<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 Toxoplasmic chorioretinitis and can you explain it in depth? [/INST] Toxoplasma chorioretinitis, more simply known as ocular toxoplasmosis, is possibly the most common cause of infections in the back of the eye (posterior segment) worldwide.  The causitive agent is Toxoplasma gondii, and in the United States, most cases are acquired congenitally.  The most common symptom is decreased visual acuity in one eye.  The diagnosis is made by examination of the eye, using ophthalmoscopy.  Sometimes serologic testing is used to rule out the disease, but due to high rates of false positives, serologies are not diagnostic of toxoplasmic retinitis.
If vision is not compromised, treatment may not be necessary.  When vision is affected or threatened, treatment consists of pyrimethamine, sulfadiazine, and folinic acid for 4–6 weeks.  Prednisone is sometimes used to decrease inflammation.

Signs and symptoms
A unilateral decrease in visual acuity is the most common symptom of toxoplasmic retinitis.
Under ophthalmic examination, toxoplasmic chorioretinitis classically appears as a focal, white retinitis with overlying moderate inflammation of the vitreous humour.  A unifocal area of acute-onset inflammation adjacent to an old chorioretinal scar is virtually pathognomonic for toxoplasmic chorioretinitis.  Focal condensation of vitreous and inflammatory cells may be seen overlying the pale yellow or gray-white raised lesion in the posterior pole.

Pathophysiology
Toxoplasma gondii is an intracellular parasite that causes a necrotizing chorioretinitis.

Congenital disease
Congenital disease occurs due to the acquisition of the organism by a pregnant woman exposed to tissue cysts or oocytes in uncooked meat or substances contaminated with cat feces. Spontaneous abortion may result if the disease is acquired during the first trimester.
Congenital toxoplasmosis may lead to hydrocephalus, seizures, lymphadenopathy, hepatosplenomegaly, rash, and fever. However, retinochoroiditis is the most common manifestation, occurring in 3/4 of cases.
In congenital toxoplasmosis, the disease is bilateral in 65–85% of cases and involves the macula in 58%.
Chronic or recurrent maternal infection during pregnancy is not thought to confer a risk of congenital toxoplasmosis because maternal immunity protects against fetal transmission. In contrast, pregnant women without serologic evidence of prior exposure to Toxoplasma should take sanitary precautions such as having someone else clean and maintain litter boxes and avoiding undercooked meats.

Diagnosis
In most instances, the diagnosis of toxoplasmic retinochoroiditis is made clinically on the basis of the appearance of the characteristic lesion on eye examination.
Seropositivity (positive blood test result) for Toxoplasma is very common and therefore not useful in diagnosis; however, a negative result i.e. absence of antibodies is often used to rule out disease. Others believe that serology is useful to confirm active toxoplasmic retinochoroiditis, not only by showing positivity but by also showing a significant elevation of titers: The mean IgG values were 147.7 ± 25.9 IU/ml for patients with active disease versus 18.3 ± 20.8 IU/ml for normal individuals.Antibodies against Toxoplasma:

IgG : appear within the first 2 weeks after infection, typically remain detectable for life, albeit at low levels;and may cross the placenta.
IgM : rise early during the acute phase of the infection, typically remain detectable for less than 1 year, and do not cross the placenta.
IgA : Measurement of IgA antibody titers may also be useful in a diagnosis of congenital toxoplasmosis in a fetus or newborn because IgM production is often weak during this period and the presence of IgG antibodies may indicate passive transfer of maternal antibodies in utero. IgA antibodies however usually disappear by 7 months.In atypical cases, ocular fluid testing to detect parasite DNA by polymerase chain reaction or to determine intraocular production of specific antibody may be helpful for establishing etiology.
Neuroimaging is warranted in AIDS patients presenting with these findings because intracranial toxoplasmic lesions have been reported in up to 29% of these patients who have toxoplasmic chorioretinitis.

Prevention
Toxoplasma infection can be prevented in large part by:

cooking meat to a safe temperature (i.e., one sufficient to kill Toxoplasma)
peeling or thoroughly washing fruits and vegetables before eating
cleaning cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables
pregnant women avoiding changing cat litter or, if no one else is available to change the cat litter, using gloves, then washing hands thoroughly
not feeding raw or undercooked meat to cats to prevent acquisition of ToxoplasmaProlonged and intense rainfall periods are significantly associated with the reactivation of toxoplasmic retinochoroiditis. Changes promoted by this climatic condition concern both the parasite survival in the soil as well as a putative effect on the host immune response due to other comorbidities.

Treatment
Small extramacular lesions (lesions not threatening vision) may be observed without treatment. Sight-threatening lesions are treated for 4–6 weeks with triple therapy consisting of pyrimethamine, sulfadiazine, and folinic acid </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 Otosclerosis and can you explain it in depth? [/INST] Otosclerosis is a condition of the middle ear where portions of the dense enchondral layer of the bony labyrinth remodel into one or more lesions of irregularly-laid spongy bone. As the lesions reach the stapes the bone is resorbed, then hardened (sclerotized), which limits its movement and results in hearing loss, tinnitus, vertigo or a combination of symptoms. The term otosclerosis is something of a misnomer: much of the clinical course is characterized by lucent rather than sclerotic bony changes, so the disease is also known as otospongiosis.

Etymology
The word otosclerosis derives from Greek ὠτός (ōtos), genitive of οὖς (oûs) "ear" + σκλήρωσις (sklērōsis), "hardening".

Presentation
The primary form of hearing loss in otosclerosis is conductive hearing loss (CHL) whereby sounds reach the ear drum but are incompletely transferred via the ossicular chain in the middle ear, and thus partly fail to reach the inner ear (cochlea). This can affect one ear or both ears. On audiometry, the hearing loss is characteristically low-frequency, with higher frequencies being affected later.Sensorineural hearing loss (SNHL) has also been noted in patients with otosclerosis; this is usually a high-frequency loss, and usually manifests late in the disease. The causal link between otosclerosis and SNHL remains controversial. Over the past century, leading otologists and neurotologic researchers have argued whether the finding of SNHL late in the course of otosclerosis is due to otosclerosis or simply to typical presbycusis.Most patients with otosclerosis notice tinnitus (head noise) to some degree. The amount of tinnitus is not necessarily related to the degree or type of hearing impairment.  Tinnitus develops due to irritation of the delicate nerve endings in the inner ear. Since the nerve carries sound, this irritation is manifested as ringing, roaring or buzzing. It is usually worse when the patient is fatigued, nervous or in a quiet environment.

