rash common in newborns. It is vesiculopustular and made up of 1–3 mm fluid-filled lesions that rupture, leaving behind a collarette of scale and a brown macule.[3] This rash occurs only in the newborn stage, usually appearing a few days after birth[2], but is sometimes already present at birth[3]. The rash usually fades over three to four weeks  but may linger for up to three months after birth.[3] It can occur anywhere on the body, including the palms and soles.[1][2][3]The cause of TNPM is unknown. No treatment is needed except for parental reassurance.

Causes
The cause of TNPM is unknown but it is a common rash in newborns.[3]

Histopathology
Gram, Wright, or Giemsa staining of the pustular contents will show polymorphic neutrophils and occasional eosinophils.[2][3] On histopathology, the pigmented macules will show basal and supra-basal increase in pigmentation without any pigmentary incontinence.[3] Bacterial culture will be negative.[4]It has been suggested that TNPM is merely a precocious form of erythema toxicum neonatorum based on the similar histopathology.[4]

Diagnosis
Transient neonatal pustular melanosis is diagnosed clinically, based on appearance alone, with no need for special testing.  Proper identification is important to distinguish it from other serious, infectious neonatal diseases[3] and to help avoid unnecessary diagnostic testing and treatments.

Treatment
No treatment is needed except for parental reassurance.  The rash spontaneously resolves, usually in three to four weeks,  but may linger for up to three months after birth.[3]

Epidemiology
Transient neonatal pustular melanosis occurs in as much as 15% of black newborns.[3] but in less than 1% of white newborns. [2]

See also
List of cutaneous conditions

References

1.    OConnor NR, McLaughlin, MR, Ham P (2008). "Newborn Skin: Part I. Common Newborn Rashes". American Family Physician. 77 (1): 47–52.
2.    Patrizi A, Neri I, Virid A, Gurioli C.(2016). "Frequent newborn skin diseases". Clinical Dermatology. 4 (3-4): 82–86. doi: 10.11138/cderm/2016.4.3.082.
3.    Ghosh S. (2015). "Neonatal Pustular Dermatosis: An Overview". Indian Journal of Dermatology </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 X-linked agammaglobulinemia and can you explain it in depth? [/INST] X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the bodys ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins), which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Brutons tyrosine kinase (Btk) gene that leads to a severe block in B cell development (at the pre-B cell to immature B cell stage) and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody.  Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme known as Brutons tyrosine kinase, or Btk. XLA was first characterized by Dr. Ogden Bruton in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system, known as primary immunodeficiency disorders.

Signs and symptoms
Affects males 50% of the time if mother is a carrier for the gene. Children are generally asymptomatic until 6–9 months of age when maternal IgG decreases. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins.

Genetics
Most antibodies are gamma globulins. Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line. The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature (naive) B cells that leave the bone marrow into the blood stream.The disorder is inherited in an X-linked recessive fashion (as the gene linked to it is on the X chromosome) and is almost entirely limited to the sons of asymptomatic female carriers.  This is because males have only one copy of the X chromosome, while females have two copies; one normal copy of an X chromosome can compensate for mutations in the other X chromosome, so they are less likely to be symptomatic.There is 30–50% chance of XLA patients having a positive family history of genetic inheritance. The rest of the cases occur as random mutations. If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA. A carrier female has a 25% chance overall of giving birth to an affected male child. An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patients daughters have a 50% chance of inheriting XLA. A female XLA patient can arise only as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus of a non-carrier mother.

Diagnosis
XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. This is due to humoral immunodeficiency. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19 and/or CD20), as well as low levels of all antibody classes, including IgG, IgA, IgM, IgE and IgD.When XLA is suspected, it is possible to do a Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy. Although the symptoms of a XLA and other primary immune diseases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.

Treatment
The most common treatment for XLA is an intravenous infusion of immunoglobulin (IVIg, human IgG antibodies) every week, for life. IVIg is a human product extracted and pooled from thousands of blood donations. IVIg does not cure XLA but increases the patients lifespan and quality of life, by generating passive immunity, and boosting the immune system. With treatment, the number and severity of infections is reduced.  With IVIg, XLA patients may live a relatively healthy life. A patient should attempt reaching a state where his IgG blood count exceeds 800 mg/kg. The dose is based on the patients weight and IgG blood-count.Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful; hence, IMIg is now uncommon. Subcutaneous treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.Antibiotics are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long-term treatment, if possible. One of the future prospects of XLA treatment is gene therapy, which could potentially cure XLA. Gene therapy technology is still in its infancy and may cause severe complications such as cancer and even death. Moreover, the long-term success and complications of this treatment are, as yet, unknown.

