<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 Subacute sclerosing panencephalitis and can you explain it in depth? [/INST] Subacute sclerosing panencephalitis (SSPE)—also known as Dawson disease—is a rare form of chronic, progressive brain inflammation caused by slow infection with certain defective strains of hypermutated measles virus. The condition primarily affects children, teens, and young adults. It has been estimated that about 2 in 10,000 people who get measles will eventually develop SSPE. However, a 2016 study estimated that the rate for unvaccinated infants under 15 months was as high as 1 in 609. No cure for SSPE exists, and the condition is almost always fatal. SSPE should not be confused with acute disseminated encephalomyelitis, which can also be caused by the measles virus, but has a very different timing and course.SSPE is caused by the wild-type virus, not by vaccine strains.

Signs and symptoms
SSPE is characterized by a history of primary measles infection, followed by an asymptomatic period that lasts 7 years on average but can range from 1 month to 27 years. After the asymptomatic period, progressive neurological deterioration occurs, characterized by behavior change, intellectual problems, myoclonic seizures, blindness, ataxia, and eventually death.

Progression
Symptoms progress through the following 4 stages:
Stage 1: There may be personality changes, mood swings, or depression. Fever, headache, and memory loss may also be present. This stage may last up to 6 months.
Stage 2: This stage may involve jerking, muscle spasms, seizures, loss of vision, and dementia.
Stage 3: Jerking movements are replaced by writhing (twisting) movements and rigidity. At this stage, complications may result in blindness or death.
Stage 4: Progressive loss of consciousness into a persistent vegetative state, which may be preceded by or concomitant with paralysis, occurs in the final stage, during which breathing, heart rate, and blood pressure are affected. Death usually occurs as a result of fever, heart failure, or the brain’s inability to control the autonomic nervous system.

Pathogenesis
A large number of nucleocapsids are produced in the neurons and the glial cells. In these cells the viral genes that encode envelope proteins have restricted expression. As a result, infectious particles like the M protein are not produced, and the virus is able to survive persistently without evoking an immune response. Eventually the infection will lead to SSPE.

Diagnosis
According to the Merck Manual: "SSPE is suspected in young patients with dementia and neuromuscular irritability. EEG, CT or MRI, CSF examination, and measles serologic testing are done. EEG shows periodic complexes with high-voltage diphasic waves occurring synchronously throughout the recording. CT or MRI may show cortical atrophy or white matter lesions. CSF examination usually reveals normal pressure, cell count, and total protein content; however, CSF globulin is almost always elevated, constituting up to 20 to 60% of CSF protein. Serum and CSF contain elevated levels of measles virus antibodies. Anti-measles IgG appears to increase as the disease progresses.
If test results are inconclusive, brain biopsy may be needed."

Treatment
If the diagnosis is made during stage 1 it may be possible to treat the disease with oral isoprinosine (Inosiplex) and intraventricular interferon alfa, but the response to these drugs varies from patient to patient, and the only accepted treatments are supportive measures such as anticonvulsants. Following onset of stage 2, the disease is invariably fatal.

Prognosis
In the classic presentation of the disease death occurs in 1 to 3 years, but faster and slower progressions can occur </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 Speech disorder and can you explain it in depth? [/INST] Speech disorders or speech impairments are a type of communication disorder in which normal speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute. Speech is a complex process that requires precise timing, nerve and muscle control, and as a result is susceptible to impairments. Speech disorders affect roughly 11.5% of the US population, and may be caused by a stroke, an accident or birth defect.

Classification
Classifying speech into normal and disordered is more problematic than it first seems. By strict classification, only 5% to 10% of the population has a completely normal manner of speaking (with respect to all parameters) and healthy voice; all others have one disorder or another.
There are three different levels of classification when determining the magnitude and type of a speech disorder and the proper treatment or therapy:
Sounds the patient can produce
Phonemic – can be produced easily; used meaningfully and constructively
Phonetic – produced only upon request; not used consistently, meaningfully, or constructively; not used in connected speech
Stimulate sounds
Easily stimulated
Stimulate after demonstration and probing (i.e. with a tongue depressor)
Cannot produce the sound
Cannot be produced voluntarily
No production ever observed

Types of disorder
Apraxia of speech may result from stroke or progressive illness, and involves inconsistent production of speech sounds and rearranging of sounds in a word ("potato" may become "topato" and next "totapo"). Production of words becomes more difficult with effort, but common phrases may sometimes be spoken spontaneously without effort.
Cluttering, a speech and fluency disorder characterized primarily by a rapid rate of speech, which makes speech difficult to understand.
Developmental verbal dyspraxia also known as childhood apraxia of speech.
Dysarthria is a weakness or paralysis of speech muscles caused by damage to the nerves or brain. Dysarthria is often caused by strokes, Parkinsons disease, ALS, head or neck injuries, surgical accident, or cerebral palsy.
Aphasia
Dysprosody is an extremely rare neurological speech disorder. It is characterized by alterations in intensity, in the timing of utterance segments, and in rhythm, cadence, and intonation of words. The changes to the duration, the fundamental frequency, and the intensity of tonic and atonic syllables of the sentences spoken, deprive an individuals particular speech of its characteristics. The cause of dysprosody is usually associated with neurological pathologies such as brain vascular accidents, cranioencephalic traumatisms, and brain tumors.
Muteness is the complete inability to speak.
Speech sound disorders involve difficulty in producing specific speech sounds (most often certain consonants, such as /s/ or /r/), and are subdivided into articulation disorders (also called phonetic disorders) and phonemic disorders. Articulation disorders are characterized by difficulty learning to produce sounds physically. Phonemic disorders are characterized by difficulty in learning the sound distinctions of a language, so that one sound may be used in place of many </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 Pulmonary-renal syndrome 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 Subacute bacterial endocarditis and can you explain it in depth? [/INST] Subacute bacterial endocarditis, abbreviated SBE, is a type of endocarditis (more specifically, infective endocarditis). Subacute bacterial endocarditis can be considered a form of type III hypersensitivity.

Signs and symptoms
Among the signs of subacute bacterial endocarditis are:
Malaise
Weakness
Excessive sweat
Fever

Causes
It is usually caused by a form of Viridans group streptococcus bacteria that normally live in the mouth (Streptococcus mutans, mitis, sanguis or milleri).Other strains of streptococci can cause subacute endocarditis as well. These include streptococcus intermedius, which can cause
acute or subacute infection (about 15% of cases pertaining to infective endocarditis).Enterococci from urinary tract infections and coagulase negative staphylococci can also be causative agents.

Mechanism
The mechanism of subacute bacterial endocarditis could be due to malformed stenotic valves which in the company of bacteremia, become infected, via adhesion and subsequent colonization of the surface area. This causes an inflammatory response, with recruitment of matrix metalloproteinases, and destruction of collagen.Underlying structural valve disease is usually present in patients before developing subacute endocarditis, and is less likely to lead to septic emboli than is acute endocarditis, but subacute endocarditis has a relatively slow process of infection and, if left untreated, can worsen for up to one year before it is fatal. In cases of subacute bacterial endocarditis, the causative organism (streptococcus viridans) needs a previous heart valve disease to colonize. On the other hand, in cases of acute bacterial endocarditis, the organism can colonize on the healthy heart valve, causing the disease.

Diagnosis
Diagnosis of subacute bacterial endocarditis can be done by collecting three blood culture specimens over a 24-hour period for analysis, also it can usually be indicated by the existence of:

Oslers nodes
Roths spots
Nail clubbing

Treatment
The standard treatment is with a minimum of four weeks of high-dose intravenous penicillin with an aminoglycoside such as gentamicin.
The use of high-dose antibiotics is largely based upon animal models.Leo Loewe of Brooklyn Jewish Hospital was the first to successfully treat subacute bacterial endocarditis with penicillin. Loewe reported at the time seven cases of subacute bacterial endocarditis in 1944.