Causes
Otosclerosis can be caused by both genetic and environmental factors, such as a viral infection (like measles).  Ribonucleic acid of the measles virus has been found in stapes footplate in most patients with otosclerosis. Populations that have been vaccinated against measles had a significant reduction in otosclerosis.  While the disease is considered to be hereditary, its penetrance and the degree of expression is so highly variable that it may be difficult to detect an inheritance pattern.  Most of the implicated genes are transmitted in an autosomal dominant fashion. One genome-wide analysis associates otosclerosis with variation in RELN gene.Loci include:

Pathophysiology
The pathophysiology of otosclerosis is complex.  The key lesions of otosclerosis are multifocal areas of sclerosis within the endochondral temporal bone.  These lesions share some characteristics with Pagets Disease, but they are not thought to be otherwise related.  Histopathological studies have all been done on cadaveric temporal bones, so only inferences can be made about progression of the disease histologically.  It seems that the lesions go through an active "spongiotic" or hypervascular phase before developing into "sclerotic" phase lesions.  There have been many genes and proteins identified that, when mutated, may lead to these lesions.  Also there is mounting evidence that measles virus is present within the otosclerotic foci, implicating an infectious etiology (this has also been noted in Pagets Disease).
Conductive hearing loss (CHL) in otosclerosis is caused by two main sites of involvement of the sclerotic (or scar-like) lesions.  The best understood mechanism is fixation of the stapes footplate to the oval window of the cochlea.  This greatly impairs movement of the stapes and therefore transmission of sound into the inner ear ("ossicular coupling").  Additionally the cochleas round window can also become sclerotic, and in a similar way impair movement of sound pressure waves through the inner ear ("acoustic coupling").
CHL is usually concomitant with impingement of abnormal bone on the stapes footplate. This involvement of the oval window forms the basis of the name fenestral otosclerosis. The most common location of involvement of otosclerosis is the bone just anterior to the oval window at a small cleft known as the fissula ante fenestram. The fissula is a thin fold of connective tissue extending through the endochondral layer, approximately between the oval window and the cochleariform process, where the tensor tympani tendon turns laterally toward the malleus.
The mechanism of sensorineural hearing loss in otosclerosis is less well understood. It may result
from direct injury to the cochlea and spiral ligament from the lytic process or from release of proteolytic enzymes into the cochlea. There are certainly a few well documented instances of sclerotic lesions directly obliterating sensory structures within the cochlea and spiral ligament, which have been photographed and reported post-mortem.  Other supporting data includes a consistent loss of cochlear hair cells in patients with otosclerosis; these cells being the chief sensory organs of sound reception.  A suggested mechanism for this is the release of hydrolytic enzymes into the inner ear structures by the spongiotic lesions.

Diagnosis
Otosclerosis is traditionally diagnosed by characteristic clinical findings, which include progressive conductive
hearing loss, a normal tympanic membrane, and no evidence of middle ear inflammation. The cochlear promontory may have a faint pink tinge reflecting the vascularity of the lesion, referred to as the Schwartz sign.Approximately 0.5% of the population will eventually be diagnosed with otosclerosis. Post-mortem studies show that as many as 10% of people may have otosclerotic lesions of their temporal bone, but apparently never had symptoms warranting a diagnosis. Caucasians are the most affected race, with the prevalence in the Black and Asian populations being much lower. In clinical practice otosclerosis is encountered about twice as frequently in females as in males, but this does not reflect the true sex ratio. When families are investigated it is found that the condition is only slightly more common in women. Usually noticeable hearing loss begins at middle-age, but can start much sooner. The hearing loss was long believed to grow worse during pregnancy, but recent research does not support this belief.

Differential testing
Audiometry
Fixation of the stapes within the oval window causes a conductive hearing loss. In pure-tone audiometry, this manifests as air-bone gaps on the audiogram (i.e. a difference of more than 10 dB between the air-conduction and bone-conduction thresholds at a given test frequency). However, medial fixation of the ossicular chain impairs both the inertial and osseotympanic modes of bone conduction, increasing the bone-conduction thresholds between 500 Hz and 4 kHz, and reducing the size of air-bone gaps. As 2 kHz is the resonant frequency of the ossicular chain, the largest increase in bone-conduction threshold (around 15 dB) occurs at this frequency – the resultant notch is called Carharts notch and is a useful clinical marker for medial ossicular-chain fixation.Tympanometry measures the peak pressure (TPP) and peak-compensated static admittance (Ytm) of the middle ear at the eardrum. As the stapes is ankylosed in otosclerosis, the lateral end of the ossicular chain may still be quite mobile. Therefore, otosclerosis may only slightly reduce the admittance, resulting in either a shallow tympanogram (type AS), or a normal tympanogram (type A). Otosclerosis increases the stiffness of the middle-ear system, raising its resonant frequency. This can be quantified using multi-frequency tympanometry. Thus, a high resonant-frequency pathology such as otosclerosis can be differentiated from low resonant-frequency pathologies such as ossicular discontinuity.In the absence of a pathology, a loud sound (generally greater than 70 dB above threshold) causes the stapedius muscle to contract, reducing the admittance of the middle ear and softening the perceived loudness of the sound. If the mobility of the stapes is reduced due to otosclerosis, then stapedius muscle contraction does not significantly decrease the admittance. When acoustic reflex testing is conducted, the acoustic reflex thresholds (ART) cannot be determined when attempting to measure on the affected side. Also, a conductive pathology will attenuate the test stimuli, resulting in either elevated reflex thresholds or absent reflexes when the stimulus is presented in the affected ear and measured in the other ear.

CT imaging
Imaging is usually not pursued in those with uncomplicated conductive hearing loss and characteristic clinical findings. Those with only conductive hearing loss are often treated medically or with surgery without imaging. The diagnosis may be unclear clinically in cases of sensorineural or mixed hearing loss and may become apparent only on imaging. Therefore, imaging is often performed when the hearing loss is sensorineural or mixed.A high-resolution CT shows very subtle bone findings. However, CT is usually not needed prior to surgery.Otosclerosis on CT can be graded using the grading system suggested by Symons and Fanning.
Grade 1, solely fenestral;
Grade 2, patchy localized cochlear disease (with or without fenestral involvement) to either the basal cochlear turn (grade 2A), or the middle/apical turns (grade 2B), or both the basal turn and the middle/apical turns (grade 2C); and
Grade 3, diffuse confluent cochlear involvement (with or without fenestral involvement).

Treatment
Medical
Earlier workers suggested the use of calcium fluoride; now sodium fluoride is the preferred compound. Fluoride ions inhibit the rapid progression of disease. In the otosclerotic ear, there occurs formation of hydroxylapatite crystals which lead to stapes (or other) fixation. The administration of fluoride replaces the hydroxyl radical with fluoride leading to the formation of fluorapatite crystals. Hence, the progression of disease is considerably slowed down and active disease process is arrested.
This treatment cannot reverse conductive hearing loss, but may slow the progression of both the conductive and sensorineural components of the disease process. Otofluor, containing sodium fluoride, is one treatment. Recently, some success has been claimed with a second such treatment, bisphosphonate medications that inhibit bone destruction. However, these early reports are based on non-randomized case studies that do not meet standards of clinical trials. There are numerous side-effects to both pharmaceutical treatments, including occasional stomach upset, allergic itching, and increased joint pains which can lead to arthritis. In the worst case, bisphosphonates may lead to osteonecrosis of the auditory canal itself. Finally, neither approach has been proven to be beneficial after the commonly preferred method of surgery has been undertaken.