Other considerations
It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or the measles, mumps, rubella (MMR vaccine). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients </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 Dentin and can you explain it in depth? [/INST] Dentin () (American English) or dentine ( or ) (British English) (Latin: substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by enamel on the crown and cementum on the root and surrounds the entire pulp. By volume, 45% of dentin consists of the mineral hydroxyapatite, 33% is organic material, and 22% is water. Yellow in appearance, it greatly affects the color of a tooth due to the translucency of enamel. Dentin, which is less mineralized and less brittle than enamel, is necessary for the support of enamel. Dentin rates approximately 3 on the Mohs scale of mineral hardness. There are two main characteristics which distinguish dentin from enamel: firstly, dentin forms throughout life; secondly, dentin is sensitive: 125  and can become hypersensitive to changes in temperature due to the sensory function of odontoblasts, especially when enamel recedes and dentin channels become exposed.

Dentinal sclerosis
Dentinal sclerosis or transparent dentin sclerosis of primary dentin is a change in the structure of teeth characterized by calcification of dentinal tubules. It can occur as a result of injury to dentin by caries or abrasion, or as part of the normal aging process.

Development
Prior to enamel formation, dentine formation begins through a process known as dentinogenesis, and this process continues throughout a persons life even after the tooth has fully developed. Events such as tooth decay and tooth wear can also initiate dentine formation.Dentinogenesis is initiated by the odontoblasts of the pulp. Odontoblasts are specialised cells that lay down an organic matrix known as pre-dentine. This pre-dentine is subsequently mineralised into dentine. Mineralisation of pre-dentine begins at the dentino-enamel junction during tooth development and progresses towards the pulp of the tooth. After growth of pre-dentine and maturation into dentine, the cell bodies of the odontoblasts remain in the pulp, along its outer wall, and project into tiny tubules in the dentine.
Pre-dentine is composed of 90% type I collagen and 10% non-collagenous proteins (including phosphoproteins, proteoglycans, growth factors, phosphatases such as alkaline phosphatase, and matrix metalloproteinases (MMPs)), and this composition is significantly altered when it is mineralised into dentine. See the Structure section for information about the composition of dentine.

Structure
Unlike enamel, dentin may be demineralized and stained for histological study. Dentin consists of microscopic channels, called dentinal tubules, which radiate outward through the dentin from the pulp to the exterior cementum or enamel border. The dentinal tubules extend from the dentinoenamel junction (DEJ) in the crown area, or dentinocemental junction (DCJ) in the root area, to the outer wall of the pulp. From the outer surface of the dentin to the area nearest the pulp, these tubules follow an S-shaped path. The diameter and density of the tubules are greatest near the pulp.: 152  Tapering from the inner to the outermost surface, they have a diameter of 2.5 μm near the pulp, 1.2 μm in the middle of the dentin, and 0.9 μm at the dentino-enamel junction. Their density is 59,000 to 76,000 per square millimeter near the pulp, whereas the density is only half as much near the enamel. Within the tubules, there is an odontoblast process, which is an extension of an odontoblast, and dentinal fluid, which contains a mixture of albumin, transferrin, tenascin and proteoglycans. In addition, there are branching canalicular systems that connect to each other.  These branches have been categorized by size, with major being 500-1000 nm in diameter, fine being 300-700 nm, and micro being less than 300 nm.: 155  The major branches are the terminal ends of the tubules. About every 1-2 μm, there are fine branches diverging from dentinal tubules at 45 degree angles. The microtubules diverge at 90 degree angles. The dentinal tubules contain the cytoplasmic extensions of odontoblasts that once formed the dentin and maintain it. The cell bodies of the odontoblasts are aligned along the inner aspect of dentin against a layer of predentin where they also form the peripheral boundary of the dental pulp Because of dentinal tubules, dentin has a degree of permeability, which can increase the sensation of pain and the rate of tooth decay. The strongest held theory of dentinal hypersensitivity suggests that it is due to changes in the dentinal fluid associated with the processes, a type of hydrodynamic mechanism.Dentin is a bone-like matrix that is porous and yellow-hued material. It is made up, by weight, of 70-72% inorganic materials (mainly hydroxylapatite and some non-crystalline amorphous calcium phosphate), 20% organic materials (90% of which is collagen type 1 and the remaining 10% ground substance, which includes dentin-specific proteins), and 8-10% water (which is adsorbed on the surface of the minerals or between the crystals). Because it is softer than enamel, it decays more rapidly and is subject to severe cavities if not properly treated, but due to its elastic properties, it is good support for enamel. Its flexibility prevents the brittle enamel fracturing.
In areas where both primary and secondary mineralization have occurred with complete crystalline fusion, these appear as lighter rounded areas on a stained section of dentin and are considered globular dentin. In contrast, the darker arc-like areas in a stained section of dentin are considered interglobular dentin. In these areas, only primary mineralization has occurred within the predentin, and the globules of dentin do not fuse completely. Thus, interglobular dentin is slightly less mineralized than globular dentin. Interglobular dentin is especially evident in coronal dentin, near the dentinoenamel junction (DEJ), and in certain dental anomalies, such as in dentinogenesis imperfecta.