See also
Endocarditis

References
Further references
Goolsby, Mary Jo; Grubbs, Laurie (2011-04-28). Advanced Assessment: Interpreting Findings and Formulating Differential Diagnoses. F.A </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 Peripheral ossifying fibroma and can you explain it in depth? [/INST] A peripheral ossifying fibroma, also known as ossifying fibrous epulis, is “a gingival nodule which is composed of a cellular fibroblastic connective tissue stroma which is associated with the formation of randomly dispersed foci of mineralised products, which consists of bone, cementum-like tissue, or a dystrophic calcification. The lesion is considered part of an ossifying fibroma, but that is usually considered to be a jaw tumor.  Because of its overwhelming incidence on the gingiva, the condition is associated with two other diseases, though not because they occur together.  Instead, the three are associated with each other because they appear frequently on gingiva: pyogenic granuloma and peripheral giant cell granuloma.  Some researchers believe peripheral ossifying fibromas to be related to pyogenic fibromas and, in some instances, are the result of a pyogenic granuloma which has undergone fibrosis and calcification.
The term peripheral ossifying fibroma has been criticized as this lesion is not related to the ossifying fibroma of bone and is not a fibroma. This term is used in America, however in Britain, this lesion would be termed a fibrous epulis containing bone.

Signs and symptoms
The color of peripheral ossifying fibromas ranges from red to pink, and is frequently ulcerated.  It can be sessile or pedunculated with the size usually being less than 2 cm </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 Oculomotor apraxia and can you explain it in depth? [/INST] Oculomotor apraxia (OMA) is the absence or defect of controlled, voluntary, and purposeful eye movement. It was first described in 1952 by the American ophthalmologist David Glendenning Cogan. People with this condition have difficulty moving their eyes horizontally and moving them quickly. The main difficulty is in saccade initiation, but there is also impaired cancellation of the vestibulo-ocular reflex. Patients have to turn their head in order to compensate for the lack of eye movement initiation in order to follow an object or see objects in their peripheral vision, but they often exceed their target. There is controversy regarding whether OMA should be considered an apraxia, since apraxia is the inability to perform a learned or skilled motor action to command, and saccade initiation is neither a learned nor a skilled action.

Symptoms
Absence of fast phase nystagmus on horizontal optokinetic testing
Problems in nerve function involved in eye movement control, called neuropathy
Inability to visually follow objects
Head thrusts to compensate for the inability to accomplish voluntary horizontal gaze.

Related developmental problems
Even though OMA is not always associated with developmental issues, children with this condition often have hypotonia, decreased muscle tone, and show developmental delays. Some common delays are seen in speech, reading and motor development

Causes
OMA is a neurological condition. Although some brain imaging studies of people with OMA reveal a normal brain, some MRI studies have revealed unusual appearance of some brain areas, in particular the corpus callosum, cerebellum, and/or fourth ventricle. Oculomotor apraxia can be acquired or congenital. Sometimes no cause is found, in which case it is described as idiopathicA person may be born with the parts of the brain for eye movement control not working, or may manifest poor eye movement control in childhood. If any part of the brain that controls eye movement becomes damaged, then OMA may develop.  One of the potential causes is bifrontal hemorrhages. In this case, OMA is associated with bilateral lesions of the frontal eye fields (FEF), located in the caudal middle frontal gyrus. The FEF control voluntary eye movements, including saccades, smooth pursuit and vergence. OMA can also be associated with bilateral hemorrhages in the parietal eye fields (PEF). The PEF surround the posterior, medial segment of the intraparietal sulcus. They have a role in reflexive saccades, and send information to the FEF. Since the FEF and PEF have complementary roles in voluntary and reflexive production of saccades, respectively, and they get inputs from different areas of the brain, only bilateral lesions to both the FEF and PEF will cause persistent OMA.  Patients with either bilateral FEF or bilateral PEF damage (but not both FEF and PEF) have been shown to regain at least some voluntary saccadic initiation some time after their hemorrhages. Other causes of OMA include brain tumors and cardiovascular problems,.

Ataxia with oculomotor apraxia
A subgroup of genetically recessive ataxias associated with OMA has been identified, with an onset during childhood. These are ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia 2 (AOA2), and ataxia telangiectasia. These are autosomal recessive disorders and the associated gene products are involved in DNA repair. Both horizontal and vertical eye movements are affected in these disorders. Although people with either type may have some mild cognitive problems, such as difficulty with concentration or performing multi-step activities, intellectual function is usually not affected.

Type 1
Ataxia-oculomotor apraxia type 1 (AOA1) usually has an onset of symptoms during childhood. It is an autosomal recessive cerebellar ataxia (ARCA) associated with hypoalbuminemia and hypercholesterolemia. Mutations in the gene APTX, which encodes for aprataxin, have been identified to be responsible for AOA1. Elevated creatine kinase is occasionally present, in addition to a sensorimotor axonal neuropathy, as shown by nerve conduction velocity studies. In addition, MRI studies have shown cerebellar atrophy, mild brainstem atrophy, and, in advanced cases, cortical atrophyThe aprataxin protein APTX can remove obstructive termini from DNA strand breaks that interfere with DNA repair. APTX is recruited to DNA single-strand breaks by XRCC1 protein, where it functions as a nick sensor to scan the single-strand breaks for 5’-AMP obstructive termini that are intermediates in failed DNA ligase reactions.  The removal of these obstructions allows DNA repair of the break to be completed.  It is not yet clear which specific single-strand breaks are the neurodegenerative agents in AOA1 patients that lack functional aprataxin protein.  However single-strand breaks with 5’-AMP termini appear to be the most likely candidate lesion.

Type 2
Ataxia-oculomotor apraxia type 2 (AOA2), also known as spinocerebellar ataxia with axonal neuropathy type 2, has its onset during adolescence </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 Haemophilia and can you explain it in depth? [/INST] Haemophilia, or hemophilia (from Ancient Greek  αἷμα (haîma) blood, and  φιλία (philía) love of), is a mostly inherited genetic disorder that impairs the bodys ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.There are two main types of haemophilia: haemophilia A, which occurs due to low amounts of clotting factor VIII, and haemophilia B, which occurs due to low levels of clotting factor IX. They are typically inherited from ones parents through an X chromosome carrying a nonfunctional gene. Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. Other types include haemophilia C, which occurs due to low levels of factor XI, Von Willebrand disease, which occur due to low level of a substance called von Willebrand factor in their blood, and parahaemophilia, which occurs due to low levels of factor V. Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors.Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. Human embryos in research can be regarded as the technical object/process. Missing blood clotting factors are replaced to treat haemophilia. This may be done on a regular basis or during bleeding episodes. Replacement may take place at home or in hospital. The clotting factors are made either from human blood or by recombinant methods. Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. The medication desmopressin may be used in those with mild haemophilia A. Studies of gene therapy are in early human trials.Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth. As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected. Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic. Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews. In the 1800s haemophilia B was common within the royal families of Europe. The difference between haemophilia A and B was determined in 1952.

Signs and symptoms
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds". People with more severe haemophilia experience more severe and more frequent bleeds, while people with mild haemophilia usually experience more minor symptoms except after surgery or serious trauma. In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces. This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.Children with mild to moderate haemophilia may not have any signs or symptoms at birth, especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.

Complications
Severe complications are much more common in cases of severe and moderate haemophilia. Complications may arise from the disease itself or from its treatment:
Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
Transfusion transmitted infection from blood transfusions that are given as treatment.
Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
Intracranial haemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction. If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis.  In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in  cartilage and bone destruction.

Genetics
Typically, females possess two X-chromosomes, and males have one X and one Y-chromosome. Since the mutations causing the disease are X-linked recessive, a female carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent dominant allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. Therefore, heterozygous females are just carriers of this genetic disposition. However, the Y-chromosome in the male has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a males X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and the disorder will develop.Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence, haemophilia is expressed far more commonly among males than females, while females, who must have two deficient X-chromosomes in order to have haemophilia, are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.A mother who is a carrier has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.As with all genetic disorders, it is also possible for a human to acquire it spontaneously through mutation, rather than inheriting it, because of a new mutation in one of their parents gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.
If a female gives birth to a haemophiliac son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not.If a male has the disease and has children with a female who is not a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).