Surgery
There are various methods to treat otosclerosis. However the method of choice is a procedure known as stapedectomy. Early attempts at hearing restoration via the simple freeing of the stapes from its sclerotic attachments to the oval window were met with temporary improvement in hearing, but the conductive hearing loss would almost always recur </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 Malignant infantile osteopetrosis and can you explain it in depth? [/INST] Malignant infantile osteopetrosis is a rare osteosclerosing type of skeletal dysplasia that typically presents in infancy and is characterized by a unique radiographic appearance of generalized hyperostosis (excessive growth of bone).
The generalized increase in bone density has a special predilection to involve the medullary portion with relative sparing of the cortices. Obliteration of bone marrow spaces and subsequent depression of the cellular function can result in serious hematologic complications. Optic atrophy and cranial nerve damage secondary to bony expansion can result in marked morbidity. The prognosis is extremely poor in untreated cases.  Plain radiography provides the key information to the diagnosis. Clinical and radiologic correlations are also fundamental to the diagnostic process, with additional gene testing being confirmatory.

Presentation
Hematologic manifestations related to bone marrow suppression and subsequent pancytopenia are a major source of morbidity and mortality. Additionally, extramedullary hematopoiesis can result in liver and spleen dysfunction </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 Prurigo simplex and can you explain it in depth? [/INST] Prurigo simplex is a chronic, itchy, idiopathic skin condition characterized by extremely itchy skin nodules and lesions.: 57  Typically, there is no known direct cause of prurigo simplex, but some factors are known to trigger or aggravate it </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 Argentine hemorrhagic fever and can you explain it in depth? [/INST] Argentine hemorrhagic fever (AHF) or OHiggins disease, also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus (an arenavirus, closely related to the Machupo virus, causative agent of Bolivian hemorrhagic fever). Its vector is the drylands vesper mouse, a rodent found in Argentina and Paraguay.

Epidemiology
The disease was first reported in the town of OHiggins in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known. Various theories about its nature were proposed: it was Weils disease, leptospirosis, caused by chemical pollution. It was associated with fields containing stubble after the harvest, giving it another of its names.
The endemic area of AHF covers approximately 150,000 km2, compromising the provinces of Buenos Aires, Córdoba, Santa Fe and La Pampa, with an estimated risk population of 5 million.
The vector, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus), has chronic asymptomatic infection, and spreads the virus through its saliva and urine. Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age.

Clinical aspects
AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks.
If untreated, the mortality of AHF reaches 15–30% </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 Polyploidy and can you explain it in depth? [/INST] Polyploidy is a condition in which the cells of an organism have more than one pair of (homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contains one or more chromosomes and comes from each of two parents, resulting in pairs of homologous chromosomes between sets. However, some organisms are polyploid. Polyploidy is especially common in plants. Most eukaryotes have diploid somatic cells, but produce haploid gametes (eggs and sperm) by meiosis. A monoploid has only one set of chromosomes, and the term is usually only applied to cells or organisms that are normally diploid. Males of bees and other Hymenoptera, for example, are monoploid. Unlike animals, plants and multicellular algae have life cycles with two alternating multicellular generations. The gametophyte generation is haploid, and produces gametes by mitosis, the sporophyte generation is diploid and produces spores by meiosis.
Polyploidy may occur due to abnormal cell division, either during mitosis, or more commonly from the failure of chromosomes to separate during meiosis or from the fertilization of an egg by more than one sperm. In addition, it can be induced in plants and cell cultures by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well. Oryzalin will also double the existing chromosome content.
Polyploidy occurs in highly differentiated human tissues in the  liver, heart muscle, bone marrow and the placenta. It occurs in the somatic cells of some animals, such as goldfish, salmon, and salamanders, but is especially common among ferns and flowering plants (see Hibiscus rosa-sinensis), including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids. Sugarcane can have ploidy levels higher than octaploid.Polyploidization can be a mechanism of sympatric speciation because polyploids are usually unable to interbreed with their diploid ancestors. An example is the plant Erythranthe peregrina. Sequencing confirmed that this species originated from E. × robertsii, a sterile triploid hybrid between E. guttata and E. lutea, both of which have been introduced and naturalised in the United Kingdom. New populations of E. peregrina arose on the Scottish mainland and the Orkney Islands via genome duplication from local populations of E. × robertsii. Because of a rare genetic mutation, E. peregrina is not sterile.

Terminology
Types
Polyploid types are labeled according to the number of chromosome sets in the nucleus. The letter x is used to represent the number of chromosomes in a single set:
haploid (one set; 1x)
diploid (two sets; 2x)
triploid (three sets; 3x), for example sterile saffron crocus, or seedless watermelons, also common in the phylum Tardigrada
tetraploid (four sets; 4x), for example Salmonidae fish, the cotton Gossypium hirsutum
pentaploid (five sets; 5x), for example Kenai Birch (Betula kenaica)
hexaploid (six sets; 6x), for example some species of wheat, kiwifruit
heptaploid or septaploid (seven sets; 7x)
octaploid or octoploid, (eight sets; 8x), for example Acipenser (genus of sturgeon fish), dahlias
decaploid (ten sets; 10x), for example certain strawberries
dodecaploid or duodecaploid (twelve sets; 12x), for example the plants Celosia argentea and Spartina anglica  or the amphibian Xenopus ruwenzoriensis.

