<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 Friedreichs ataxia and can you explain it in depth? [/INST] Friedreichs ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens.   As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.
The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some myelin sheath.
No effective treatment is known, but several therapies are in trials. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older.
FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician Nikolaus Friedreich, who first described it in the 1860s.

Symptoms
Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years.  The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.

Classical symptoms
There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop neurological symptoms, including dysarthria and loss of lower limb reflexes, and more than 90% present with ataxia. Cardiac issues are very common with early onset FRDA . Most individuals develop heart problems such as enlargement of the heart, symmetrical hypertrophy, heart murmurs, atrial fibrillation, tachycardia, hypertrophic cardiomyopathy, and conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young.

Other symptoms
People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness.  Hearing loss is present in about 10.9% of cases.  Some patients report bladder and bowel symptoms. Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation.Other later stage symptoms can include, cerebellar effects such as nystagmus, fast saccadic eye movements, dysmetria and loss of coordination (truncal ataxia, and stomping gait). Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation.The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair.  Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s.
The disease is progressive, with increasing staggering or stumbling gait and frequent falling.  By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility.

Early-onset cases
Non-neurological symptoms such as scoliosis, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.

Genetics
FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin.In 96% of cases, the mutant FXN gene has 90–1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles. This expansion causes epigenetic changes and formation of heterochromatin near the repeat. The length of the shorter GAA repeat is correlated with the age of onset and disease severity. The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms.In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. A missense point mutation can have milder symptoms. Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.

Pathophysiology
FRDA affects the nervous system, heart, pancreas, and other systems.Degeneration of nerve tissue in the spinal cord causes ataxia. The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected. The disease primarily affects the spinal cord and peripheral nerves.
The spinal cord becomes thinner and nerve cells lose some myelin sheath. The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia. The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons. In peripheral nerves, a loss of large myelinated sensory fibers occurs.Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum. The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.

Frataxin
The exact role of frataxin remains unclear. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes. One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage. Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase and iron dysmetabolism of the entire cell.

Diagnosis
Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination. Diagnostic tests are made to confirm a physical examination such as electromyogram, nerve conduction studies, electrocardiogram, echocardiogram, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis.  MRI and CT scans of brain and spinal cord are done to rule out other neurological conditions. Finally, a genetic test is conducted to confirm.Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2,  and other early-onset ataxias.

Management
Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection.

Rehabilitation
Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains.  Low intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities.  Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. Other physical therapy goals include increased transfer and locomotion independence, muscle strengthening, increased physical resilience, "safe fall" strategy, learning to use mobility aids, learning how to reduce the bodys energy expenditure, and developing specific breathing patterns.  Speech therapy can improve voice quality.

Devices
Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity, and prevent foot deformities and scoliosis.Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair.

Medication and surgery
Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility to alleviate equinus deformity. An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure.

Prognosis
The disease evolves differently in different people. In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms.Congestive heart failure and abnormal heart rhythms are the leading causes of death, but people with fewer symptoms can live into their 60s or older.

Epidemiology
FRDA affects Indo-European populations. It is rare in East Asians, sub-Saharan Africans, and Native Americans.  FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent. Males and females are affected equally. The estimated carrier prevalence is 1:100.  A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000.   The prevalence rate of FRDA in Japan is 1:1,000,000.FRDA follows the same pattern as haplogroup R1b. Haplogroup R1b is the most frequently occurring paternal lineage in Western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland, and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age.

History
The condition is named after the 1860s German pathologist and neurologist, Nikolaus Friedreich. Friedreich reported the disease in 1863 at the University of Heidelberg. Further observations appeared in a paper in 1876.Frantz Fanon wrote his medical thesis on FRDA, in 1951.A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.

Research
Active research is ongoing to find a treatment. Patients can enroll in a registry to make clinical trial recruiting easier </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 Choline and can you explain it in depth? [/INST] Choline  is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). To maintain health, it must be obtained from the diet as choline or as choline phospholipids, like phosphatidylcholine. Humans, as well as most other animal species, do make choline de novo; however, production is generally insufficient. Choline is often not classified as a vitamin, but as a nutrient with an amino acid–like metabolism. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell organelles, and in very low-density lipoproteins. Choline is required to produce acetylcholine – a neurotransmitter – and S-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into homocysteine.
Symptomatic choline deficiency – rare in humans – causes nonalcoholic fatty liver disease and muscle damage. Excessive consumption of choline (greater than 7.5 g/day) can cause low blood pressure, sweating, diarrhea and fish-like body odor due to trimethylamine, which forms in its metabolism. Rich dietary sources of choline and choline phospholipids include organ meats and egg yolks, dairy products, peanuts, certain beans, nuts, seeds and vegetables with pasta and rice also contributing to choline intake in the American diet.

Chemistry
The cholines are a family of water-soluble quaternary ammonium compounds. Choline is the parent compound of the cholines class, consisting of ethanolamine having three methyl substituents attached to the amino function. Choline hydroxide is known as choline base. It is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.Choline chloride can be made by treating TMA with 2-chloroethanol:
(CH3)3N + ClCH2CH2OH → (CH3)3N+CH2CH2OH · Cl–The 2-chloroethanol can be generated from ethylene oxide. Choline has historically been produced from natural sources, such as via hydrolysis of lecithin.

Metabolism
Biosynthesis
In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine, which is catalyzed by a serine decarboxylase. The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive N-methylation steps catalyzed by a methyl transferase are carried out on either the free-base, phospho-bases, or phosphatidyl-bases. The source of the methyl group is S-adenosyl-L-methionine and S-adenosyl-L-homocysteine is generated as a side product.

In humans and most other animals, de novo synthesis of choline is via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, but biosynthesis is not enough to meet human requirements. In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 acyl groups from acyl-CoA forming a phosphatidic acid. It reacts with cytidine triphosphate to form cytidine diphosphate-diacylglycerol. Its hydroxyl group reacts with serine to form phosphatidylserine which decarboxylates to ethanolamine and phosphatidylethanolamine (PE) forms. A PEMT enzyme moves three methyl groups from three S-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three S-adenosylhomocysteines (SAHs) are formed as a byproduct.Choline can also be released from more complex choline containing molecules. For example, phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, cytosolic choline kinases (CK) phosphorylate choline with ATP to phosphocholine (PChol). This happens in some cell types like liver and kidney. Choline-phosphate cytidylyltransferases (CPCT) transform PChol to CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).In humans, certain PEMT-enzyme mutations and estrogen deficiency (often due to menopause) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route. In knockout mice, PEMT inactivation makes them completely dependent on dietary choline.

Absorption
In humans, choline is absorbed from the intestines via the SLC44A1 (CTL1) membrane protein via facilitated diffusion governed by the choline concentration gradient and the electrical potential across the enterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the portal vein, passes the liver and enters systemic circulation. Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide.Phosphocholine and glycerophosphocholines are hydrolyzed via phospholipases to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and sphingomyelins) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons.

Transport
In humans, choline is transported as a free molecule in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoproteins. Blood plasma choline levels in healthy fasting adults is 7–20 micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly.Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes. Three types of choline transporters are known:
SLC5A7
CTLs: CTL1 (SLC44A1), CTL2 (SLC44A2) and CTL4 (SLC44A4)
OCTs: OCT1 (SLC22A1) and OCT2 (SLC22A2)SLC5A7s are sodium- (Na+) and ATP-dependent transporters. They have high binding affinity for choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production. Their deficient function causes hereditary weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In knockout mice, their dysfunction results easily in death with cyanosis and paralysis.CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta and mitochondria. CTL1s supply choline for phosphatidylcholine and trimethylglycine production. CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles and heart. They are associated with the mitochondrial oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with the acetylcholine production, but transport choline together via the blood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of astrocytes and neurons.OCT1s and OCT2s are not associated with the acetylcholine production. They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain.