Severity
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, people with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5% and 40% of normal levels of active clotting factor.

Diagnosis
Haemophilia can be diagnosed before, during or after birth if there is a family history of the condition. Several options are available to parents. If there is no family history of haemophilia, it is usually only diagnosed when a child begins to walk or crawl. They may experience joint bleeds or easy bruising.Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.

Before pregnancy
Genetic testing and counselling are available to help determine the risk of passing the condition onto a child. This may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia.

During pregnancy
A pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. Such tests include:

chorionic villus sampling (CVS): a small sample of the placenta is removed from the womb and tested for the haemophilia gene, usually during weeks 11–14 of pregnancy
amniocentesis: a sample of amniotic fluid is taken for testing, usually during weeks 15–20 of pregnancyThere is a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care.

After birth
If haemophilia is suspected after a child has been born, a blood test can usually confirm the diagnosis. Blood from the umbilical cord can be tested at birth if theres a family history of haemophilia. A blood test will also be able to identify whether a child has haemophilia A or B, and how severe it is.

Classification
There are several types of haemophilia: haemophilia A, haemophilia B, haemophilia C, parahaemophilia, acquired haemophilia A, and acquired haemophilia B.Haemophilia A is a recessive X-linked genetic disorder resulting in a deficiency of functional clotting Factor VIII. Haemophilia B is also a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. Haemophilia C is an autosomal genetic disorder involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, as heterozygous individuals also show increased bleeding.The type of haemophilia known as parahaemophilia is a mild and rare form and is due to a deficiency in factor V. This type can be inherited or acquired.A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as acquired haemophilia A. It is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors. Acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth.

Management
There is no long-term cure. Treatment and prevention of bleeding episodes is done primarily by replacing the missing blood clotting factors.

Clotting factors
Clotting factors are usually not needed in mild haemophilia. In moderate haemophilia clotting factors are typically only needed when bleeding occurs or to prevent bleeding with certain events. In severe haemophilia preventive use is often recommended two or three times a week and may continue for life. Rapid treatment of bleeding episodes decreases damage to the body.Factor VIII is used in haemophilia A and factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some people develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.If a person becomes refractory to replacement coagulation factor as a result of high levels of circulating inhibitors, this may be partially overcome with recombinant human factor VIII.In early 2008, the US Food and Drug Administration (FDA) approved an anti-haemophilic drug completely free of albumin, which made it the first anti-haemophilic drug in the US to use an entirely synthetic purification process. Since 1993 recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.Clotting factors are either given preventively or on-demand. Preventive use involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand (or episodic) treatment involves treating bleeding episodes once they arise. In 2007, a trial comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Preventative treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin. Most haemophiliacs in third world countries have limited or no access to commercial blood clotting factor products.

Other
Desmopressin (DDAVP) may be used in those with mild haemophilia A. Tranexamic acid or epsilon aminocaproic acid may be given along with clotting factors to prevent breakdown of clots.Pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint. In those with severe hemophilia A already receiving FVIII, emicizumab may provide some benefit. Different treatments are used to help those with an acquired form of hemophilia in addition to the normal clotting factors. Often the most effective treatment is corticosteroids which remove the auto-antibodies in half of people. As a secondary route of treatment, cyclophosphamide and cyclosporine are used and are proven effective for those who did not respond to the steroid treatments. In rare cases a third route or treatment is used, high doses of intravenous immunoglobulin or immunosorbent that works to help control bleeding instead of battling the auto-antibodies.

Contraindications
Anticoagulants such as heparin and warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects. For instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.

Prognosis
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who do not receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years. By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of people with haemophilia. Two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage.

Epidemiology
Haemophilia frequency is about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B. About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females. It is estimated that about 2,500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.

History
Scientific discovery
The excessive bleeding was known to ancient people. The Talmud instructs that a boy must not be circumcised if he had two brothers who died due to complications arising from their circumcisions, and Maimonides says that this excluded paternal half-brothers. This may have been due to a concern about hemophilia. The first medical professional to describe the disease was Arab surgeon Al-Zahrawi, also known as Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas. While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.In 1803, John Conrad Otto, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders". He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness by John Dalton who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth, New Hampshire, in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John F. Hay, published an account in The New England Journal of Medicine.In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to haemophilia localised in Åland, southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".
The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin. In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.

European royalty
Haemophilia has featured prominently in European royalty and thus is sometimes known as the royal disease. Queen Victoria passed the mutation for haemophilia B to her son Leopold and, through two of her daughters, Alice and Beatrice, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevich Alexei, the son and heir of Tsar Nicholas II, famously had haemophilia, which he had inherited from his mother, Empress Alexandra, one of Queen Victorias granddaughters. The haemophilia of Alexei would result in the rise to prominence of the Russian mystic Grigori Rasputin, at the imperial court.It was claimed that Rasputin was successful at treating Tsarevich Alexeis haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Tsarevich Alexei.In Spain, Queen Victorias youngest daughter, Princess Beatrice, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain </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 Ulegyria and can you explain it in depth? [/INST] Ulegyria is a diagnosis used to describe a specific type of cortical scarring in the deep regions of the sulcus that leads to distortion of the gyri. Ulegyria is identified by its characteristic "mushroom-shaped" gyri, in which scarring causes shrinkage and atrophy in the deep sulcal regions while the surface gyri are spared. This condition is most often caused by hypoxic-ischemic brain injury in the perinatal period. The effects of ulegyria can range in severity, although it is most commonly associated with cerebral palsy, mental retardation and epilepsy. N.C. Bresler was the first to view ulegyria in 1899 and described this abnormal morphology in the brain as “mushroom-gyri." Although ulegyria was first identified in 1899, there is still limited information known or reported about the condition.

Anatomy
The physical features of ulegyria consist of small radial scars which occupy the cortical sulci. Overall, the physical structure of affected areas in the brain is described as a “mushroom”-like shape in which the gyri are unusually large and the sulci become wider deeper in the cortex. N.C. Bresler, the first person to view a brain with ulegyria in 1899, coined the phrase mushroom gyri. He also named the disorder, basing it off the Latin root ule, meaning scar. This mushroom-like structure is the result of the lower parts of the ulegyria-affected area being more prone to deterioration, while the upper gyri are usually spared. However, the entire affected area shrinks and presents brown coloration as a result of ulegyria. In addition, “islands” of neurons that are relatively unaffected can exist between ulegyria affected neurons. Ulegyria can develop bilaterally or unilaterally, though the former is more commonly diagnosed.Ulegyria can affect many parts of the brain including the cerebral cortex, parasagittal areas and posterior regions of the brain, such as the parietal and occipital lobes. These areas are situated either near artery rich regions or near a major cerebral artery. For instance, specifically in neonatal children, ulegyria-affected areas are found near the posterior cerebral artery or near the artery rich region between the middle and posterior regions of the brain, often referred to as watershed regions.Neurons affected by ulegyria exhibit properties that differ from normally functioning neurons. For instance, ulegyria affected neurons experience gliosis in which glial cells, specifically astrocytes, build up near and around neurons. Ulegyria affected neurons also display decreases in their white matter content, showing signs of sclerosis, which is characterized by the deterioration of myelin in neurons. However, in regions of grey matter, large dense aggregates of myelin are present.  Ulegyria affected neurons also display metabolic disorders which could be linked to the disease phenylketonuria and disruptions in the urea cycle. Hypoglycemia and  hypoxia are also thought to accompany the symptoms of ulegyria-affected neurons as well.

Causes
Ulegyria develops as a result of a brain injury called cerebral ischemia surrounding the time of an infants birth. Oftentimes, fetal hypoxic-ischemic brain injuries occur as a result of a pregnancy complications such as placental abruption, cord accident, or cardiovascular stress due to a difficult delivery. A lack of oxygen to the brain contributes to the formation of lesions usually near the three main cerebral arteries, located near the parietal lobe and occipital lobes of the brain. The cause of perinatal brain injuries includes:

1. cerebral ischemia
2. cerebral hemorrhage
3. ascending intrauterine infections.Some risk factors for perinatal brain injuries include: low birth weight, preterm birth, poor perinatal cardiorespiratory fitness, and artificial ventilation.