Classification
Autopolyploidy
Autopolyploids are polyploids with multiple chromosome sets derived from a single taxon.
Two examples of natural autopolyploids are the piggyback plant, Tolmiea menzisii and the white sturgeon, Acipenser transmontanum.  Most instances of autopolyploidy result from the fusion of unreduced (2n) gametes, which results in either triploid (n + 2n = 3n) or tetraploid (2n + 2n = 4n) offspring. Triploid offspring are typically sterile (as in the phenomenon of triploid block), but in some cases they may produce high proportions of unreduced gametes and thus aid the formation of tetraploids. This pathway to tetraploidy is referred to as the triploid bridge. Triploids may also persist through asexual reproduction. In fact, stable autotriploidy in plants is often associated with apomictic mating systems. In agricultural systems, autotriploidy can result in seedlessness, as in watermelons and bananas. Triploidy is also utilized in salmon and trout farming to induce sterility.Rarely, autopolyploids arise from spontaneous, somatic genome doubling, which has been observed in apple (Malus domesticus) bud sports. This is also the most common pathway of artificially induced polyploidy, where methods such as protoplast fusion or treatment with colchicine, oryzalin or mitotic inhibitors are used to disrupt normal mitotic division, which results in the production of polyploid cells. This process can be useful in plant breeding, especially when attempting to introgress germplasm across ploidal levels.Autopolyploids possess at least three homologous chromosome sets, which can lead to high rates of multivalent pairing during meiosis (particularly in recently formed autopolyploids, also known as neopolyploids) and an associated decrease in fertility due to the production of aneuploid gametes. Natural or artificial selection for fertility can quickly stabilize meiosis in autopolyploids by restoring bivalent pairing during meiosis, but the high degree of homology among duplicated chromosomes causes autopolyploids to display polysomic inheritance. This trait is often used as a diagnostic criterion to distinguish autopolyploids from allopolyploids, which commonly display disomic inheritance after they progress past the neopolyploid stage. While most polyploid species are unambiguously characterized as either autopolyploid or allopolyploid, these categories represent the ends of a spectrum of divergence between parental subgenomes. Polyploids that fall between these two extremes, which are often referred to as segmental allopolyploids, may display intermediate levels of polysomic inheritance that vary by locus.About half of all polyploids are thought to be the result of autopolyploidy, although many factors make this proportion hard to estimate.

Allopolyploidy
Allopolyploids or amphipolyploids or heteropolyploids  are polyploids with chromosomes derived from two or more diverged taxa.
As in autopolyploidy, this primarily occurs through the fusion of unreduced (2n) gametes, which can take place before or after hybridization. In the former case, unreduced gametes from each diploid taxon – or reduced gametes from two autotetraploid taxa – combine to form allopolyploid offspring. In the latter case, one or more diploid F1 hybrids produce unreduced gametes that fuse to form allopolyploid progeny. Hybridization followed by genome duplication may be a more common path to allopolyploidy because F1 hybrids between taxa often have relatively high rates of unreduced gamete formation – divergence between the genomes of the two taxa result in abnormal pairing between homoeologous chromosomes or nondisjunction during meiosis. In this case, allopolyploidy can actually restore normal, bivalent meiotic pairing by providing each homoeologous chromosome with its own homologue. If divergence between homoeologous chromosomes is even across the two subgenomes, this can theoretically result in rapid restoration of bivalent pairing and disomic inheritance following allopolyploidization. However multivalent pairing is common in many recently formed allopolyploids, so it is likely that the majority of meiotic stabilization occurs gradually through selection.Because pairing between homoeologous chromosomes is rare in established allopolyploids, they may benefit from fixed heterozygosity of homoeologous alleles. In certain cases, such heterozygosity can have beneficial heterotic effects, either in terms of fitness in natural contexts or desirable traits in agricultural contexts. This could partially explain the prevalence of allopolyploidy among crop species. Both bread wheat and Triticale are examples of an allopolyploids with six chromosome sets. Cotton, peanut, or quinoa are allotetraploids with multiple origins. In Brassicaceous crops, the Triangle of U describes the relationships between the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploid species. A similar relationship exists between three diploid species of Tragopogon (T. dubius, T. pratensis, and T. porrifolius) and two allotetraploid species (T. mirus and T. miscellus). Complex patterns of allopolyploid evolution have also been observed in animals, as in the frog genus Xenopus.

Aneuploid
Organisms in which a particular chromosome, or chromosome segment, is under- or over-represented are said to be aneuploid (from the Greek words meaning "not", "good", and "fold"). Aneuploidy refers to a numerical change in part of the chromosome set, whereas polyploidy refers to a numerical change in the whole set of chromosomes.

Endopolyploidy
Polyploidy occurs in some tissues of animals that are otherwise diploid, such as human muscle tissues. This is known as endopolyploidy. Species whose cells do not have nuclei, that is, prokaryotes, may be polyploid, as seen in the large bacterium Epulopiscium fishelsoni. Hence ploidy is defined with respect to a cell.

Monoploid
A monoploid has only one set of chromosomes and the term is usually only applied to cells or organisms that are normally diploid. The more general term for such organisms is haploid.

Temporal terms
Neopolyploidy
A polyploid that is newly formed.

Mesopolyploidy
That has become polyploid in more recent history; it is not as new as a neopolyploid and not as old as a paleopolyploid. It is a middle aged polyploid. Often this refers to whole genome duplication followed by intermediate levels of diploidization.

Paleopolyploidy
Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike the other copy. Over time, it is also common for duplicated copies of genes to accumulate mutations and become inactive pseudogenes.In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include bakers yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes. Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history.

Other similar terms
Karyotype
A karyotype is the characteristic chromosome complement of a eukaryote species. The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics.
Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karyotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases, there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology.

Homoeologous chromosomes
Homoeologous chromosomes are those brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. For example, durum wheat is the result of the inter-species hybridization of two diploid grass species Triticum urartu and Aegilops speltoides. Both diploid ancestors had two sets of 7 chromosomes, which were similar in terms of size and genes contained on them. Durum wheat contains a hybrid genome with two sets of chromosomes derived from Triticum urartu and two sets of chromosomes derived from Aegilops speltoides. Each chromosome pair derived from the Triticum urartu parent is homoeologous to the opposite chromosome pair derived from the Aegilops speltoides parent, though each chromosome pair unto itself is homologous.

Examples
Animals
Examples in animals are more common in non-vertebrates such as flatworms, leeches, and brine shrimp. Within vertebrates, examples of stable polyploidy include the salmonids and many cyprinids (i.e. carp). Some fish have as many as 400 chromosomes. Polyploidy also occurs commonly in amphibians; for example the biomedically important genus Xenopus contains many different species with as many as 12 sets of chromosomes (dodecaploid). Polyploid lizards are also quite common. Most are sterile and reproduce by parthenogenesis; others, like Liolaemus chiliensis, maintain sexual reproduction. Polyploid mole salamanders (mostly triploids) are all female and reproduce by kleptogenesis, "stealing" spermatophores from diploid males of related species to trigger egg development but not incorporating the males DNA into the offspring.
While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death. An octodontid rodent of Argentinas harsh desert regions, known as the plains viscacha rat (Tympanoctomys barrerae) has been reported as an exception to this rule. However, careful analysis using chromosome paints shows that there are only two copies of each chromosome in T. barrerae, not the four expected if it were truly a tetraploid. This rodent is not a rat, but kin to guinea pigs and chinchillas. Its "new" diploid (2n) number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n = 56. It was therefore surmised that an Octomys-like ancestor produced tetraploid (i.e., 2n = 4x = 112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents.
Polyploidy was induced in fish by Har Swarup (1956) using a cold-shock treatment of the eggs close to the time of fertilization, which produced triploid embryos that successfully matured. Cold or heat shock has also been shown to result in unreduced amphibian gametes, though this occurs more commonly in eggs than in sperm. John Gurdon (1958) transplanted intact nuclei from somatic cells to produce diploid eggs in the frog, Xenopus (an extension of the work of Briggs and King in 1952) that were able to develop to the tadpole stage. The British scientist J. B. S. Haldane hailed the work for its potential medical applications and, in describing the results, became one of the first to use the word "clone" in reference to animals. Later work by Shinya Yamanaka showed how mature cells can be reprogrammed to become pluripotent, extending the possibilities to non-stem cells. Gurdon and Yamanaka were jointly awarded the Nobel Prize in 2012 for this work.