Storage
Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.

Excretion
Even at choline doses of 2–8 g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine (tetrahydrofolate receives one of the methyl groups). Methylglycine forms, is excreted into urine, or is demethylated to glycine.

Function
Choline and its derivatives have many functions in humans and in other organisms. The most notable function is that choline serves as a synthetic precursor for other essential cell components and signalling molecules, such as phospholipids that form cell membranes, the neurotransmitter acetylcholine, and the osmoregulator trimethylglycine (betaine). Trimethylglycine in turn serves as a source of methyl groups by participating in the biosynthesis of S-adenosylmethionine.

Phospholipid precursor
Choline is transformed to different phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell organelles. Phosphatidylcholines are structurally important part of the cell membranes. In humans 40–50% of their phospholipids are phosphatidylcholines.Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol. The rafts are centers, for example for receptors and receptor signal transduction enzymes.Phosphatidylcholines are needed for the synthesis of VLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans.Choline is also needed for the synthesis of pulmonary surfactant, which is a mixture consisting mostly of phosphatidylcholines. The surfactant is responsible for lung elasticity, that is for lung tissues ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome.Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with the intestinal absorption of lipids.

Acetylcholine synthesis
Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in muscle contraction, memory and neural development, for example. Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine.

Source of trimethylglycine
In humans, choline is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases. This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine. Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the BHMT-enzyme, which methylates homocysteine to methionine. This is a S-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological methylation reactions. For example, it methylates guanidines of DNA and certain lysines of histones. Thus it is part of gene expression and epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.

Content in foods
Choline occurs in foods as a free molecule and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest in organ meats and egg yolks though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit and dairy products. Cooking oils and other food fats have about 5 mg/100 g of total choline. In the United States, food labels express the amount of choline in a serving as a percentage of daily value (%DV) based on the adequate intake of 550 mg/day. 100% of the daily value means that a serving of food has 550 mg of choline. "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.Human breast milk is rich in choline. Exclusive breastfeeding corresponds to about 120 mg of choline per day for the baby. Increase in a mothers choline intake raises the choline content of breast milk and low intake decreases it. Infant formulas may or may not contain enough choline. In the EU and the US, it is mandatory to add at least 7 mg of choline per 100 kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed.Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only partially. High amounts of trimethylglycine occur in wheat bran (1,339 mg/100 g), toasted wheat germ (1,240 mg/100 g) and spinach (600–645 mg/100 g), for example.

Daily values
The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels. It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.
DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older. The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.
The U.S. Department of Agricultures (USDAs) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.

Dietary recommendations
Recommendations are in milligrams per day (mg/day). The European Food Safety Authority (EFSA) recommendations are general recommendations for the EU countries. The EFSA has not set any upper limits for intake. Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States, Australia and New Zealand.

Intake in populations
Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women.A study based on the NHANES 2009–2012 survey estimated the choline intake to be too low in some US subpopulations. Intake was 315.2–318.8 mg/d in 2+ year olds between this time period. Out of 2+ year olds, only 15.6±0.8% of males and 6.1±0.6% of females exceeded the adequate intake (AI). AI was exceeded by 62.9±3.1% of 2- to 3-year-olds, 45.4±1.6% of 4- to 8-year-olds, 9.0±1.0% of 9- to 13-year-olds, 1.8±0.4% of 14–18 and 6.6±0.5% of 19+ year olds. Upper intake level was not exceeded in any subpopulations.A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be 256±3.8 mg/day and 339±3.9 mg/day in adults 20 and over. Intake was 402±6.1 mg/d in men 20 and over and 278 mg/d in women 20 and over.

Deficiency
Signs and symptoms
Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and are able to biosynthesize limited amounts of it. Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and non-alcoholic fatty liver disease, which may develop into cirrhosis.Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This is suspected to be due to deficiency of choline derived trimethylglycine, which functions as an osmoregulator.

Causes and mechanisms
Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have lower dietary need for choline than men due to womens higher estrogen production. Without estrogen therapy, the choline needs of post-menopausal women are similar to mens. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of the liver decreases leading to fat accumulation in the liver. Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their inavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient, which, among other things, is needed for degrading fatty acids via β-oxidation. Fat metabolism within liver therefore decreases.

Excess intake
Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause low blood pressure, nausea, diarrhea and fish-like body odor. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria).The liver oxidizes TMA to trimethylamine N-oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk of atherosclerosis and mortality. Thus, excessive choline intake has been hypothetized to increase these risks in addition to carnitine, which also is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying from cardiovascular diseases. It is plausible that elevated TMA and TMAO levels are just a symptom of other underlying illnesses or genetic factors that predispose individuals for increased mortality. Such factors may have not been properly accounted for in certain studies observing TMA and TMAO level related mortality. Causality may be reverse or confounding and large choline intake might not increase mortality in humans. For example, kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion.

Health effects
Neural tube closure
Some human studies showed low maternal intake of choline to significantly increase the risk of neural tube defects (NTDs) in newborns. Folate deficiency also causes NTDs. Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to form SAM (S-adenosylmethionine). SAM is the substrate for almost all methylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for the relation between folate and NTDs. This may also apply to choline. Certain mutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015.

Cardiovascular diseases and cancer
Choline deficiency can cause fatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which partakes in DNA methylation – this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases has been studied. However, observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers. Studies on prostate cancer have been contradictory.

Cognition
Studies observing the effect between higher choline intake and cognition have been conducted in human adults, with contradictory results. Similar studies on human infants and children have been contradictory and also limited.

Perinatal development
Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity, the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations in amniotic fluid can be ten times higher than in maternal blood.

Functions in the fetus
Choline is in high demand during pregnancy as a substrate for building cellular membranes (rapid fetal and mother tissue expansion), increased need for one-carbon moieties (a substrate for methylation of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions). In particular, there is interest in the impact of choline consumption on the brain. This stems from cholines use as a material for making cellular membranes (particularly in making phosphatidylcholine). Human brain growth is most rapid during the third trimester of pregnancy and continues to be rapid to approximately five years of age. During this time, the demand is high for sphingomyelin, which is made from phosphatidylcholine (and thus from choline), because this material is used to myelinate (insulate) nerve fibers. Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions, neurogenesis, myelination, and synapse formation. Acetylcholine is even present in the placenta and may help control cell proliferation and differentiation (increases in cell number and changes of multiuse cells into dedicated cellular functions) and parturition.Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier. Transport occurs when arterial plasma choline concentrations increase above 14 μmol/L, which can occur during a spike in choline concentration after consuming choline-rich foods. Neurons, conversely, acquire choline by both high- and low-affinity transporters. Choline is stored as membrane-bound phosphatidylcholine, which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards, acetylcholinesterase degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again.

Uses
Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopicity. Certain choline salts are used to supplement chicken, turkey and some other animal feeds. Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist. Choline theophyllinate and choline salicylate are used as medicines, as well as structural analogs, like methacholine and carbachol. Radiolabeled cholines, like 11C-choline, are used in medical imaging. Other commercially used salts include tricholine citrate and choline bicarbonate.