Cerebral ischemia
Cerebral ischemia occurs when the brain is not receiving adequate oxygen to continue normal functions. When this occurs, the body makes restoring oxygenated blood flow to life-sustaining organs a priority. The brain alters the diameter of major blood vessels to redistribute blood to key organs such as the brain, heart, and adrenal glands. If sympathetic nervous system activation does not produce any improvement, oxygen levels will continue to fall and disruptions to metabolism, other cellular processes, and overall functioning will ensue.
Another serious result of inefficient blood flow is that cells do not receive adequate amounts of glucose. An immediate effect of low intracellular glucose is reduced ATP production in the cell. This effectively inactivates the Na-K pump, leading to the uptake of calcium ions by the cell. Continued influx of calcium serves to constitutively activate downstream effectors, including lipases, proteases, and endonucleases, whose actions eventually destroy the cell skeleton. Intracellular calcium concentrations are increased further due to the opening of glutamate-regulated ion channels. Ischemia causes anoxic cell depolarizations and it is this increase in membrane potential at the presynaptic cell that triggers the release of glutamate, an excitatory neurotransmitter.Glucose deprivation in the brain for any amount of time has the potential to pose serious consequences, and the amount of time the brain spends under these anoxic conditions is directly related to accumulation of irreversible damage to protein biosynthesis pathways. Protein synthesis all over the body is severely inhibited and essentially comes to a standstill while the brain is suffering from acute oxygen deprivation. Once oxygen sufficiently saturates the tissues again, protein biosynthesis returns to normal in non-vulnerable areas but remains at below normal levels in other areas. Insufficient protein synthesis in the brain is especially troubling in the fetal brain given the amount of growth and development that normally occurs. Areas particularly vulnerable to the damaging effects of hypoxic episodes include: the superior brainstem, the cerebellum, white matter and subcortical structures supplied by the branches of deep and superficial penetrating blood vessels. Vulnerable areas where protein synthesis is interrupted usually indicate impending cell death in neurons. When oxygen levels return, oxygen radicals, nitric oxide and an imbalance of neurotransmitters cause further damage and lead to cellular death through apoptosis. Neuron cell death is responsible for gliosis and results in the mushroom appearance of areas and is characteristic of ulegyria.

Cerebral hemorrhage
A cerebral hemorrhage is the result of immature blood vessels of a brain lesion bursting. The germinal matrix is a part of the brain that normally disappears as the fetal brain develops but during this process it is not unusual for changes in vessel volume to cause a vessel to burst. According to recent microscopic studies, the most common location for a cerebral hemorrhage is where the medullary veins drain to the terminal vein in the sub-ependymal region. It has been hypothesized that because pre-term babies dont have fully developed sympathetic nervous systems, they cannot react as well to low oxygen saturation levels caused by the cerebral hemorrhage. Although babies born at full-term are still susceptible to this, they are likely to respond better and thus, tend to have better outcomes in response to low-oxygen events.

Ascending intrauterine infections
Recent research has found a connection between intrauterine infections and inflammation in the mother and an increased likelihood of perinatal brain damage in the fetus. This study suggested that intrauterine infections in the mother could affect glial cells and toll-like receptors (TLRs) which are important in moderating the inflammatory response in the fetal brain. When glial cells and TLRs are negatively affected they are not able to react to developing inflammation in the brain as well. The connection between ascending intrauterine infections and perinatal brain damage is a developing research theory but a more detailed explanation of the connection is not yet known.

Signs and symptoms
Ulegyria was found in about 1/3 of patients with defects caused by circulatory disease in the perinatal period. Most clinical observations of the condition report mental retardation, cerebral palsy, and seizures as the main defects. However, milder cases have been reported in which patients that exhibit ulegyria develop relatively normally. The main movement disorders associated with ulegyria that are classified as cerebral palsy are choreoathetosis, dystonia, and ataxia. It is suspected that ulegyria leads to epilepsy because malformation of the cortex obstructs the differentiation of neurons, glial cells, and synapses. Parietal-occipital lobe epilepsy, which is often synonymous with posterior cortex epilepsy (PCE), is the form of the disease seen in most cases involving ulegyria. This type of epilepsy is very rare, making up about 5% of all reports of epilepsy. This form of the disease involves symptoms that would be expected from damage to the parietal and occipital lobes: seizures with visual hallucinations, visuospatial dysfunction, tingling, numbness, pain, and a burning sensation. In addition to ulegyria, tumors and cortical dysplasia constitute the major causes of PCE. Most of the epilepsy seen in conjunction with ulegyria is classified as medically refractory, meaning it is not responsive to treatment. Patients usually present symptoms of epilepsy at an early age. The severity of epilepsy has been shown to depend on this age of onset as well as the quantity of cortical lesions; earlier onset of epilepsy and a larger extent of lesions tends to mean more severe seizures.

Similar conditions
Ulegyria is often confused with a similar distortion of the cortex known as polymicrogyria. Polymicrogyria is characterized by excessive folding of the surface gyri and a thickening of the cerebral cortex, rather than the sulcal scarring that is typical of ulegyria. In addition to morphological differences, the period in which polmicrogyria and ulegyria emerge is also different. Polymicrogyria typically forms while the embryos central nervous system is maturing. Ulegyria is acquired later in development during the perinatal period after neuronal migration has already occurred. It is also suspected that polymicrogyra is genetically linked, whereas ulegyria is caused by environmental factors—namely lack of oxygen.Polymicrogyria can lead to similar conditions that are linked to ulegyria such as mental retardation, cerebral palsy, and epilepsy. It has been observed that patients with polymicrogyria are not receptive to epilepsy surgery. However, responses of patients with ulegyria to similar surgeries are still not fully known, which makes distinction of these two disorders significant. In vivo neuroimaging techniques, namely MRI, have been instrumental in making this distinction. An MRI image of ulegyria is identified by mushroom shaped gyri, deformities in white matter, and localization mainly in the posterior cerebral region. Polymicrogyria is typically recognized by a scalloped appearance at the bordering region between grey and white matter. Although these distinctions have been made with many patients, there is still some difficulty in defining distinct boundaries between these two similar conditions.

Detection
Primarily, the main method of detecting ulegyria is through the use of MRI screening for epilepsy. Normally an MRI of an ulegyria affected region will reveal groups of deteriorated neurons with gliosis present. In addition, unaffected gyri are also present in especially bilateral watershed regions indicating delayed effects of perinatal hypoxic damage. However, there are three main criteria for diagnosing ulegyria using MRI in addition to the features mentioned above:
1.The presence of a poorly demarcated lesion
2. Atrophy and thinning of the cortex resulting in the characteristic “mushroom” like shape of ulegyria.
3. Presence of white matter signal abnormalities as a result of FLAIR signaling (fluid attenuated inversion recovery).Another sign of ulegyria that is visible on an MRI scan is the presence of a widened subarachnoid space, signifying cortex atrophy. FLAIR signaling can help visualize the depths of the parietal-occipital sulci, which also allows ulegyria-affected gyri to be identified </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 Hypogonadotropic hypogonadism and can you explain it in depth? [/INST] Hypogonadotropic hypogonadism (HH),  is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis).  Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary.
The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH.
GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Types
There are two subtypes of HH, congenital HH (CHH) and acquired HH (AHH). CHH is due to genetic abnormalities resulting in non-functional GnRH secreting neurons or gonadotropic cell dysfunction in the anterior pituitary. CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (Kallman syndrome) and normosmic HH.
AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects.