Humans
True polyploidy rarely occurs in humans, although polyploid cells occur in highly differentiated tissue, such as liver parenchyma, heart muscle, placenta and in bone marrow. Aneuploidy is more common.
Polyploidy occurs in humans in the form of triploidy, with 69 chromosomes (sometimes called 69, XXX), and tetraploidy with 92 chromosomes (sometimes called 92, XXXX). Triploidy, usually due to polyspermy, occurs in about 2–3% of all human pregnancies and ~15% of miscarriages. The vast majority of triploid conceptions end as a miscarriage; those that do survive to term typically die shortly after birth. In some cases, survival past birth may be extended if there is mixoploidy with both a diploid and a triploid cell population present. There has been one report of a child surviving to the age of seven months with complete triploidy syndrome. He failed to exhibit normal mental or physical neonatal development, and died from a Pneumocystis carinii infection, which indicates a weak immune system.Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is mostly caused by reduplication of the paternal haploid set from a single sperm, but may also be the consequence of dispermic (two sperm) fertilization of the egg. Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages, while digyny predominates among triploid zygotes that survive into the fetal period. However, among early miscarriages, digyny is also more common in those cases less than 8+1⁄2 weeks gestational age or those in which an embryo is present. There are also two distinct phenotypes in triploid placentas and fetuses that are dependent on the origin of the extra haploid set. In digyny, there is typically an asymmetric poorly grown fetus, with marked adrenal hypoplasia and a very small placenta. In diandry, a partial hydatidiform mole develops. These parent-of-origin effects reflect the effects of genomic imprinting.Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1–2% of early miscarriages. However, some tetraploid cells are commonly found in chromosome analysis at prenatal diagnosis and these are generally considered harmless. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism.
Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells.

Fish
A polyploidy event occurred within the stem lineage of the teleost fish.

Plants
Polyploidy is frequent in plants, some estimates suggesting that 30–80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes. Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species. It has been established that 15% of angiosperm and 31% of fern speciation events are accompanied by ploidy increase.Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes. Both autopolyploids (e.g. potato) and allopolyploids (such as canola, wheat and cotton) can be found among both wild and domesticated plant species.
Most polyploids display novel variation or morphologies relative to their parental species, that may contribute to the processes of speciation and eco-niche exploitation. The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels. Many of these rapid changes may contribute to reproductive isolation and speciation. However seed generated from interploidy crosses, such as between polyploids and their parent species, usually have aberrant endosperm development which impairs their viability, thus contributing to polyploid speciation.
Some plants are triploid. As meiosis is disturbed, these plants are sterile, with all plants having the same genetic constitution: Among them, the exclusively vegetatively propagated saffron crocus (Crocus sativus). Also, the extremely rare Tasmanian shrub Lomatia tasmanica is a triploid sterile species.
There are few naturally occurring polyploid conifers. One example is the Coast Redwood Sequoia sempervirens, which is a hexaploid (6x) with 66 chromosomes (2n = 6x = 66), although the origin is unclear.Aquatic plants, especially the Monocotyledons, include a large number of polyploids.

Crops
The induction of polyploidy is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.
In some situations, polyploid crops are preferred because they are sterile. For example, many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques, such as grafting.
Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine.

Examples
Triploid crops: some apple varieties (such as Belle de Boskoop, Jonagold, Mutsu, Ribston Pippin), banana, citrus, ginger, watermelon, saffron crocus, white pulp of coconut
Tetraploid crops: very few apple varieties, durum or macaroni wheat, cotton, potato, canola/rapeseed, leek, tobacco, peanut, kinnow, Pelargonium
Hexaploid crops: chrysanthemum, bread wheat, triticale, oat, kiwifruit
Octaploid crops: strawberry, dahlia, pansies, sugar cane, oca (Oxalis tuberosa)
Dodecaploid crops: some sugar cane hybridsSome crops are found in a variety of ploidies: tulips and lilies are commonly found as both diploid and triploid; daylilies (Hemerocallis cultivars) are available as either diploid or tetraploid; apples and kinnow mandarins can be diploid, triploid, or tetraploid.

Fungi
Besides plants and animals, the evolutionary history of various fungal species is dotted by past and recent whole-genome duplication events (see Albertin and Marullo 2012 for review). Several examples of polyploids are known:

autopolyploid: the aquatic fungi of genus Allomyces, some Saccharomyces cerevisiae strains used in bakery, etc.
allopolyploid: the widespread Cyathus stercoreus, the allotetraploid lager yeast Saccharomyces pastorianus, the allotriploid wine spoilage yeast Dekkera bruxellensis, etc.
paleopolyploid: the human pathogen Rhizopus oryzae, the genus Saccharomyces, etc.In addition, polyploidy is frequently associated with hybridization and reticulate evolution that appear to be highly prevalent in several fungal taxa. Indeed, homoploid speciation (hybrid speciation without a change in chromosome number) has been evidenced for some fungal species (such as the basidiomycota Microbotryum violaceum).

As for plants and animals, fungal hybrids and polyploids display structural and functional modifications compared to their progenitors and diploid counterparts. In particular, the structural and functional outcomes of polyploid Saccharomyces genomes strikingly reflect the evolutionary fate of plant polyploid ones. Large chromosomal rearrangements leading to chimeric chromosomes have been described, as well as more punctual genetic modifications such as gene loss. The homoealleles of the allotetraploid yeast S. pastorianus show unequal contribution to the transcriptome. Phenotypic diversification is also observed following polyploidization and/or hybridization in fungi, producing the fuel for natural selection and subsequent adaptation and speciation.

Chromalveolata
Other eukaryotic taxa have experienced one or more polyploidization events during their evolutionary history (see Albertin and Marullo, 2012 for review). The oomycetes, which are non-true fungi members, contain several examples of paleopolyploid and polyploid species, such as within the genus Phytophthora </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 Crush injury and can you explain it in depth? [/INST] A crush injury is injury by an object that causes compression of the body. This form of injury is rare in normal civilian practice, but common following a natural disaster. Other causes include industrial accidents, road traffic collisions, building collapse, accidents involving heavy plant, disaster relief or terrorist incidents.