Antagonists and inhibitors
Hundreds of choline antagonists and enzyme inhibitors have been developed for research purposes. Aminomethylpropanol is among the first ones used as a research tool. It inhibits choline and trimethylglycine synthesis. It is able to induce choline deficiency that in turn results in fatty liver in rodents. Diethanolamine is another such compound, but also an environmental pollutant. N-cyclohexylcholine inhibits choline uptake primarily in brains. Hemicholinium-3 is a more general inhibitor, but also moderately inhibits choline kinases. More specific choline kinase inhibitors have also been developed. Trimethylglycine synthesis inhibitors also exist: carboxybutylhomocysteine is an example of a specific BHMT inhibitor.The cholinergic hypothesis of dementia has not only lead to medicinal acetylcholinesterase inhibitors, but also to a variety of acetylcholine inhibitors. Examples of such inhibiting research chemicals include triethylcholine, homocholine and many other N-ethyl derivates of choline, which are false neurotransmitter analogs of acetylcholine. Choline acetyltransferase inhibitors have also been developed.

History
Discovery
In 1849, Adolph Strecker was the first to isolate choline from pig bile </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 Subacromial bursitis and can you explain it in depth? [/INST] Subacromial bursitis is a condition caused by inflammation of the bursa that separates the superior surface of the supraspinatus tendon (one of the four tendons of the rotator cuff) from the overlying coraco-acromial ligament, acromion, and coracoid (the acromial arch) and from the deep surface of the deltoid muscle. The subacromial bursa helps the motion of the supraspinatus tendon of the rotator cuff in activities such as overhead work.
Musculoskeletal complaints are one of the most common reasons for primary care office visits, and rotator cuff disorders are the most common source of shoulder pain.Primary inflammation of the subacromial bursa is relatively rare and may arise from autoimmune inflammatory conditions such as rheumatoid arthritis, crystal deposition disorders such as gout or pseudogout, calcific loose bodies, and infection. More commonly, subacromial bursitis arises as a result of complex factors, thought to cause shoulder impingement symptoms. These factors are broadly classified as intrinsic (intratendinous) or extrinsic (extratendinous). They are further divided into primary or secondary causes of impingement. Secondary causes are thought to be part of another process such as shoulder instability or nerve injury.In 1983 Neer described three stages of impingement syndrome. He noted that "the symptoms and physical signs in all three stages of impingement are almost identical, including the impingement sign..., arc of pain, crepitus, and varying weakness". The Neer classification did not distinguish between partial-thickness and full-thickness rotator cuff tears in stage III. This has led to some controversy about the ability of physical examination tests to accurately diagnose between bursitis, impingement, impingement with or without rotator cuff tear and impingement with partial versus complete tears.
In 2005, Park et al. published their findings which concluded that a combination of clinical tests were more useful than a single physical examination test. For the diagnosis of impingement disease, the best combination of tests were "any degree (of) a positive Hawkins–Kennedy test, a positive painful arc sign, and weakness in external rotation with the arm at the side", to diagnose a full thickness rotator cuff tear, the best combination of tests, when all three are positive, were the painful arc, the drop-arm sign, and weakness in external rotation.

Signs and symptoms
Subacromial bursitis often presents with a constellation of symptoms called impingement syndrome. Pain along the front and side of the shoulder is the most common symptom and may cause weakness and stiffness. If the pain resolves and weakness persists other causes should be evaluated such as a tear of the rotator cuff or a neurological problem arising from the neck or entrapment of the suprascapular nerve. The onset of pain may be sudden or gradual and may or may not be related to trauma. Night time pain, especially sleeping on the affected shoulder, is often reported. Localized redness or swelling are less common and suggest an infected subacromial bursa. Individuals affected by subacromial bursitis commonly present with concomitant shoulder problems such as arthritis, rotator cuff tendinitis, rotator cuff tears, and cervical radiculopathy (pinched nerve in neck).Impingement may be brought on by sports activities, such as overhead throwing sports and swimming, or overhead work such as painting, carpentry, or plumbing. Activities that involve repetitive overhead activity, or directly in front, may cause shoulder pain. Direct upward pressure on the shoulder, such as leaning on an elbow, may increase pain.

Pathophysiology
The literature on the pathophysiology of bursitis describes inflammation as the primary cause of symptoms. Inflammatory bursitis is usually the result of repetitive injury to the bursa. In the subacromial bursa, this generally occurs due to microtrauma to adjacent structures, particularly the supraspinatus tendon. The inflammatory process causes synovial cells to multiply, increasing collagen formation and fluid production within the bursa and reduction in the outside layer of lubrication.Less frequently observed causes of subacromial bursitis include hemorrhagic conditions, crystal deposition and infection.Many causes have been proposed in the medical literature for subacromial impingement syndrome. The bursa facilitates the motion of the rotator cuff beneath the arch, any disturbance of the relationship of the subacromial structures can lead to impingement. These factors can be broadly classified as intrinsic such as tendon degeneration, rotator cuff muscle weakness and overuse. Extrinsic factors include bone spurs from the acromion or AC joint, shoulder instability and neurologic problems arising outside of the shoulder.

Diagnosis
It is often difficult to distinguish between pain caused by bursitis or that caused by a rotator cuff injury as both exhibit similar pain patterns in the front or side of the shoulder. Subacromial bursitis can be painful with resisted abduction due to the pinching of the bursa as the deltoid contracts. If the therapist performs a treatment direction test and gently applies joint traction or a caudal glide during abduction (MWM), the painful arc may reduce if the problem is bursitis or adhesive capsulitis (as this potentially increases the subacromial space).The following clinical tests, if positive, may indicate bursitis:

The patient actively abducts the arm and a painful arc occurs between 60° and 120°. This is due to the compression of the supraspinatus tendon or subacromial bursa between the anterior acromial arch and humeral head. When lowering from full abduction there is often a painful "catch" at midrange. If the patient can achieve adequate muscle relaxation, passive motion tends to be less painful.
The patient performs an isometric flexion contraction against resistance of the therapist (Speed’s Test). When the therapist’s resistance is removed, a sudden jerking motion results and latent pain indicates a positive test for bursitis.
Neer’s Sign: If pain occurs during forward elevation of the internally rotated arm above 90°. This will identify impingement of the rotator cuff but is also sensitive for subacromial bursitis.Irritation or entrapment of the lower subscapular nerve, which innervates the subscapularis and teres major muscles, will produce muscle guarding at the shoulder that will restrict motion into external rotation, abduction, or flexion. The aforementioned tests will assist in diagnosing bursitis over other conditions. The diagnosis of impingement syndrome should be viewed with caution  in people who are less than forty years old, because such individuals may have subtle glenohumeral instability.

Imaging
X-rays may help visualize bone spurs, acromial anatomy and arthritis. Further, calcification in the subacromial space and rotator cuff may be revealed. Osteoarthritis of the acromioclavicular (AC) joint may co-exist and is usually demonstrated on radiographs.MRI imagining can reveal fluid accumulation in the bursa and assess adjacent structures. In chronic cases caused by impingement tendinosis and tears in the rotator cuff may be revealed. At US, an abnormal bursa may show

fluid distension,
synovial proliferation, and/or
thickening of the bursal walls.In any case, the magnitude of pathological findings does not correlate with the magnitude of the symptoms.

Special considerations
In patients with bursitis who have rheumatoid arthritis, short term improvements are not taken as a sign of resolution and may require long term treatment to ensure recurrence is minimized. Joint contracture of the shoulder has also been found to be at a higher incidence in type two diabetics, which may lead to frozen shoulder (Donatelli, 2004).

Treatment
Many non-operative treatments have been advocated, including rest; oral administration of non-steroidal anti-inflammatory drugs; physical therapy; chiropractic; and local modalities such as cryotherapy, ultrasound, electromagnetic radiation, and subacromial injection of corticosteroids.Shoulder bursitis rarely requires surgical intervention and generally responds favorably to conservative treatment. Surgery is reserved for patients who fail to respond to non-operative measures. Minimally invasive surgical procedures such as arthroscopic removal of the bursa allows for direct inspection of the shoulder structures and provides the opportunity for removal of bone spurs and repair of any rotator cuff tears that may be found.