Pathogenesis
CHH is a type of HH resulting from the abnormal migration of GnRH neurons during embryonic development. GnRH neurons are derived from the olfactory placode and migrate into the central nervous system (CNS) during embryonic development. Embryonic migration can be affected by several gene mutations including but not limited to, KAL1, fibroblast growth factor (FGF8), sex determining region Y-Box 10 (SOX10), GNRHR, GNRH1 and KISS1R.  Kallmann syndrome results in a loss of smell (anosmia) and is associated with KAL1 mutations. The KAL1 gene encodes anosmin-1, an extracellular adhesion molecule that plays a role in GnRH neuronal migration and adhesion.
Mutated KAL1 genes leads to ill GnRH neuronal migration as well as olfactory neuron disorder causing anosmia and non-functional GnRH releasing neurons. Mutations of KAL1 are mostly nucleotide insertion or deletion causing frame shifts in the translation of anosmin-1 resulting in a faulty protein.
Inactivating mutations in the genes encoding GNRH1 or its receptor will result in the failure of the HPG axis and give rise to normosmic CHH.
Inactivating mutations of KISS1 or KISS1R causes normosmic CHH in humans.
This is because KISS1 is the mediator for the feedback loop in the HPG axis allowing low levels of sex steroid to stimulate GnRH secretion from the hypothalamus.CHH is a genetically heterogenous disorder with cases reported as being X-linked, recessive and autosomally inherited.
The prevalence has been estimated to be 1/4000 to 1/10000 in males and 2 to 5 times less frequent in females. The prevalence difference between male and females is unknown, and is likely to be underreported for females.Acquired hypogonadotropic hypogonadism (AHH) is a postnatal onset of a GnRH releasing disorder and/or pituitary gonadotroph cell disorder.
There are many causes of AHH, mostly due to structural or functional abnormalities involving the HPG axis such as sarcoidosis, lymphocytic hypophysitis, pituitary adenomas, craniopharyngiomas and other CNS tumours. Most of these patients have multiple pituitary hormone deficiencies.  Hyperprolactinaemia is the most common cause of AHH. It is a well-established cause of infertility in both male and female mammals. Prolactin inhibits GnRH neurons and therefore inhibits the subsequent release of LH, FSH and sex steroids. The mechanism of prolactin induced inhibition of GnRH release is poorly understood.
It is suspected that the prolactin receptor is expressed on a small subset of GnRH neurons in mice and thus has a direct inhibitory effect on GnRH release. There is evidence to suggest indirect inhibition of GnRH neurons mediated by other neurotransmitters such as dopamine, opioid, neuropeptide Y and γ-aminobutyric acid.
Drug usage of glucocorticoids and opioid analgesics in high dosages can lead to the inhibition of GnRH synthesis.
Opioid receptors reside in the hypothalamus and when bound to opioids they decrease the normal pulsatile secretion of GnRH and therefore result in HH.
Chronic treatment with supraphysiological doses of glucocorticoids results in a marked decrease in testosterone without an increase of LH levels, suggestive of a central mechanism of induced HH.

Diagnosis
The clinical presentation of HH depend on the time of onset as well as the severity of the defect.
Diagnostic tests to measure GnRH levels are difficult. This is because GnRH is confined within hypophyseal portal system and has a short half-life of 2–4 minutes.
GnRH levels are thus checked indirectly via LH and FSH levels which will be totally or partially absent in HH. Exogenous GnRH can be used as a diagnostic tool. If the patient has hypothalamic GnRH deficiency, LH and FSH will gradually appear in response to the exogenous GnRH but in pituitary cases of HH, a minimal response will be generated.
Typically, CHH is diagnosed in adolescence due to a lack of pubertal development, but it can be possible to diagnose in male neonates. Clinical presentations of CHH involve an absence of puberty by 18 years of age, poorly developed secondary sexual characteristics, or infertility.In men with CHH, serum levels of inhibin B are typically very low as inhibin B is a marker of Sertoli cell number.
For females, CHH is most commonly revealed by primary amenorrhea. Breast development is variable and pubic hair may or may not be present.
CHH can be diagnosed in the male neonate with cryptorchidism (maldescended testes) and a micropenis as signs of GnRH deficiency.
There are no clear signs of CHH in female neonates.
Another clinical sign of CHH, more specifically Kallmann syndrome, is a lack of a sense of smell due to the altered migration of GnRH neurons on the olfactory placode. Kallmann syndrome can also be shown through MRI imaging with irregular morphology or aplasia of the olfactory bulb and olfactory sulci </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 Pseudopseudohypoparathyroidism and can you explain it in depth? [/INST] Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. It is more properly Albright hereditary osteodystrophy although without resistance of parathyroid hormone as frequently seen in that affliction. The term Pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of Pseudohypoparathyroidism type 1a, but has (unexpected for the phenotype) normal labs including calcium and PTH.It can be considered a variant of Albright hereditary osteodystrophy, or Pseudohypoparathyroidism type 1A, as they present with the same constellation of signs and symptoms, including short stature, brachydactyly, subcutaneous calcification, and obesity.

Presentation
Pseudopseudohypoparathyroidism can be best understood by comparing it to other conditions:

Hormone resistance is not present in Pseudopseudohypoparathyroidism. Short stature may be present. Obesity is less common in Pseudopseudohypoparathyroidism  than in Pseudohypoparathyroidism. Osteoma cutis may be present.

Genetics
A male with Pseudohypoparathyroidism has a 50% chance of passing on the defective GNAS gene to his children, although in an imprinted, inactive form. Any of his children receiving this gene will have Pseudopseudohypoparathyroidism </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 Scapular fracture and can you explain it in depth? [/INST] A scapular fracture is a fracture of the scapula, the shoulder blade.  The scapula is sturdy and located in a protected place, so it rarely breaks.   When it does, it is an indication that the individual was subjected to a considerable amount of force and that severe chest trauma may be present.  High-speed vehicle accidents are the most common cause. This could be anywhere from a car accident, motorcycle crash, or high speed bicycle crash but falls and blows to the area can also be responsible for the injury.  Signs and symptoms are similar to those of other fractures: they include pain, tenderness, and reduced motion of the affected area although symptoms can take a couple of days to appear.  Imaging techniques such as X-ray are used to diagnose scapular fracture, but the injury may not be noticed in part because it is so frequently accompanied by other, severe injuries that demand attention. The injuries that usually accompany scapular fracture generally have the greatest impact on the patients outcome.  However, the injury can also occur by itself; when it does, it does not present a significant threat to life.  Treatment involves pain control and immobilizing the affected area, and, later, physical therapy.

Signs and symptoms
As with other types of fractures, scapular fracture may be associated with pain localized to the area of the fracture, tenderness, swelling, and crepitus (the crunching sound of bone ends grinding together).  Since scapular fractures impair the motion of the shoulder, a person with a scapular fracture has a reduced ability to move the shoulder joint.  Signs and symptoms may be masked by other injuries that accompany the scapular fracture.

Causes
Usually, it takes a large amount of energy to fracture the scapula; the force may be indirect but is more often direct.  The scapula is fractured as the result of significant blunt trauma, as occurs in vehicle collisions. About three quarters of cases are caused by high-speed car and motorcycle collisions. Falls and blows to the shoulder area can also cause the injury.  Crushing injuries (as may occur in railroad or forestry accidents) and sports injuries (as may occur in horseback riding, mountain biking, bmxing or skiing) can also fracture the scapula.  Scapular fracture can result from electrical shocks and from seizures: muscles pulling in different directions contract powerfully at the same time.  In cardiopulmonary resuscitation, the chest is compressed significantly; scapular fracture may occur as a complication of this technique.

Anatomy
The scapula has a body, neck, and spine; any of these may be fractured. The most commonly injured areas are the scapular body, spine, neck, and glenoid rim; the scapular body or neck is injured in about 80% of cases. Fractures that occur in the body may be vertical, horizontal, or comminuted (involving multiple fragments).  Those that occur in the neck are usually parallel to the glenoid fossa.  When they occur in the glenoid fossa, fractures are usually small chips out of the bone or extensions of fractures occurring in the scapular neck.The scapula is protected from the front by the ribcage and chest, and from the back it is protected by a thick layer of muscles.  Also, the scapula is able to move, so traumatic forces exerted on it are dissipated, not absorbed by the bone.  Thus a large amount of force is required to fracture it.