Regional variations in dentin structure and composition
The different regions in dentin can be recognized due to their structural differences. The outermost layer, known as the mantle dentin layer, is found in the crown of the tooth. It can and can be identified by the presence of various characteristics, including collagen fibres found perpendicular to the enamel-dentin junction and it is slightly less mineralized (by approximately 5%, compared to the enamel. The dentin undergoes mineralization in the presence of matrix vesicles ("hydroxyapatite-containing, membrane-enclosed vesicles secreted by odontoblasts, osteoblasts, and some chondrocytes; believed to serve as nucleation centers for the mineralization process in dentin, bone, and calcified cartilage.") The dentinal tubules in this region branch profusely.
In the root of the tooth there are two morphologically distinguishable outer layers: the hyaline layer on the periphery of dentin and the granular layer of Tomes beneath this. The granular layer has a dark, granular appearance which occurs due to the branching and looping back of dentinal tubules in this region. This appearance, specific to root dentin, is possibly due to differences in the rates of formation of coronal and root dentin. The hyaline layer, which has an obscure origin, is a clear layer, unlike the granular layer, with a width of up to 20μm. It can have clinical significance during periodontal regeneration.
Circumpulpal dentin forms the majority of the dentin and is generally constant in structure. Peripherally, mineralization can be seen to be incomplete, whereas centrally the mineralizing front shows ongoing mineralizing.
The innermost layer of dentin is known as predentin, and is the initial dentin matrix that is laid down prior to mineralization. It can be distinguished by its pale color when stained with haematoxylin and eosin. The presence of odontoblastic processes here allows the secretion of matrix components. Predentin can be 10-40μm in width, depending on its rate of deposition.: 134–137

Types
There are three types of dentin, primary, secondary and tertiary. Secondary dentin is a layer of dentin produced after the root of the tooth is completely formed.  Tertiary dentin is created in response to a stimulus, such as a carious attack or wear.

Primary dentin
Primary dentin, the most prominent dentin in the tooth, lies between the enamel and the pulp chamber (near dentinoenamel junction). The outer layer closest to enamel is known as mantle dentin.  This layer is unique to the rest of primary dentin.  Mantle dentin is formed by newly differentiated odontoblasts and forms a layer consistently 15-20 micrometers (µm) wide. Unlike primary dentin, mantle dentin lacks phosphorylation, has loosely packed collagen fibrils and is less mineralized. Below it lies the circumpulpal dentin, more mineralized dentin which makes up most of the dentin layer and is secreted after the mantle dentin by the odontoblasts. Circumpulpal dentin is formed before the root formation is completed.
Newly secreted dentin is unmineralized and is called predentin. It is easily identified in hematoxylin and eosin stained sections since it stains less intensely than dentin. It is usually 10-47μm and lines the innermost region of the dentin. It is unmineralized and consists of collagen, glycoproteins, and proteoglycans. It is similar to osteoid in bone and is thickest when dentinogenesis is occurring.