Early / initial
Middle / intermittent
Late / return to function
Prognosis
In 1997 Morrison et al. published a study that reviewed the cases of 616 patients (636 shoulders) with impingement syndrome (painful arc of motion) to assess the outcome of non-surgical care. An attempt was made to exclude patients who were suspected of having additional shoulder conditions such as, full-thickness tears of the rotator cuff, degenerative arthritis of the acromioclavicular joint, instability of the glenohumeral joint, or adhesive capsulitis. All patients were managed with anti-inflammatory medication and a specific, supervised physical-therapy regimen. The patients were followed up from six months to over six years. They found that 67% (413 patients) of the patients improved, while 28% did not improve and went to surgical treatment. 5% did not improve and declined further treatment.Of the 413 patients who improved, 74 had a recurrence of symptoms during the observation period and their symptoms responded to rest or after resumption of the exercise program.The Morrison study shows that the outcome of impingement symptoms varies with patient characteristics. Younger patients (20 years or less) and patients between 41 and 60 years of age, fared better than those who were in the 21 to 40 years age group. This may be related to the peak incidence of work, job requirements, sports and hobby related activities, that may place greater demands on the shoulder. However, patients who were older than sixty years of age had the "poorest results". It is known that the rotator cuff and adjacent structures undergo degenerative changes with ageing.The authors were unable to posit an explanation for the observation of the bimodal distribution of satisfactory results with regard to age. They concluded that it was "unclear why (those) who were twenty-one to forty years old had less satisfactory results". The poorer outcome for patients over 60 years old was thought to be potentially related to "undiagnosed full-thickness tears of the rotator cuff".

References
Anderson, D., M, (2000), Dorland’s Illustrated Medical Dictionary, 29th ed, W.B. Saunders Company, Canada, 965-967.
Buschbacher, R., M, Braddom, R., L. (1994). Sports medicine & rehabilitation: A sport-specific approach. Hanley and Belfus Inc, Philadelphia.
Hartley, A. (1990). Practical joint assessment: A sports medicine manual, St Louis, Sydney.

Further reading
Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on bursae around the shoulder joint.
Wilk, Kevin E.; Andrews, James R. (1994). The Athletes shoulder. Edinburgh: Churchill Livingstone. ISBN 978-0-443-08847-6.
Blaine TA, Kim YS, Voloshin I,  et al. (2005). "The molecular pathophysiology of subacromial bursitis in rotator cuff disease". J Shoulder Elbow Surg. 14 (1 Suppl S): 84S–89S. doi:10.1016/j.jse.2004.09.022. PMID 15726092.
Brox JI, Gjengedal E, Uppheim G,  et al. (1999). "Arthroscopic surgery versus supervised exercises in patients with rotator cuff disease (stage II impingement syndrome): a prospective, randomized, controlled study in 125 patients with a 2 1/2-year follow-up". J Shoulder Elbow Surg. 8 (2): 102–11. doi:10.1016/S1058-2746(99)90001-0. PMID 10226960.
Butcher JD, Salzman KL, Lillegard WA (1996). "Lower extremity bursitis". Am Fam Physician. 53 (7): 2317–24. PMID 8638508.
Donatelli, Robert (2004). Physical therapy of the shoulder. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06614-6.
Handa A, Gotoh M, Hamada K,  et al. (2003). "Vascular endothelial growth factor 121 and 165 in the subacromial bursa are involved in shoulder joint contracture in type II diabetics with rotator cuff disease". J. Orthop. Res. 21 (6): 1138–44. doi:10.1016/S0736-0266(03)00102-5. PMID 14554230. S2CID 29665718.
Hartley, Anne (1990). Practical joint assessment: a sports medicine manual. St. Louis, MO: Mosby Year Book. ISBN 978-0-8016-2050-8.
Sports Medicine and Rehabilitation: A Sport-Specific Approach. Hagerstown, MD: Lippincott Williams & Wilkins. 1994. ISBN 978-1-56053-133-3.
Lo IK, Boorman R, Marchuk L, Hollinshead R, Hart DA, Frank CB (2005). "Matrix molecule mRNA levels in the bursa and rotator cuff of patients with full-thickness rotator cuff tears". Arthroscopy. 21 (6): 645–51. doi:10.1016/j.arthro.2005.03.008. PMID 15944617.
Ishii H, Brunet JA, Welsh RP, Uhthoff HK (1997). ""Bursal reactions" in rotator cuff tearing, the impingement syndrome, and calcifying tendinitis". J Shoulder Elbow Surg. 6 (2): 131–6. doi:10.1016/S1058-2746(97)90033-1. PMID 9144600.
McAfee JH, Smith DL (1988). "Olecranon and prepatellar bursitis. Diagnosis and treatment". West. J. Med. 149 (5): 607–10. PMC 1026560. PMID 3074561.
Perry J (1983). "Anatomy and biomechanics of the shoulder in throwing, swimming, gymnastics, and tennis". Clin Sports Med. 2 (2): 247–70. doi:10.1016/S0278-5919(20)31406-X. PMID 9697636.
Reilly JP, Nicholas JA (1987). "The chronically inflamed bursa". Clin Sports Med. 6 (2): 345–70. doi:10.1016/S0278-5919(20)31035-8. PMID 3319205.Trojian T, Stevenson JH, Agrawal N (2005). "What can we expect from nonoperative treatment options for shoulder pain?". J Fam Pract. 54 (3): 216–23. PMID 15755374.
Shamus, Jennifer; Shamus, Eric (2001). Sports injury: prevention & rehabilitation. New York: McGraw-Hill Medical Pub. Div. ISBN 978-0-07-135475-2.
Starr M, Harbhajan K (June 2001). "Recognition and Management of Common Forms of Tendinitis and Bursitis" (PDF). The Canadian Journal of Continuing Medical Education: 155–63. ISSN 0843-994X.
Trojian T, Stevenson JH, Agrawal N (2005). "What can we expect from nonoperative treatment options for shoulder pain?". J Fam Pract. 54 (3): 216–23. PMID 15755374.
van Holsbeeck M, Strouse PJ (1993). "Sonography of the shoulder: evaluation of the subacromial-subdeltoid bursa". AJR Am J Roentgenol. 160 (3): 561–4. doi:10.2214/ajr.160.3.8430553 </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 Microlissencephaly and can you explain it in depth? [/INST] Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly (small head) with lissencephaly (smooth brain surface due to absent sulci and gyri). Microlissencephaly is a heterogeneous disorder, i.e. it has many different causes and a variable clinical course. Microlissencephaly is a malformation of cortical development (MCD) that occurs due to failure of neuronal migration between the third and fifth month of gestation as well as stem cell population abnormalities. Numerous genes have been found to be associated with microlissencephaly, however, the pathophysiology is still not completely understood.
The combination of lissencephaly with severe congenital microcephaly is designated as microlissencephaly only when the cortex is abnormally thick. If such combination exists with a normal cortical thickness (2.5 to 3 mm), it is known as "microcephaly with simplified gyral pattern" (MSGP). Both MLIS and MSGP have a much more severe clinical course than microcephaly alone. They are inherited in autosomal recessive manner. Prior to 2000, the term "microlissencephaly" was used to designate both MLIS and MSGP.

Types
Microlissencephaly is one of five subtypes of lissencephaly. Microlissencephaly, in turn, can be subclassified based on imaging and clinical picture into 4 types:

MLIS1
Microlissencephaly Type A or Norman-Roberts syndrome (NRS): a microlissencephaly with thick cortex without infratentorial anomalies.Other clinical features may include: a bitemporal narrowing, a broad nasal root. There is postnatal growth retardation, severe mental retardation associated with pyramidal spasticity and epilepsy. This entity could be identical to "lissencephaly with cerebellar hypoplasia type B" (LCHb), and therefore linked to mutations in RELN gene.