Presentation
Complications
Hypovolaemic Shock. Loss of plasma volume across damaged cell membranes and capillary walls can lead directly to severe hypovolaemia. Furthermore, shock can develop from myocardial depression following release of intracellular electrolytes. In addition, as a result of the mechanism of injury, blood loss from pelvic or long bone fractures may also co-exist.
Hyperkalaemia and electrolyte imbalance. Disruption of cell membranes can result in a significant release of potassium, which is a largely intracellular cation that can precipitate cardiac arrest. Sequestration of plasma calcium into injured tissue can lead to a relative hypocalcaemia, which may worsen disruption of clotting abilities and shock. Metabolic acidosis may result from reperfusion injury and hypoperfusion related to shock.
Compartment syndrome. Compartment syndrome is a common complication of crush injury as a consequence of oedematous tissue injury, redistribution of fluid into the intracellular compartment and bleeding. Established compartment syndrome may result in worsened systemic crush syndrome and irreversible muscle cell death.
Acute Kidney Injury. Release of myoglobin by injured muscle leads to rhabdomyolysis coupled with shock leads to a significant rate of acute kidney injury, estimated as up to 15% </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 Functional constipation 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 Reynolds syndrome and can you explain it in depth? [/INST] Reynolds syndrome is a rare secondary laminopathy, consisting of the combination of primary biliary cirrhosis and progressive systemic sclerosis.  In some patients this syndrome has also been associated with Sjögrens syndrome and hemolytic anemia.  Typical clinical features include jaundice, elevated blood levels of alkaline phosphatase, calcinosis cutis, telangiectasias, and pruritus. This disease may cause white or yellow-ish spots on the arms or legs. The syndrome, a special case of scleroderma, is named after the American physician, Telfer B. Reynolds, MD (1921–2004), who first described it.  He is also known for creating one of the worlds first hepatology programs at the University of Southern California.
It should not be confused with the more common Raynauds phenomenon.

References

T. B. Reynolds, E. K </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 Lysinuric protein intolerance and can you explain it in depth? [/INST] Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport.
About 140 patients have been reported, almost half of them of Finnish origin. Individuals from Japan, Italy, Morocco and North Africa have also been reported plus one in Bixby, Oklahoma.

Signs and symptoms
Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning </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 Delta-aminolevulinic acid dehydratase and can you explain it in depth? [/INST] Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme (EC 4.2.1.24) that in humans is encoded by the ALAD gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. Porphobilinogen synthase is the prototype morpheein.

Function
It catalyzes the following reaction, the second step of the biosynthesis of porphyrin:

2 5-Aminolevulinic acid

        ⇌

    {\displaystyle \rightleftharpoons }
   porphobilinogen + 2 H2OIt therefore catalyzes the condensation of 2 molecules of 5-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). This reaction is the first common step in the biosynthesis of all biological tetrapyrroles. Zinc is essential for enzymatic activity.

Structure
The structural basis for allosteric regulation of Porphobilinogen synthase (PBGS) is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 6mer* ↔ 2mer* ↔ 2mer ↔ 8mer.  The * represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers.

PBGS is encoded by a single gene and each PBGS multimer is composed of multiple copies of the same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzymes active site in its center, and a >25 residue N-terminal arm domain.  Allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain.
Each N-terminal arm has up to two interactions with other subunits in a PBGS multimer </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 Dental fluorosis and can you explain it in depth? [/INST] Dental fluorosis is a common disorder, characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation.It appears as a range of visual changes in enamel causing degrees of intrinsic tooth discoloration, and, in some cases, physical damage to the teeth. The severity of the condition is dependent on the dose, duration, and age of the individual during the exposure. The "very mild" (and most common) form of fluorosis, is characterized by small, opaque, "paper white" areas scattered irregularly over the tooth, covering less than 25% of the tooth surface.  In the "mild" form of the disease, these mottled patches can involve up to half of the surface area of the teeth.  When fluorosis is moderate, all of the surfaces of the teeth are mottled and teeth may be ground down and brown stains frequently "disfigure" the teeth.  Severe fluorosis is characterized by brown discoloration and discrete or confluent pitting; brown stains are widespread and teeth often present a corroded-looking appearance.People with fluorosis are relatively resistant to dental caries (tooth decay caused by bacteria), although there may be cosmetic concern. In moderate to severe fluorosis, teeth are weakened and suffer permanent physical damage.

Diagnosis
The adequate diagnosis of fluorosis can be diagnosed by visual clinical examination. This requires inspection of dry and clean tooth surfaces under a good lighting. There are individual variations in clinical fluorosis manifestation which are highly dependent on the duration, timing, and dosage of fluoride exposure.There are different classifications to diagnose the severity based on the appearances. The clinical manifestation of mild dental fluorosis is mostly characterised a snow flaking appearance that lack a clear border, opaque, white spots, narrow white lines following the perikymata or patches as the opacities may coalesce with an intact, hard and smooth enamel surface on most of the teeth. With increasing severity, the subsurface enamel, all along the tooth becomes more porous. Enamel may appear yellow/ brown discolouration and/ or many and pitted white-brown lesions that look like cavities. They are often described as "mottled teeth". Fluorosis does not cause discolouration to the enamel directly, as upon eruption into the mouth, affected permanent teeth are not discoloured yet. In dental enamel, fluorosis causes subsurface porosity or hypomineralizations, which extend toward the dentinal-enamel junction as the condition progresses and the affected teeth become more susceptible to staining. Due to diffusion of exogenous ions (e.g., iron and copper), stains develop into the increasingly and abnormally porous enamel.
The differential diagnosis for this condition includes:

Turners hypoplasia (although this is usually more localized)
Enamel defects caused by an undiagnosed and untreated celiac disease.
Some mild forms of amelogenesis imperfecta and enamel hypoplasia
Enamel defects caused by infection of a primary tooth predecessor
Dental caries: Fluorosis-resembling enamel defects are often misdiagnosed as dental caries.
Dental trauma: Mechanical trauma to the primary tooth may cause disturbance to the maturation phase of enamel formation, which may result in enamel opacities on the permanent successors.

Classification
The two main classification systems are described below. Others include the tooth surface fluorosis index (Horowitz et al. 1984), which combines Deans index and the TF index; and the fluorosis risk index (Pendrys 1990), which is intended to define the time at which fluoride exposure occurs, and relates fluorosis risk with tooth development stage.

Deans index
Deans fluorosis index was first published in 1934 by H. Trendley Dean. The index underwent two changes, appearing in its final form in 1942. An individuals fluorosis score is based on the most severe form of fluorosis found on two or more teeth.

TF index
Proposed by Thylstrup and Fejerskov in 1978, the TF index represents a logical extension of Deans index, incorporating modern understanding of the underlying pathology of fluorosis. It scores the spectrum of fluorotic changes in enamel from 0 to 9, allowing more precise definition of mild and severe cases.