Diagnosis
Most fractures of the scapula can be seen on a chest X-ray; however, they may be missed during examination of the film.  Serious associated injuries may distract from the scapular injury, and diagnosis is often delayed.  Computed tomography may also be used.  Scapular fractures can be detected in the standard chest and shoulder radiographs that are given to patients who have had significant physical trauma, but much of the scapula is hidden by the ribs on standard chest X-rays. Therefore, if scapular injury is suspected, more specific images of the scapular area can be taken.

Classification
Body fractures
Described based upon anatomic location

Neck fractures
Coracoid process fractures
Acromion fractures
Glenoid fossa fractures
Described by the Ideberg classification

Treatment
Treatment involves pain medication and immobilization at first; later, physical therapy is used. Ice over the affected area may increase comfort. Movement exercises are begun within at least a week of the injury; with these, fractures with little or no displacement heal without problems. Over 90% of scapular fractures are not significantly displaced; therefore, most of these fractures are best managed without surgery.  Fractures of the scapular body with displacement may heal with malunion, but even this may not interfere with movement of the affected shoulder.  However, displaced fractures in the scapular processes or in the glenoid do interfere with movement in the affected shoulder if they are not realigned properly.  Therefore, while most scapular fractures are managed without surgery, surgical reduction is required for fractures in the neck or glenoid; otherwise motion of the shoulder may be impaired.

Epidemiology
Scapular fracture is present in about 1% of cases of blunt trauma and 3–5% of shoulder injuries. An estimated 0.4–1% of bone fractures are scapular fractures.The injury is associated with other injuries 80–90% of the time.  Scapular fracture is associated with pulmonary contusion more than 50% of the time.  Thus when the scapula is fractured, other injuries such as abdominal and chest trauma are automatically suspected.  People with scapular fractures often also have injuries of the ribs, lung, and shoulder.  Pneumothorax (an accumulation of air in the space outside the lung), clavicle fractures, and injuries to the blood vessels are among the most commonly associated injuries.  The forces involved in scapular fracture can also cause tracheobronchial rupture, a tear in the airways. Fractures that occur in the scapular body are the type most likely to be accompanied by other injuries; other bony and soft tissue injuries accompany these fractures 80–95% of the time.  Associated injuries can be serious and potentially deadly, and usually it is the associated injuries, rather than the scapular fracture, that have the greatest effect on the outcome </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 Acromicric dysplasia 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 Primary cutaneous histoplasmosis 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 Pelvic floor dysfunction and can you explain it in depth? [/INST] Pelvic floor dysfunction is a term used for a variety of disorders that occur when pelvic floor muscles and ligaments are impaired. The condition affects up to 50 percent of women who have given birth. Although this condition predominantly affects women, up to 16 percent of men are affected as well. Symptoms can include pelvic pain, pressure, pain during sex, urinary incontinence (UI), overactive bladder, bowel incontinence, incomplete emptying of feces, constipation, myofascial pelvic pain and pelvic organ prolapse. When pelvic organ prolapse occurs, there may be visible organ protrusion or a lump felt in the vagina or anus.Common treatments for pelvic floor dysfunction are surgery, medication, physical therapy and lifestyle modifications.

Epidemiology
Pelvic floor dysfunction is defined as a herniation of the pelvic organs through the pelvic organ walls and pelvic floor. The condition is widespread, affecting up to 50 percent of women at some point in their lifetime. About 11 percent of women will undergo surgery for urinary incontinence or pelvic organ prolapse by age 80. Women who experience pelvic floor dysfunction are more likely to report issues with arousal combined with dyspareunia. For women, there is a 20.5% risk for having a surgical intervention related to stress urinary incontinence. The literature suggests that white women are at increased risk for stress urinary incontinence.Though pelvic floor dysfunction is thought to more commonly affect women, 16% of men have been identified with pelvic floor dysfunction. Pelvic floor dysfunction and its multiple consequences, including urinary incontinence, is a concerning health issue becoming more evident as the population of advancing age individuals rises.

Causes
Mechanistically, the causes of pelvic floor dysfunction are two-fold: widening of the pelvic floor hiatus and descent of pelvic floor below the pubococcygeal line, with specific organ prolapse, graded relative to the hiatus. People with an inherited deficiency in their collagen type may be more likely to develop pelvic floor dysfunction. Additionally, people with congenitally weak connective tissue and fascia are at an increased risk for stress urinary incontinence and pelvic organ prolapse. Recent literature demonstrates that defects in endopelvic fascia and compromised levator ani muscle function have been categorized as important etiologic factors in the development of pelvic floor dysfunction. Some circumstances are clearly associated with collagen defects. These include vaginally delivering a child, being post-menopausal, and being of advanced age.Some lifestyle behaviors can lead to pelvic floor dysfunction. This includes avoiding urinating or bowel movements, obesity, use of muscle relaxants or narcotics, and use of antihistamines or anticholinergics. Using muscle relaxants or narcotics can lead to increased smooth and skeletal muscle relaxation, potentially related to urinary incontinence. Antihistamines and anticholinergics have additive effects that lead to urinary hesitancy and retention, ultimately leading to pelvic floor dysfunction. Urinary incontinence can also affect athletes, especially those in sports that require high impact such as jumping. Gymnasts, for example, report a high prevalence of urinary incontinence. Studies show that athletes in sports requiring high spinal stability may also have this condition, as the activation of abdominal wall muscles can cause urinary alterations during activities. In some cases, sexual abuse can also be associated with chronic pelvic pain and pelvic floor dysfunction.Pelvic floor dysfunction can result after pelvic radiation, as well as other treatments for gynecological cancers.

Diagnosis
Pelvic floor dysfunction can be assessed with a strong clinical history and physical exam, though imaging is often needed for diagnosis. As part of the clinical history, a healthcare provider may ask about obstetric history, including how many pregnancies and deliveries, what mode of delivery and if there were any complications during delivery. Providers will also ask about presence and severity of symptoms such as pelvic pain or pressure, problems with urination or defecation, painful sex, or sexual dysfunction. The physical exam may include both examination with a speculum to visualize the cervix and check for inflammation, as well as manual examination with the providers fingers to assess for pain and strength of pelvic floor muscle contraction.Imaging provides a more complete picture of the type and severity of pelvic floor dysfunction than history and physical exam alone. Historically, fluoroscopy with defecography and cystography were used. More recently, MRI has been used to complement and sometimes replace fluoroscopic assessment of the disorder. This technique is less invasive, and allows for less radiation exposure and increased patient comfort, though an enema is required the evening before the procedure. Both fluoroscopy and MRI assess the pelvic floor at rest and during maximum strain using coronal and sagittal views.When grading individual organ prolapse for severity, the rectum, bladder and uterus are individually assessed. Prolapse of the rectum is referred to as a rectocele, bladder prolapse through the anterior vaginal wall is called a cystocele, and prolapse of the small bowel is an enterocele. To assess the degree of dysfunction, three measurements are taken into account. First, an anatomic landmark known as the pubococcygeal line must be determined, which is a straight line connecting the inferior margin of the pubic symphysis at the midline with the junction of the first and second coccygeal elements on a sagittal image. After this, the location of the Puborectalis muscle sling is assessed, and a perpendicular line between the pubococcygeal line and muscle sling is drawn. This line provides a reference point for the measurement of pelvic floor descent. Descent greater than 2 cm below this line is considered mild and descent greater than 6 cm is considered severe. Lastly, a line from the pubic symphysis to the puborectalis muscle sling is drawn, which is a measurement of the pelvic floor hiatus. Measurements greater than 6 cm are considered mild, and greater than 10 cm severe. The degree of organ prolapse is assessed relative to the hiatus.
The grading for organ prolapse relative to the hiatus is more strict. Any descent below the hiatus is considered abnormal, and descent greater than 4 cm is considered severe.Ultrasound can also be used to diagnose pelvic floor dysfunction. Transabdominal, transvaginal, transperineal and endoanal ultrasound (EUS) are important tools for diagnosing pelvic floor dysfunction. For EUS, an ultrasound probe is inserted into the anal canal and can be used to visualize and assess the anatomy and function the pelvic floor. Ultrasound is easily accessible and noninvasive, however it may compress certain structures, does not produce high quality images and cannot be used to visualize the entire pelvic floor.