MLIS2
Microlissencephaly Type B or Barth microlissencephaly syndrome: is a microlissencephaly with thick cortex, severe cerebellar and brainstem hypoplasia. The Barth-type of MLIS is the most severe of all the known lissencephaly syndromes.This phenotype consists of polyhydramnios (probably due to poor fetal swallowing), severe congenital microcephaly, weak respiratory effort, and survival for only a few hours or days. Barth described two siblings with this type as having a very low brainweight, wide ventricles, a very thin neopallium, absent corpus callosum and absent olfactory nerve.

MLIS3
Microlissencephaly with intermediate cortex and abrupt anteroposterior gradient

MLIS4
Microlissencephaly with mildly to moderately thick (6–8 mm) cortex, callosal agenesis

Presentation
Microlissencephalic patients suffer from spasticity, seizures, severe developmental delay and intellectual disabilities with survival varying from days to years. Patients may also have dysmorphic craniofacial features, abnormal genitalia, and arthrogryposis.Microlissencephaly may arise as a part of Baraitser-Winter syndrome which comprises also ptosis, coloboma, hearing loss and learning disability.
Moreover, it is the distinct developmental brain abnormality in "microcephalic osteodysplastic primordial dwarfism" (MOPD1). Microlissencephaly may be accompanied by micromelia as in Basel-Vanagaite-Sirota syndrome (a.k.a. Microlissencephaly-Micromelia syndrome).

Pathophysiology
The genetic basis and pathophysiology of microlissencephaly are still not completely understood.
Most cases of microlissencephaly are described in consanguineous families suggesting an autosomal recessive inheritance. Mutation of RELN gene or CIT could cause MLIS. Human NDE1 mutations and mouse Nde1 loss lead to cortical lamination deficits, which, together with reduced neuronal production cause microlissencephaly. Homozygous frameshift mutations in NDE1 gene was found to cause microlissencephaly with up to 90% reduction in brain mass and seizures starting early in life. Some other disease-causing genes include: KATNB1 and WDR62. It is hypothesized that the KATNB1-associated microlissencephaly is the result of a combined effect of reduced neural progenitor populations and impaired interaction between the Katanin P80 subunit (encoded by KATNB1) and LIS1 (a.k.a. PAFAH1B1), a protein mutated in type 1 lissencephaly. Missense mutation in ACTG1 gene was identified in three cases of microlissencephaly. ACTG1 is the same gene that, when mutated, causes Baraitser-Winter syndrome. A loss-of-function mutation in the Doublesex- and Mab-3–Related Transcription factor A2 (DMRTA2, also known as DMRT5) gene has been reported in a case of microlissencephaly, implicating DMRTA2 as a critical regulator of cortical neural progenitor cell dynamics.Microlissencepahly is considered a tubulinopathy (tubulin gene defect) i.e. is caused by mutation in tubulin genes, mainly TUBA1A and less commonly TUBB2B, TUBB3, TUBA3E and TUBG1 </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 Achromatopsia and can you explain it in depth? [/INST] Achromatopsia, also known as Rod monochromacy, is a medical syndrome that exhibits symptoms relating to five conditions, most notably monochromacy. Historically, the name referred to monochromacy in general, but now typically refers only to an autosomal recessive congenital color vision condition. The term is also used to describe cerebral achromatopsia, though monochromacy is usually the only common symptom. The conditions include: monochromatic color blindness poor visual acuity and day-blindness. The syndrome is also present in an incomplete form that exhibits milder symptoms, including residual color vision. Achromatopsia is estimated to affect 1 in 30,000 live births worldwide.

Signs and symptoms
The five symptoms associated with achromatopsia are:

Color blindness - usually monochromacy
Reduced visual acuity - uncorrectable with lenses
Hemeralopia – with the subject exhibiting photophobia
Nystagmus
Iris operating abnormalitiesThe syndrome is typically first noticed in children around six months of age due to their photophobia or their nystagmus. The nystagmus becomes less noticeable with age but the other symptoms of the syndrome become more relevant as school age approaches. Visual acuity and stability of the eye motions generally improve during the first six to seven years of life – but remain near 20/200. Otherwise the syndrome is considered stationary and does not worsen with age.If the light level during testing is optimized, achromats may achieve corrected visual acuity of 20/100 to 20/150 at lower light levels, regardless of the absence of color. The fundus of the eye appears completely normal.Achromatopsia can be classified as complete or incomplete. In general, symptoms of incomplete achromatopsia are attenuated versions of those of complete achromatopsia. Individuals with incomplete achromatopsia have reduced visual acuity with or without nystagmus or photophobia. Incomplete achromats show only partial impairment of cone cell function.

Cause
Achromatopsia is sometimes called rod monochromacy (as opposed to blue cone monochromacy), as achromats exhibit a complete absence of cone cell activity via electroretinography in photopic lighting. There are at least four genetic causes of achromatopsia, two of which involve cyclic nucleotide-gated ion channels (ACHM2, ACHM3), a third involves the cone photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown.Known genetic causes of this include mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2) and CNGB3 (ACHM3), the cone cell transducin, GNAT2 (ACHM4), subunits of cone phosphodiesterase PDE6C (ACHM5, OMIM 613093) and PDEH (ACHM6, OMIM 610024), and ATF6 (ACHM7, OMIM 616517).

Pathophysiology
The hemeralopic aspect of achromatopsia can be diagnosed non-invasively using electroretinography. The response at low (scotopic) and median (mesopic) light levels will be normal but the response under high light level (photopic) conditions will be absent. The mesopic level is approximately a hundred times lower than the clinical level used for the typical high level electroretinogram. When as described; the condition is due to a saturation in the neural portion of the retina and not due to the absence of the photoreceptors per se.In general, the molecular pathomechanism of achromatopsia is either the inability to properly control or respond to altered levels of cGMP; particularly important in visual perception as its level controls the opening of cyclic nucleotide-gated ion channels (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization and cessation of glutamate release. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in cone cells. When expressed alone, CNGB3 cannot produce functional channels, whereas this is not the case for CNGA3. Coassembly of CNGA3 and CNGB3 produces channels with altered membrane expression, ion permeability (Na+ vs. K+ and Ca2+), relative efficacy of cAMP/cGMP activation, decreased outward rectification, current flickering, and sensitivity to block by L-cis-diltiazem.Mutations tend to result in the loss of CNGB3 function or gain of function—often increased affinity for cGMP—of CNGA3. cGMP levels are controlled by the activity of the cone cell transducin, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels by photons. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia phenotype.Molecular diagnosis can be established by identification of biallelic variants in the causative genes. Molecular genetic testing approaches used in achromatopsia can include targeted analysis for the common CNGB3 variant c.1148delC (p.Thr383IlefsTer13), use of a multigenerational panel, or comprehensive genomic testing.

ACHM2
While some mutations in CNGA3 result in truncated and, presumably, non-functional channels this is largely not the case. While few mutations have received in-depth study, at least one mutation does result in functional channels. Curiously, this mutation, T369S, produces profound alterations when expressed without CNGB3. One such alteration is decreased affinity for Cyclic guanosine monophosphate. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increased calcium permeability.When mutant T369S channels coassemble with CNGB3, however, the only remaining aberration is increased calcium permeability. While it is not immediately clear how this increase in Ca2+ leads to achromatopsia, one hypothesis is that this increased current decreases the signal-to-noise ratio. Other characterized mutations, such as Y181C and the other S1 region mutations, result in decreased current density due to an inability of the channel to traffic to the surface. Such loss of function will undoubtedly negate the cone cells ability to respond to visual input and produce achromatopsia. At least one other missense mutation outside of the S1 region, T224R, also leads to loss of function.