Causes
Dental fluorosis is caused by a higher than normal amount of fluoride ingestion whilst teeth are forming. Primary dentine fluorosis and enamel fluorosis can only happen during tooth formation, so fluoride exposure occurs in childhood. Enamel fluorosis has a white opaque appearance which is due to the surface of the enamel being hypomineralised.The most superficial concern in dental fluorosis is aesthetic changes in the permanent dentition (the adult teeth). The period when these teeth are at highest risk of developing fluorosis is between when the child is born up to 6 years old, though there has been some research which proposes that the most crucial course is during the first 2 years of the childs life. From roughly 7 years old thereafter, most childrens permanent teeth would have undergone complete development (except their wisdom teeth), and therefore their susceptibility to fluorosis is greatly reduced, or even insignificant, despite the amount of intake of fluoride. The severity of dental fluorosis depends on the amount of fluoride exposure, the age of the child, individual response, weight, degree of physical activity, nutrition, and bone growth. Individual susceptibility to fluorosis is also influenced by genetic factors.Many well-known sources of fluoride may contribute to overexposure including dentifrice/fluoridated mouthrinse (which young children may swallow), excessive ingestion of fluoride toothpaste, bottled waters which are not tested for their fluoride content, inappropriate use of fluoride supplements, ingestion of foods especially imported from other countries, and public water fluoridation. The last of these sources is directly or indirectly responsible for 40% of all fluorosis, but the resulting effect due to water fluoridation is largely and typically aesthetic. Severe cases can be caused by exposure to water that is naturally fluoridated to levels above the recommended levels, or by exposure to other fluoride sources such as brick tea or pollution from high fluoride coal.Dental fluorosis has been growing in the United States concurrent with fluoridation of municipal water supplies, although disproportionately by race. A 2010 CDC report acknowledges an overall incidence of dental fluorosis of 22% from 1986-87 increased to 41% in the early 21st century, with an increase in moderate to severe dental fluorosis from 1% to 4%. The 2011-12 NHANES figures documented another 31% overall increase among American teens since the previous decade, with a total adolescent population impact of 61% afflicted. More than one in five American teens (23%) have moderate to severe dental fluorosis on at least two teeth.

Mechanism
Teeth are the most studied body tissues to examine the impact of fluoride to human health. There are a few possible mechanisms that have been proposed. It is generally believed that the hypomineralization of affected enamel is mainly due to in-situ toxic effects of the fluoride on the ameloblasts in the enamel formation, and not caused by the general effects of fluoride on the calcium metabolism, or by the poisoning effects that suppress the fluoride metabolism. However, despite decades of research and studies, there have yet to be any studies that substantiates the believed mechanism whereby dental fluorosis is a result of alteration in the mineralisation that takes place when fluoride interacts with mineralising tissues.In the extra-cellular environment of maturing enamel, an excess of fluoride ions alters the rate at which enamel matrix proteins (amelogenin) are enzymatically broken down and the rate at which the subsequent breakdown products are removed. Fluoride may also indirectly alter the action of protease via a decrease in the availability of free calcium ions in the mineralization environment. This results in the formation of enamel with less mineralization. This hypomineralized enamel has altered optical properties and appears opaque and lusterless relative to normal enamel.Traditionally severe fluorosis has been described as enamel hypoplasia, however, hypoplasia does not occur as a result of fluorosis. The pits, bands, and loss of areas of enamel seen in severe fluorosis are the result of damage to the severely hypomineralized, brittle and fragile enamel which occurs after they erupt into the mouth.Hydroxyapatite is converted to fluoroapatite in a three step process.  Dental fluorosis can be prevented at a population level through defluoridation. It is the downward adjustment of the level of fluoride in drinking water.

Management
Dental fluorosis may or may not be of cosmetic concern. In some cases, there may be varying degrees of negative psychosocial effects. The treatment options are:

Mild cases: Tooth bleaching
Moderate cases: Enamel microabrasion (outer affected layer of enamel is abraded in an acidic environment)
Severe cases: Composite fillings, Micro-abrasion, Veneers, Crowns

Epidemiology
Fluorosis is extremely common, with 41% of adolescents having definite fluorosis, and another 20% "questionably" having fluorosis according to the Centers for Disease Control.
As of 2005 surveys conducted by the National Institute of Dental and Craniofacial Research in the USA between 1986 and 1987 and by the Center of Disease Control between 1999 and 2004 are the only national sources of data concerning the prevalence of dental fluorosis.  Before the 1999-2004 study was published, CDC published an interim report covering data from 1999 to 2002.
The U.S. Centers for Disease Control found a 9 percentage point increase in the prevalence of confirmed dental fluorosis in a 1999-2002 study of American children and adolescents than was found in a similar survey from 1986-1987 (from 22.8% in 1986-1987 to 32% in 1999-2002). In addition, the survey provides further evidence that African Americans suffer from higher rates of fluorosis than Caucasian Americans.
The condition is more prevalent in rural areas where drinking water is derived from shallow wells or hand pumps. It is also more likely to occur in areas where the drinking water has a fluoride content greater than 1 ppm (part per million).

If the water supply is fluoridated at the level of 1 ppm, one must consume one litre of water in order to take in 1 mg of fluoride. It is thus improbable a person will receive more than the tolerable upper limit from consuming optimally fluoridated water alone.
Fluoride consumption can exceed the tolerable upper limit when someone drinks a lot of fluoride-containing water in combination with other fluoride sources, such as swallowing fluoridated toothpaste, consuming food with a high fluoride content, or consuming fluoride supplements. The use of fluoride supplements as a prevention for tooth decay is rare in areas with water fluoridation, but was recommended by many dentists in the UK until the early 1990s.
In November 2006 the American Dental Association published information stating that water fluoridation is safe, effective and healthy; that enamel fluorosis, usually mild and difficult for anyone except a dental health care professional to see, can result from ingesting more than optimal amounts of fluoride in early childhood;  that it is safe to use fluoridated water to mix infant formula; and that the probability of babies developing fluorosis can be reduced by using ready-to-feed infant formula or using water that is either free of fluoride or low in fluoride to prepare  powdered or liquid concentrate formula. They go on to say that the way to get the benefits of fluoride but minimize the risk of fluorosis for a child is to get the right amount of fluoride, not too much and not too little. "Your dentist, pediatrician or family physician can help you determine how to optimize your childs fluoride intake."

Prevention
Dental fluorosis can be prevented by lowering the amount of fluoride intake to below the tolerable upper limit. This can be achieved by consuming de-fluorinated water and improving the general nutritional status of the people.

History
In ancient times, Galen describes what is thought to be dental fluorosis </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 Dermatopathia pigmentosa reticularis and can you explain it in depth? [/INST] Dermatopathia pigmentosa reticularis (DPR) is a rare, autosomal dominant congenital disorder that is a form of ectodermal dysplasia.  Dermatopathia pigmentosa reticularis is composed of the triad of generalized reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy.: 856  DPR is a non life-threatening disease that largely affects the skin, hair, and nails.  It has also been identified as a keratin disorder. Historically, as of 1992, only 10 cases had been described in world literature; however, due to recent advances in genetic analysis, five additional families studied in 2006 have been added to the short list of confirmed cases.