Treatment
There are several approaches to treatment of pelvic floor dysfunction, and often several approaches are used in combination.

Physical therapy
Pelvic floor muscle (PFM) training is vital for treating different types of pelvic floor dysfunction. Two common problems are uterine prolapse and urinary incontinence both of which stem from muscle weakness. Pelvic floor muscle therapy is the first-line of treatment for urinary incontinence and thus should be considered before more invasive procedures such as surgery. Being able to control the pelvic floor muscles is vital for a well functioning pelvic floor. Without the ability to control the pelvic floor muscles, pelvic floor training cannot be done successfully. Pelvic floor muscle therapy strengthens the muscles of the pelvic floor through repeated contractions of varying strength. Through vaginal palpation exams and the use of biofeedback, the tightening, lifting, and squeezing actions of these muscles can be determined. Biofeedback can be used to treat urinary incontinence as it records contractions of the pelvic floor muscles and can help patients become aware of the use of their muscles. PFM training can also increase female sexual satisfaction by improving sexual function and the ability to orgasm.In addition, abdominal muscle training has been shown to improve pelvic floor muscle function. By increasing abdominal muscle strength and control, a person may have an easier time activating the pelvic floor muscles in sync with the abdominal muscles. Many physiotherapists are specially trained to address the muscle weaknesses associated with pelvic floor dysfunction and can effectively treat pelvic floor dysfunction through strengthening exercises. Overall, physical therapy can significantly improve the quality of life of those with pelvic floor dysfunction by relieving symptoms.

Medication
Overactive bladder can be treated with medications, including those in the class of antimuscarinics and beta 3 agonists. Antimuscarinics are the most commonly used, however, beta 3 agonists can be used for those that are unable to take antimuscarinics due to side effects or other reasons.

Devices
A pessary is a plastic or silicone device that may be used for women with pelvic organ prolapse. This treatment is useful for individuals who do not want to have surgery or are unable to have surgery due risk of the procedure. Some pessaries have a knob that can also treat urinary incontinence. To be effective, pessaries must be fit by a medical provider and the largest device that fits comfortably should be used.

Lifestyle modifications
Treatment for pelvic floor dysfunction, especially the symptom of urinary incontinence, is essential, but so is prevention </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 Myoclonic dystonia and can you explain it in depth? [/INST] Myoclonic dystonia or Myoclonus dystonia syndrome is a rare movement disorder that induces spontaneous muscle contraction causing abnormal posture.  The prevalence of myoclonus dystonia has not been reported, however, this disorder falls under the umbrella of movement disorders which affect thousands worldwide. Myoclonus dystonia results from mutations in the SGCE gene coding for an integral membrane protein found in both neurons and muscle fibers.  Those suffering from this disease exhibit symptoms of rapid, jerky movements of the upper limbs (myoclonus), as well as distortion of the bodys orientation due to simultaneous activation of agonist and antagonist muscles (dystonia).
Myoclonus dystonia is caused by loss-of-function-mutations in the epsilon sarcoglycan gene (SGCE). The disease is dominantly inherited, however SGCE is an imprinted gene, so only the paternal allele is expressed. Therefore, children suffering from this disease inherit the mutation from the father. If the mutated allele is inherited from the mother, the child is not likely to exhibit symptoms.
While no cure has been found for myoclonus dystonia, treatment options are available to those suffering from the disease. Ethanol often ameliorates the symptoms well, and so the syndrome is also called "Alcohol-responsive dystonia". Alcohol may be substituted by benzodiazepines,  such as clonazepam, which work through the same mechanism.  Deep brain stimulation (DBS) is another viable option that can alleviate symptoms without the unwanted side effects of medications, and has been successful in treating other movement disorders.

Signs and symptoms
Myoclonus dystonia is characterized by two primary features: myoclonus and dystonia. For the majority of individuals with myoclonus dystonia, the myoclonus component of the disorder is often the primary and most disabling feature in comparison to the dystonia component.  The symptoms of myoclonus dystonia vary substantially in severity.

Myoclonus
Myoclonus is characterized by rapid contractions that affect the upper body including the neck, torso and arms, but may also affect the legs. These movements are stimulated by various factors including stress, noise, caffeine, and physical stimuli. Myoclonus can be characterized in multiple ways including neurological basis, muscular activity, and by stimuli. Myoclonus can be positive or negative; positive myoclonus results from brief spurts of muscle activity and negative myoclonus occurs when there is a lack of any muscular activity. Myoclonus is usually classified physiologically to optimize treatment. Myoclonus is a precursor effect to myoclonus dystonia and most commonly begins in childhood or adolescence.Myoclonus is classified as cortical, subcortical, peripheral or spinal. Cortical myoclonus is the most common of these four and affects the upper limbs and face. Myoclonus dystonia has been characterized under subcortical origin, specifically under nonsegmented myoclonus or brainstem myoclonus. Symptoms within this classification include the startle response and reticular reflex myoclonus. Sudden stimuli like noise or touch to areas around the head or chest cause the startle response which will go up the brain stem and down the spinal cord causing jerk-like movements. Hyperekplexia is a heightened brainstem response where an affected person will continue to elicit the same response to a repeated stimuli. In contrast, reticular reflex myoclonus occurs spontaneously to stimuli applied to distal limbs. Spinal myoclonus is caused by defects in spinal organization or connections, and peripheral myoclonus has symptoms of rhythmic jerks due to a neuron-the most common being the hemifacial spasm.

Dystonia
Dystonia is a response to simultaneous contraction of agonist and antagonist muscles seen as twisting and contorting that affect posture and stance. Other symptoms can include tremors and muscle spasms due to various interactions of muscle, contractions and movement. Dystonia can be either primary or secondary with the latter being more common. Primary dystonia or "pure" dystonia is only physiological in origin. Secondary dystonia has multiple origins that are physiological, pathological or neurological.

Myoclonus dystonia
Myoclonus dystonia includes the rapid contractions of myoclonus alongside the abnormal postures classified under dystonia, as well as neurological and psychiatric issues. This disease typically begins during childhood with symptoms of myoclonus and slight dystonia, most commonly cervical dystonia or writers cramp. Dystonia symptoms tend to not get exaggerated over the course of the disease and is rarely the only associated symptom, while the myoclonus symptoms can become more severe. Psychiatric issues are clinically diagnosed with the aforementioned symptoms and include depression, anxiety, personality disorders and addiction. Obsessive-compulsive disorder is associated with myoclonus dystonia as both have been found to have a commonality on chromosome 7 in various studies.Neurological symptoms are relatively common in those with myoclonus dystonia. Any neurological abnormalities will not normally be present in those affected at a young age. Neurological testing has been performed to determine the origins of these symptoms and multiple parts of the brain have been pinpointed including the brainstem, neocortex, pallidum, and thalamus. These cause various effects in those diagnosed with myoclonus dystonia including changes in posture and tremors, and very rarely dementia and ataxia.