ACHM3
While very few mutations in CNGB3 have been characterized, the vast majority of them result in truncated channels that are presumably non-functional. This will largely result in haploinsufficiency, though in some cases the truncated proteins may be able to coassemble with wild-type channels in a dominant negative fashion. The most prevalent ACHM3 mutation, T383IfsX12, results in a non-functional truncated protein that does not properly traffic to the cell membrane.The three missense mutations that have received further study show a number of aberrant properties, with one underlying theme. The R403Q mutation, which lies in the pore region of the channel, results in an increase in outward current rectification, versus the largely linear current-voltage relationship of wild-type channels, concomitant with an increase in cGMP affinity. The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP. It is the increased affinity for cGMP and cAMP in these mutants that is likely the disorder-causing change. Such increased affinity will result in channels that are insensitive to the slight concentration changes of cGMP due to light input into the retina.

ACHM4
Upon activation by light, cone opsin causes the exchange of GDP for GTP in the guanine nucleotide binding protein (G-protein) α-transducing activity polypeptide 2 (GNAT2). This causes the release of the activated α-subunit from the inhibitory β/γ-subunits. This α-subunit then activates a phosphodiesterase that catalyzes the conversion of cGMP to GMP, thereby reducing current through CNG3 channels. As this process is absolutely vital for proper color processing it is not surprising that mutations in GNAT2 lead to achromatopsia. The known mutations in this gene, all result in truncated proteins. Presumably, then, these proteins are non-functional and, consequently, cone opsin that has been activated by light does not lead to altered cGMP levels or photoreceptor membrane hyperpolarization.

Management
Gene therapy
As achromatopsia is linked to only a few single-gene mutations, it is a good candidate for gene therapy. Gene therapy is a technique for injecting functional genes into the cells that need them, replacing or overruling the original alleles linked to achromatopsia, thereby curing it - at least in part. Achromatopsia has been a focus of gene therapy since 2010, when achromatopsia in dogs was partially cured. Several clinical trials on humans are ongoing with mixed results.

Eyeborg
Since 2003, a cybernetic device called the eyeborg has allowed people to perceive color through sound waves. This form of Sensory substitution maps the hue perceived by a camera worn on the head to a pitch experienced through bone conduction according to a sonochromatic scale. This allows achromats (or even the totally blind) to perceive - or estimate - the color of an object. Achromat and artist Neil Harbisson was the first to use the eyeborg in early 2004, which allowed him to start painting in color. He has since acted as a spokesperson for the technology, namely in a 2012 TED Talk. A 2015 study suggests that achromats who use the Eyeborg for several years exhibit neural plasticity, which indicates the sensory substitution has become intuitive for them.

Other accommodations
While gene therapy and the Eyeborg may currently have low uptake with achromats, there are several more practical ways for achromats to manage their condition:

Some colors can be estimated through the use of colored filters. By comparing the luminosity of a color with and without a filter (or between two different filters), the color can be estimated. This is the premise of monocular lenses and the SeeKey. In some US states, achromats can use a red filter while driving to determine the color of a traffic light.
To alleviate photophobia stemming from hemeralopia, dark red or plum colored filters as either sunglasses or tinted contacts are very helpful at decreasing light sensitivity.
To manage the low visual acuity that is typical of achromatopsia, achromats may use telescopic systems, specifically when driving, to increase the resolution of an object of interest.

Epidemiology
Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people.However, on the small Micronesian atoll of Pingelap, approximately five percent of the atolls 3,000 inhabitants are affected. This is the result of a population bottleneck caused by a typhoon and ensuing famine in the 1770s, which killed all but about twenty islanders, including one who was heterozygous for achromatopsia.The people of this region have termed achromatopsia "maskun", which literally means "not see" in Pingelapese </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 Harlequin syndrome and can you explain it in depth? [/INST] Harlequin syndrome is a condition characterized by asymmetric sweating and flushing on the upper thoracic region of the chest, neck and face. Harlequin syndrome is considered an injury to the autonomic nervous system (ANS). The ANS controls some of the bodys natural processes such as sweating, skin flushing and pupil response to stimuli. Such individuals with this syndrome have an absence of sweat skin flushing unilaterally; usually on the one side of the face, arms and chest. It is an autonomic disorder that may occur at any age. Harlequin syndrome affects fewer than 200,000 people in the United States.
Symptoms associated with Harlequin syndrome are more likely to appear when a person has been in the following conditions: exercising, warm environment and intense emotional situation. Since one side of the body sweats and flushes appropriately to the condition, the other side of the body will have an absence of such symptoms. This syndrome has also been called the "Harlequin sign" and thought to be one of the spectrum of diseases that may cause Harlequin syndrome.
It can also be the outcome of a one sided endoscopic thoracic sympathectomy (ETS) or endoscopic sympathetic blockade (ESB) surgery.Harlequin syndrome can also be seen as a complication of VA (veno-arterial) extracorporeal membrane oxygenation (ECMO). This involves differential hypoxemia (low oxygen levels in the blood) of the upper body in comparison to the lower body.

Signs and symptoms
The "Harlequin sign" is unilateral flushing and sweating of the face, neck, and upper chest usually after exposure to heat or strenuous exertion. Horner syndrome, another problem associated with the sympathetic nervous system, is often seen in conjunction with harlequin syndrome.Since Harlequin syndrome is associated with a dysfunction in the autonomic nervous system, main symptoms of this dysfunction are in the following: Absence of sweat(anhidrosis) and flushing on one side of the face, neck, or upper thoracic area. In addition, other symptoms include cluster headaches, tearing of the eyes, nasal discharge, abnormal contraction of the pupils, weakness in neck muscles, and drooping of one side of the upper eyelid.

Causes
One possible cause of Harlequin syndrome is a lesion to the preganglionic or postganglionic cervical sympathetic fibers and parasympathetic neurons of the ciliary ganglion. It is also believed that torsion (twisting) of the thoracic spine can cause blockage of the anterior radicular artery leading to Harlequin syndrome. The sympathetic deficit on the denervated side causes the flushing of the opposite side to appear more pronounced. It is unclear whether or not the response of the undamaged side was normal or excessive, but it is believed that it could be a result of the body attempting to compensate for the damaged side and maintain homeostasis.Since the cause and mechanism of Harlequin syndrome is still unknown, there is no way to prevent this syndrome.

Mechanism
Although the exact mechanism for Harlequin syndrome is still unclear, understanding what is affected with this syndrome is important. The majority of cases are thought to occur when nerve bundles in the head and neck are injured. Such bundles are able to send an action potential from the autonomic nervous system to the rest of the body. However, action potentials in this system are not being received by the second or third thoracic vertebrae which innervates the face, neck, and upper chest. Damage or lesions near T2 or T3 could be between the stellate ganglion and superior cervical ganglion. This is where we would observe absence of sweat and skin flushing on one side of the face, neck, and upper chest.

Diagnosis
Diagnosis of Harlequin syndrome is made when the individual has consistent signs and symptoms of the condition, therefore, it is made by clinical observation. In addition, a neurologist or primary care physician may require an MRI test to rule out similar disorders such as Horners syndrome, Adies syndrome, and Ross syndrome. In an MRI, a radiologist may observe areas near brain or spinal cord for lesions, or any damage to the nerve endings. It is also important that the clinician rules out traumatic causes by performing autonomic function tests. Such tests includes the following: tilt table test, orthostatic blood pressure measurement, head-up test, valsalva maneuver, thermoregulatory sweat test, tendon reflex test, and electrocardiography (ECG). CT scan of the heart and lungs may also be performed to rule out a structural underlying lesion. The medical history of the individual should be carefully noted.