Secondary dentin
Secondary dentin (adventitious dentin) is formed after root formation is complete, normally after the tooth has erupted and is functional. It grows much more slowly than primary dentin but maintains its incremental aspect of growth. It has a similar structure to primary dentin, although its deposition is not always even around the pulp chamber. It appears greater in amounts on the roof and floor of the coronal pulp chamber, where it protects the pulp from exposure in older teeth. The secondary dentin formed is not in response to any external stimuli, and it appears very much similar to the primary dentine.  It is the growth of this dentin that causes a decrease in the size of the pulp chamber with age. This is clinically known as pulp recession; cavity preparation in young patients, therefore, carries a greater risk of exposing the pulp. If this occurs, the pulp can be treated by different therapies such as direct pulp capping. Previously it was thought that Pulp capping was most successful if followed by a stainless steel crown, however this procedure is most of the times unnecessary in children. it requires the unnecessary removal of enamel which is key to the life of the tooth. Adhesive dentistry allows for conservative restoration techniques that minimize the loss of tooth structure and should be used. In order to maintain space in the primary dentition, attempts are made not to extract a pulpal exposure.

Tertiary dentin (including reparative dentin or sclerotic dentin) – pathologic
Tertiary dentin is dentin formed as a reaction to external stimulation such as cavities and wear. It is of two types, either reactionary, where dentin is formed from a pre-existing odontoblast, or reparative, where newly differentiated odontoblast-like cells are formed due to the death of the original odontoblasts, from a pulpal progenitor cell. Tertiary dentin is only formed by an odontoblast directly affected by a stimulus; therefore, the architecture and structure depend on the intensity and duration of the stimulus, e.g., if the stimulus is a carious lesion, there is extensive destruction of dentin and damage to the pulp, due to the differentiation of bacterial metabolites and toxins. Thus, tertiary dentin is deposited rapidly, with a sparse and irregular tubular pattern and some cellular inclusions; in this case, it is referred to as "osteodentin". Osteodentin is seen in Vit.A deficiency during development </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 Scott syndrome and can you explain it in depth? [/INST] Scott syndrome is a rare congenital bleeding disorder that is due to a defect in a platelet mechanism required for blood coagulation.Normally when a vascular injury occurs, platelets are activated and phosphatidylserine (PS) in the inner leaflet of the platelet membrane is transported to the outer leaflet of the platelet membrane, where it provides a binding site for plasma protein complexes that are  involved in the conversion of prothrombin to thrombin, such as factor VIIIa-IXa (tenase) and factor Va-Xa (prothrombinase).In Scott syndrome, the mechanism for translocating PS to the platelet membrane is defective, resulting in impaired thrombin formation. A similar defect in PS translocation has also been demonstrated in Scott syndrome red blood cells and Epstein–Barr virus transformed lymphocytes, suggesting that the defect in Scott syndrome reflects a mutation in a stem cell that affects multiple hematological lineages.The basis for the defect in PS translocation is, at present, unknown. A candidate protein, scramblase, that may be involved in this process appears to be normal in Scott syndrome platelets. Other possible defects in PS translocation, reported in some patients, require further study. The initially reported patient with Scott Syndrome has been found to have a mutation at a splice-acceptor site of the gene encoding anoctamin 6 (ANO6, transmembrane protein 16F, TMEM16F). At present, the only treatment for episodes of bleeding is the transfusion of normal platelets.

References
Further reading
Heemskerk JWM, Bevers EM, Lindhout T. Platelet activation and blood coagulation, Thromb Haem 2002; 88:186–194
Martinez MC, Martin S, Toti F, Fressinaud E, Dachary-Prigent J, Meyer D, et al. Significance of capacitative Ca2+ entry to the regulation of phoshatidylserine expression at the surface of stimulated cells. Biochemistry 1999; 38:10092–10098
Munnix ICA, Harmsma M, Diddings JC, Collins PW, Feijge P, Comfurius JWM, et al. Store-mediated Ca2+ entry in the regulation of phoshatidylserine exposure in blood cells from Scott patients. Thromb Haemost 2003; 89:687–695
Weiss HJ, Vicic WJ, Lages BA, Rogers J. Isolated deficiency of platelet procoagulant activity. Am J Med 1979; 67:206–213
Miletich JP, Kane WH, Hofmann SL, Stanford N, Majerus PW. Deficiency of factor Xa-factor Va binding sites on the platelets of a patient with a bleeding disorder. Blood 1979; 54:1015–1022
Bevers EM, Wiedmer T, Comfurius P, Shattil SJ, Weiss HJ, Zwaal RFA, et al </s>