Cause
The majority of myoclonus dystonia cases are the result of a mutation in the epsilon sarcoglycan gene (SGCE).  This gene is found on chromosome 7, with its specific cytogenic location being 7q21.3.  The 70,985 bp SGCE gene encodes the protein epsilon (ε)-sarcoglycan.  The five proteins that make up the sarcoglycan family function as integral membrane proteins that anchor the cytoskeleton of cells to the extracellular matrix.  Epsilon sarcoglycan is a membrane protein that can be found in the liver, lungs, kidney, and spleen, but is most prevalent in muscle and neuronal cells.  Its prevalence in both muscle fibers and the synapses of neurons suggest why symptoms of both myoclonus and dystonia appear from the improperly functioning protein.  Recessive mutations in the other sarcoglycans also result in muscular disorders, further supporting that mutations in the SGCE gene cause myoclonus dystonia.Epsilon sarcoglycan itself is part of the dystrophin-associated protein (DAP) complex that binds the sarcolemma of muscle cells to the extracellular connective tissue.  The purpose is to reduce the mechanical force on the sarcolemma as a result of muscle contraction.  In addition to myoclonus dystonia, problems associated with a dysfunctional DAP complex include Duchenne muscular dystrophy.Upwards of 65 mutations of the SGCE gene are thought to cause myoclonus dystonia.  The majority of the mutations lead to a truncated protein product that results in the loss-of-function of the epsilon sarcoglycan protein.  The dysfunctional protein is ultimately recycled by the cell by degradation mediated by the proteasome, resulting in significant shortages of the integral membrane protein in both neurons and muscle fibers.
The mutant allele is inherited in a dominant fashion—that is the mutation can be inherited if one parent has that allele.  However, genomic imprinting occurs on the mothers allele, so only the fathers allele is expressed. Therefore, inheriting a mutated, paternal allele of the SGCE gene will result in the expression of the dysfunctional epsilon sarcoglycan protein.  Offspring will not produce a mutant protein product in 95% of cases where the mother passes on a mutation in the SGCE gene.While SGCE gene mutations are the central cause of myoclonus dystonia, there have been separate cases where individuals and families present symptoms akin to myoclonus dystonia but lack the mutations at this locus.  Base-pair deletions of the DYT1 gene, missense mutations in the DRD2 gene, maternal uniparental disomy, and chromosome 18 linkage have all been associated in rare cases myoclonus dystonia where the SGCE gene is unaffected.

Treatment
To date, there is no single, universal treatment that has been found to cure myoclonus dystonia. However, there are several treatment methods that have been found to be effective for helping to reduce the symptoms associated with the syndrome.

Medications
Many drugs used to treat myoclonus dystonia do not have a significant impact individually, but when combined, can work on different brain mechanisms to best alleviate symptoms. The method of treatment used depends on the severity of the symptoms presented in the individual, and whether the underlying cause of the syndrome is known.

Benzodiazepines
Benzodiazepines such as clonazepam improve tremors caused by the myoclonus aspect of this syndrome by binding allosterically to GABAA ionotropic receptors, causing an influx of chloride ions that produce an inhibitory effect that can calm myoclonic jerks.

Antiepileptics
Antiepileptics like valproate must act upon GABA receptors and manipulate ionic conductance to reduce tremors and spasms in myoclonus dystonia. GABA neurons that fire rapidly and affect the motor cortex are blocked by antiepileptics in addition to changes in sodium and calcium concentrations that can excite the neuron. Different antiepileptics vary in sufficiency to control ionic conductance and can also produce seizures or myoclonus symptoms in some patients. Another agent that has been used is zonisamide.

Anticholinergics
Anticholinergics like benzatropine alleviate dystonia symptoms by blocking the activity of acetylcholine. Acetylcholine is involved in the pathophysiology of dystonia within the basal ganglia, although its exact role has not been determined. Acetylcholine is involved with dopamine and glutamate pathways in the basal ganglia, in addition to presynaptic muscarinic receptors which are involved in motor control. Acetylcholine is usually overactive in dystonia patients and blocking of this neurotransmitter would reduce contortion of the upper body, but can produce side effects of drowsiness, confusion and memory issues in adults.

Botulinum toxin
Botulinum toxin injections also act upon acetylcholine to reduce dystonia symptoms. The neurotoxin is active in presynaptic terminals and blocks exocytosis of acetylcholine into the synaptic cleft which reduces muscle activity. Botulinum may also have a role in inhibiting glutamate and changing muscle movement. Studies have also shown possible axon transport of this neurotoxin as well as its function as a pain reliever without effect on overactive muscle movement in myoclonus dystonia patients.

Alcohol
Consumption of alcohol has also been found to be an effective agent for temporarily easing the severity of the tremors associated with myoclonus dystonia. Alcohol causes an increase in GABA transmission between interneurons and Purkinje cells. This then reduces the transmission of glutamate at granule cell-Purkinje cell synapses, which decreases muscle movements. This treatment only alleviates the strength of the tremors for a short duration and does not change how often tremors will occur. Doctors inform patients of risks associated with the use of alcohol for myoclonus dystonia due to the high susceptibility for excessive alcohol use and dependency. Alcohol use disorder itself causes tremors in the hands and degeneration of the Purkinje cells and other parts of the cerebral cortex, counteracting alcohols original corrective effects.

Deep brain stimulation
Deep brain stimulation (DBS) has been found to be an effective and safe treatment for myoclonus dystonia patients, whose severe and debilitating symptoms are resistant to drug treatments. Electrical stimulation within the brain is a common treatment for many movement disorders because of the ability to excite or inhibit neurons within the brain. Deep brain stimulation patients have electrodes inserted into the brain and then an electrical signal is sent from an external source to elicit a response. The frequency and intensity of this signal can be changed to monitor the effects on neuronal activity using voltage recordings or neuroimaging, like functional MRIs. By re-positioning the electrodes in different areas or changing the size or timing of the stimulus, varying effects can be seen on the patient depending on the origin of the disorder.In one study, five patients with genetically determined epsilon sarcoglycan protein deficiency  underwent deep brain stimulation of the internal pallidum </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 Kasabach–Merritt syndrome and can you explain it in depth? [/INST] Kasabach–Merritt syndrome, also known as hemangioma with thrombocytopenia, is a rare disease, usually of infants, in which a vascular tumor leads to decreased platelet counts and sometimes other bleeding problems, which can be life-threatening.  It is also known as hemangioma thrombocytopenia syndrome. It is named after Haig Haigouni Kasabach and Katharine Krom Merritt, the two pediatricians who first described the condition in 1940.

Signs and symptoms
Initially a vascular lesion is usually noted on the skin which can be firm and hard (indurated). Areas of tiny red dots (petechiae) can appear around the lesion or on other parts of the body. If the vascular lesion is internal, these petechiae and bruising can be seen on the skin. Bruising and spontaneous bleeding can also occur. The tumors are not hemangiomas. They usually present in young infants, less than three months of age, but have also been reported in the toddler age group. These tumors occur in the extremities, chest, neck, abdomen and pelvis. They infiltrate across tissue and can be aggravated by interventions, infection and trauma. When the tumors associated with KMP are internal such as in the chest or abdomen, they can cause significant illness and can be life-threatening due to bleeding. Internal lesions can take a longer time to diagnose.

Pathophysiology
Kasabach–Merritt syndrome is usually caused by a hemangioendothelioma or other vascular tumor, often present at birth. Although these tumors are relatively common, they only rarely cause Kasabach–Merritt syndrome.When these tumors are large or are growing rapidly, sometimes they can trap platelets, causing severe thrombocytopenia.  The combination of vascular tumor and consumptive thrombocytopenia defines Kasabach–Merritt syndrome.  Tumors can be found in the trunk, upper and lower extremities, retroperitoneum, and in the cervical and facial areas.This consumptive coagulopathy also uses up clotting factors, such as fibrinogen which may worsen bleeding.  The coagulopathy can progress to disseminated intravascular coagulation and even death. Hemolytic anemia secondary to microangiopathic destruction (physical damage) of the RBCs can be expressed as mild, moderate, or severe.

Diagnosis
The diagnostic workup is directed by the presenting signs and symptoms, and can involve:

blood counts, clotting studies, and other laboratory testing
imaging tests (ultrasound, CT scan, MRI, sometimes angiography, and rarely nuclear medicine scans)
Biopsy of the tumor is contraindicated due to risk of bleeding.Patients uniformly show severe thrombocytopenia, low fibrinogen levels, high fibrin degradation products (due to fibrinolysis), and microangiopathic hemolysis.

Management
Management of Kasabach–Merritt syndrome, particularly in severe cases, can be complex and require the joint effort of multiple subspecialists </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 Dysostosis and can you explain it in depth? [/INST]  </s>