Treatment and prognosis
Harlequin syndrome is not debilitating so treatment is not normally necessary. In cases where the individual may feel socially embarrassed, contralateral sympathectomy may be considered, although compensatory flushing and sweating of other parts of the body may occur. In contralateral sympathectomy, the nerve bundles that cause the flushing in the face are interrupted. This procedure causes both sides of the face to no longer flush or sweat. Since symptoms of Harlequin syndrome do not typically impair a persons daily life, this treatment is only recommended if a person is very uncomfortable with the flushing and sweating associated with the syndrome.

Research
In August 2016, researchers at the Instituto de Assistência dos Servidores do Estado do Rio de Janeiro used botulinum toxin as a method to block the acetylcholine release from the presynaptic neurons. Although they have seen a reduction in one sided flushing, sweating still occurs.There have been case studies of individuals who have experienced this syndrome after an operation. Two female patients with metastatic cancer, ages 37-years-old and 58-years-old, were scheduled for placement of an intrathecal pump drug delivery system </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 Analgesic nephropathy and can you explain it in depth? [/INST] Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.
The specific kidney injuries induced by analgesics are renal papillary necrosis and chronic interstitial nephritis. They appear to result from decreased blood flow to the kidney, rapid consumption of antioxidants, and subsequent oxidative damage to the kidney. This kidney damage may lead to progressive chronic kidney failure, abnormal urinalysis results, high blood pressure, and anemia. A small proportion of individuals with analgesic nephropathy may develop end-stage kidney disease.
Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts of Europe, Australia, and the United States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s.

Presentation
Common findings in people with analgesic nephropathy include headache, anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia, pyuria). Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria).

Complications
Complications of analgesic nephropathy include pyelonephritis and end-stage kidney disease. Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure. Analgesic nephropathy also appears to increase the risk of developing cancers of the urinary system.

Pathophysiology
The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy. Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis.How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney toxicities of NSAIDs and the antipyretics phenacetin and paracetamol may combine to give rise to analgesic nephropathy. A committee of investigators reported in 2000 that there was insufficient evidence to suggest that non-phenacetin analgesics by themselves are associated with analgesic nephropathy.

Aspirin and NSAIDs
Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases.Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the renal cortex (outside) and then the renal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, known as the renal papillae, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of renal papillary necrosis.NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia.
Most healthy kidneys contain enough physiologic reserve to compensate for this NSAID-induced decrease in blood flow. However, those subjected to additional injury from phenacetin or paracetamol may progress to analgesic nephropathy.

Phenacetin and paracetamol
It is unclear how phenacetin induces injury to the kidney. Bach and Hardy have proposed that phenacetins metabolites lead to lipid peroxidation that damages cells of the kidney.Paracetamol is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI depletes glutathione via non-enzymatic conjugation with glutathione, a naturally occurring antioxidant. With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.

Diagnosis
Diagnosis is traditionally based on the clinical findings above in combination with excessive analgesic use. It is estimated that between 2 and 3 kg each of phenacetin or aspirin must be consumed before evidence of analgesic nephropathy becomes clinically apparent.Once suspected, analgesic nephropathy can be confirmed with relative accuracy using computed tomography (CT) imaging without contrast. One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92% sensitive and 100% specific for the diagnosis of analgesic nephropathy.

Treatment
Treatment of analgesic nephropathy begins with the discontinuation of analgesics, which often halts the progression of the disease and may even result in normalization of kidney function. In Stage 5 chronic kidney disease patients renal replacement therapy may become necessary.

History
Analgesics are a class of medications widely used in the treatment of pain. They include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), as well as the antipyretics paracetamol (known as acetaminophen in the United States) and phenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States. These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, and caffeine or codeine.In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin. They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namely renal papillary necrosis and chronic interstitial nephritis </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 Acute cerebellar ataxia of childhood and can you explain it in depth? [/INST] Acute cerebellar ataxia of childhood is a childhood condition characterized by an unsteady gait, most likely secondary to an autoimmune response to infection, drug induced or paraneoplastic. Most common virus causing acute cerebellar ataxia are chickenpox virus and Epstein–Barr virus, leading to a childhood form of post viral cerebellar ataxia. It is a diagnosis of exclusion.

Signs and symptoms
Acute cerebellar ataxia usually follows 2–3 weeks after an infection </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 Autoimmune lymphoproliferative syndrome and can you explain it in depth? [/INST] Autoimmune lymphoproliferative syndrome (ALPS) is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis.It is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.

Signs and symptoms
All people with ALPS have signs of lymphoproliferation, which makes it the most common clinical manifestation of the disease. The increased proliferation of lymphoid cells can cause the size of lymphoid organs such as the lymph nodes and spleen to increase (lymphadenopathy and splenomegaly, present in respectively over 90% and over 80% of patients). The liver is enlarged (hepatomegaly) in 30–40% of patients.Autoimmune disease is the second most common clinical manifestation and one that most often requires treatment. The most common autoimmune presentations include autoimmune cytopenias, which can be mild to very severe and intermittent or chronic. These include autoimmune hemolytic anemia, autoimmune neutropenia, and autoimmune thrombocytopenia. Other autoimmune manifestations can be similar to systemic lupus erythematosus (least common, affecting <5% of patients). Manifestations within the nervous system can include autoimmune cerebellar ataxia, Guillain–Barré syndrome, and transverse myelitis. Manifestations in the gastrointestinal system can include atrophic gastritis, and autoimmune hepatitis, esophagitis, colitis, and pancreatitis. Other manifestations can affect the skin (hives), lungs (bronchiolitis obliterans), or kidneys (autoimmune glomerulonephritis and nephrotic syndrome).
Another sign are cancers such as Hodgkin and non-Hodgkin lymphomas, which appear to be increased, possibly due to Epstein–Barr virus-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer.

Genetics
This condition is usually caused by mutations in the FAS gene. Rarely cases due to mutations in other genes including the
FAS ligand gene have been reported. The disease is inherited in an autosomal dominant manner, but it shows incomplete penetrance with up to 40% of people with a FAS mutation not showing symptoms.

Diagnosis
Diagnostic algorithm
The old diagnostic criteria for the illness included: Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.
The new criteria require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10).
The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion. A probable diagnosis is the same but with one secondary accessory criterion.

Classification
2003 nomenclature
IA - Fas
IB - Fas ligand
IIA - Caspase 10
IIB  - Caspase 8
III - unknown
IV - Neuroblastoma RAS viral oncogene homologRevised nomenclature (2010)
ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.
ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment. 10% of patients
ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases
ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients
ALPS-U: Undefined. 20% of patients
CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lymphocyte compartment. No longer considered a subtype of ALPS but distinct disease

Treatment
Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.Second line therapies include: mycophenolate mofetil (cellcept) which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%) With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs </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 Torus mandibularis and can you explain it in depth? [/INST] Torus mandibularis is a bony growth in the mandible along the surface nearest to the tongue. Mandibular tori are usually present near the premolars and above the location of the mylohyoid muscles attachment to the mandible. In 90% of cases, there is a torus on both the left and right sides.
The prevalence of mandibular tori ranges from 5-40%. It is less common than bony growths occurring on the palate, known as torus palatinus. Mandibular tori are more common in Asian and Inuit populations, and slightly more common in males </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 Sclerosteosis 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 Hemopneumothorax and can you explain it in depth? [/INST] Hemopneumothorax, or haemopneumothorax, is the condition of having air in the chest cavity (pneumothorax) and blood in the chest cavity (hemothorax). A hemothorax, pneumothorax, or the combination of both can occur due to an injury to the lung or chest.

Cause
The pleural space is located anatomically between the visceral membrane, which is firmly attached to the lungs, and the parietal membrane which is firmly attached to the chest wall (a.k.a. ribcage and intercostal muscles, muscles between the ribs).  The pleural space contains pleural fluid.  This fluid holds the two membranes together by surface tension, as much as a drop of water between two sheets of glass prevents them from separating.  Because of this, when the intercostal muscles move the ribcage outward, the lungs are pulled out as well, dropping the pressure in the lungs and pulling air into the bronchi, when we breathe in </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 Fetus in fetu and can you explain it in depth? [/INST] Fetus in fetu (or foetus in foetu) is a rare developmental abnormality in which a mass of tissue resembling a fetus forms inside the body of its twin. An early example of the phenomenon was described in 1808 by George William Young.There are two hypotheses for the origin of a "fetus in fetu". One hypothesis is that the mass begins as a normal fetus but becomes enveloped inside its twin. The other hypothesis is that the mass is a highly developed teratoma </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 Lipschütz ulcer 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 Undifferentiated connective tissue disease 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 Uterine malformation and can you explain it in depth? [/INST] A uterine malformation is a type of female genital malformation resulting from an abnormal development of the Müllerian duct(s) during embryogenesis. Symptoms range from amenorrhea, infertility, recurrent pregnancy loss, and pain, to normal functioning depending on the nature of the defect.

Types
The American Fertility Society (now American Society of Reproductive Medicine) Classification distinguishes:

Class I—Müllerian agenesis (absent uterus).
This condition is represented by the hypoplasia or the agenesis (total absence) of the different parts of the uterus:
Vaginal hypoplasia or agenesis
Cervical hypoplasia or agenesis
Fundal hypoplasia or agenesis (absence or hypoplasia of the fundus of the uterus)
Tubal hypoplasia or agenesis (absence or hypoplasia of the Fallopian tubes)
Combined hypoplasia the agenesis of different part of the uterus
This condition is also called Mayer-Rokitansky-Kuster-Hauser syndrome. The patient with MRKH syndrome will have primary amenorrhea.
Class II—Unicornuate uterus (a one-sided uterus).
Rare condition in which a partial or complete lack of one Müllerian duct is present. The uterus has a typical "banana shape" on imaging systems. This condition can be sub-classified in:
Communicating: a rudimentary uterine horn is formed and it presents a cavity that communicates with the body of the uterus
Non-communicating: a rudimentary uterine horn is formed and it presents a cavity that does not communicate with the body of the uterus
No cavity: a rudimentary uterine horn is present without any cavity
No horn: there is no rudimentary uterine horn, just the functioning one is presentClass III—Uterus didelphys, also uterus didelphis (double uterus).
Both Müllerian ducts develop but fail to fuse, thus the patient has a "double uterus". This may be a condition with a double cervix and a vaginal partition (v.i.), or the lower Müllerian system fused into its unpaired condition. See Triplet-birth with Uterus didelphys for a case of a woman having spontaneous birth in both wombs with twins.
Class IV—Bicornuate uterus (uterus with two horns).
Only the upper part of that part of the Müllerian system that forms the uterus fails to fuse, thus the caudal part of the uterus is normal, the cranial part is bifurcated. The uterus is "heart-shaped". This condition can be complete or partial.
Class V—Septated uterus (uterine septum or partition).
The two Müllerian ducts have fused, but the partition between them is still present, splitting the system into two parts. With a complete septum the vagina, cervix and the uterus can be partitioned. Usually the septum affects only the cranial part of the uterus. A uterine septum is the most common uterine malformation and a cause for miscarriages </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 Mycotic aneurysm 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 Moorens ulcer and can you explain it in depth? [/INST] Moorens ulcer is a rare idiopathic ocular disorder that may lead to blindness due to progressive destruction of the peripheral cornea. Although the etiology of Moorens ulcer is poorly understood, recent evidence suggests that the pathogenesis of this disease appears to be the result of an autoimmune process directed against molecules expressed in the corneal stroma.Moorens ulcer is also defined as a special and the most common type of peripheral ulcerative keratitis (PUK).

Signs and symptoms
Symptoms of Moorens ulcer can include:
Pain in the affected eye(s)
Redness of the affected eye(s)
Progressive ulceration of the cornea
Blurred vision
Photophobia
TearingSome epidemiological studies have noted that men tend to be affected more than women.

Classification
The most commonly used classification was proposed by Watson in 1997. He divided the disease into three types based on the clinical picture:
Unilateral Moorens ulceration is characterized by extremely painful progressive ulceration of the cornea in one eye. This form is more common in elderly patients.
Bilateral aggressive Moorens ulceration which is observed more often in young patients and progresses along the entire circumference, then captures the central area of the cornea.
Bilateral indolent Moorens ulceration (BIM) usually occurs in middle-aged patients and manifested by a progressive peripheral corneal guttering in both eyes.

Risk factors
Several risk factors affecting the development of Moorens ulcer have been suggested.

Corneal trauma
Previous ocular trauma or infection can cause disruption of the corneal integrity resulting in the expression of tissue-specific antigens that are normally hidden from the immune system. It may lead to an increased risk of a sensitization to corneal antigens and an autoimmune reaction against antigens expressed in corneal tissues.

HLA association
Like most autoimmune diseases, Moorens ulcer is thought to be associated with specific HLA haplotypes. In some studies, HLA-DR17 and HLA-DQ2 have been found in increased frequencies in affected patients compared to healthy controls. These results propose a possible association between HLA and Moorens ulcer.

Pathology
The precise pathophysiological mechanism of Moorens ulcer remains unclear, but most data suggest that both cell-mediated immunity and humoral immunity are involved in the pathogenesis of the disease.Reduces numbers of suppressor T cells have been found in peripheral blood from patients with Moorens ulcer. This deficit in systematic immunoregulatory mechanism may lead to loss of a control over autoreactive T and B cells and contributes to disease pathogenesis.Immunohistochemical studies in patients suffered from Moorens ulcer showed massive infiltration of multiple types of inflammatory cells in the conjunctival tissue.
The cell types in the inflammatory lesion includes CD4+ and CD8+ T-lymphocytes, B-lymphocytes, macrophages, a small amount of neutrophils was also observed in the conjunctiva from patients with Moorens ulcer.In addition, circulating IgG antibodies with specificity for corneal and conjunctival antigens have been isolated from patients with Mooren’s ulcer. Gottsch and colleagues have suggested that calgranulin C, a protein expressed in the corneal stroma, may be a possible main target for autoimmune response causing Mooren’s ulcer.Also, significantly increased expression levels of adhesion and co-stimulatory molecules have been found in ocular tissues affected by Moorens ulcer compared to healthy eyes. Upregulation of adhesion molecules allows leukocyte migration into inflamed tissues. Co-stimulatory molecules may contribute to sustained local immune activation. Therefore, blockage of these molecules suppose to be a protentional therapeutic strategy for suppressing the inflammatory progression.Elevated levels of proteases and collagenases which damage the corneal stroma have also been found in affected conjunctival tissues.

Diagnosis
In view of rarity and limited knowledge of the etiology of Mooren’s ulcer, the diagnosis of the disease is complicated.The absence of any systematic disorders which can lead to peripheral corneal ulceration supports the diagnosis of Mooren’s ulcer. To diagnose Mooren’s ulcer, it is necessary to rule out other forms of non-infectious peripheral ulcerative keratitis.

Treatment
Medical treatment
Topical corticosteroids are usually used as first line of therapy </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 Xanthoma disseminatum and can you explain it in depth? [/INST]  </s>