Signs and Symptoms (Presentation)
Symptoms include lack of sweat glands, thin hair, brittle nails, mottled skin, and lack of fingerprints. It is also characterized by a widespread, early-onset reticulate hyperpigmentation. Those affected may also have adermatoglyphia, abnormal epithelial differentiation, palmoplantar hyperkeratosis of the palms and soles, acral dorsal blistering, as well as hypohidrosis or hyperhidrosis.DPR is very similar to the related Naegeli-Franceschetti-Jadassohn syndrome (NFJS). Both cause an affected person to lack fingerprints, as well as present a lace-like pattern of hyperpigmentation and hyperkeratosis of the palms of the hands and soles of the feet. DPR is distinguished from NFJS by the duration of hyperpigmentation and lack of dental abnormalities. Since these differences are very slight and relatively minimal, researchers recommend that NFJS and DPR be considered a single disorder.

Molecular Genetics
The disease interval for DPR was found to harbor 230 genes associated with the condition. DPR and NFJS syndromes were specifically found to be differentiated from other syndromes by a mutation of the keratin 14 gene, located on chromosome 17q21.2. This was found when keratin genes KRT14, KRT16, and KRT17 were reassessed in 2006, revealing pathogenic mutations of KRT14 in all patients with NFJS/DPR, displaying a strong correlation and suggesting a potential causation. The type of mutations observed were heterozygous nonsense or frameshift mutations, meaning the function of the gene was completely disrupted (missense is correlated with EBS). The different phenotypic presentations of recessive (EBS-causing) versus dominant (NFJS/DPR-causing) premature truncation mutations in KRT14 are still unclear. The NFJS/DPR mutations were verified using two screening approaches, in which it was found that 17delG was absent from a panel of 100 control individuals, and C18X and Q7X were found to create a novel recognition site for the endonucleases DdeI and BfaI. Because the mutations were found to be heterozygous, the condition was concluded to be autosomal dominant in its inheritance pattern.Interestingly, a study conducted on five families using a two-point linkage analysis of the combined genotyping data for three families across the NFJS/DPR candidate region generated an LOD score of 6.2 at marker D17S800, with a recombination score of 0. Further analysis revealed that NFJS may be caused by an identical founder mutation located within a 6-Mb interval between D17S946 and D17S2180 </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 Endolymphatic hydrops and can you explain it in depth? [/INST] Endolymphatic hydrops is a disorder of the inner ear </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 Wrist osteoarthritis and can you explain it in depth? [/INST] Wrist osteoarthritis is a group of mechanical abnormalities resulting in joint destruction, which can occur in the wrist. These abnormalities include degeneration of cartilage and hypertrophic bone changes, which can lead to pain, swelling and loss of function. Osteoarthritis of the wrist is one of the most common conditions seen by hand surgeons.Osteoarthritis of the wrist can be idiopathic, but it is mostly seen as a post-traumatic condition. There are different types of post-traumatic osteoarthritis. Scapholunate advanced collapse (SLAC) is the most common form, followed by scaphoid non-union advanced collapse (SNAC).  Other post-traumatic causes such as intra-articular fractures of the distal radius or ulna can also lead to wrist osteoarthritis, but are less common.

Types
SLAC and SNAC are two patterns of wrist osteoarthritis, following predictable patterns depending on the type of underlying injury. SLAC is caused by scapholunate ligament rupture, and SNAC is caused by a scaphoid fracture which does not heal and because of that will develop in a non-union fracture. SLAC is more common than SNAC; 55% of the patients with wrist osteoarthritis has a SLAC wrist.

SLAC
Scapholunate advanced collapse (SLAC) is a predictable pattern of wrist osteoarthritis that results from untreated long-standing scapholunate instability, which in turn is secondary to a rupture of the scapholunate ligament. The main type of such misalignment is dorsal intercalated segment instability (DISI) which is where the lunate angulates to the posterior side of the hand.

SNAC
Scaphoid non-union fractures changes scaphoid bone shape, which leads to abnormal joint kinematics. Due to lack of stability from the distorted scaphoid, a DISI can be developed.
Scaphoid Non-union Advanced collapse (SNAC) is the pattern of osteoarthritis that eventually develops by this process.

Stages
Post-traumatic osteoarthritis can be classified into four stages. These stages are similar between SLAC and SNAC wrists. Each stage has a different treatment.

Stage I: the osteoarthritis is only localized in the distal scaphoid and radial styloid.
Stage II: the osteoarthritis is localized in the entire radioscaphoid joint.
Stage III: the osteoarthritis is localized in the entire radioscaphoid joint with involvement of the capitolunate joint.
Stage IV: the osteoarthritis is located in the entire radiocarpal joint and in the intercarpal joints. It also may involve the distal radio-ulnar joint (DRUJ).

Signs and symptoms
The most common initial symptom of wrist osteoarthritis is joint pain. The pain is brought on by activity and increases when there is activity after resting. Other signs and symptoms, as with any joint affected by osteoarthritis, include:

Morning stiffness, which usually lasts less than 30 minutes. This is also present in patients with rheumatoid arthritis, but in those patients this typically lasts for more than 45 minutes.
Swelling of the wrist.
Crepitus (crackling), which is felt when the hand is moved passively.
Joint locking, where the joint is fixed in an extended position.
Joint instability.These symptoms can lead to loss of function and less daily activity.

Mechanism
In order to understand the cause of post-traumatic wrist osteoarthritis it is important to know and understand the anatomy of the wrist. The hand is subdivided into three parts:
Wrist
Metacarpus
DigitsThe wrist consists of eight small carpal bones. Each of these carpal bones has a different size and shape. They contribute towards the stability of the wrist and are ranked in two rows, each consisting of four bones.

Proximal row
From lateral to medial and when viewed from anterior, the proximal row is formed by the:
Scaphoid
Lunate
Triquetral
Pisiform

Distal row
From lateral to medial and when viewed from anterior, the distal row is formed by the:

Trapezium
Trapezoid
Capitate
Hamate

Diagnosis
Osteoarthritis of the wrist is predominantly a clinical diagnosis, and thus is primarily based on the patients medical history, physical examination and wrist X-rays.

Medical history
Medical history of the patient should include age, hand dominance, occupation and most important an evaluation of recent hand traumas.

Physical examination
Examination will often show tenderness at the radioscaphoid joint (when palpated or while moving the radioscaphoid joint), dorsal radial swelling and instability of the wrist joint. Notice that people may say they have trouble with rising from a chair when pressure is exerted on the hands by pushing against the handrail. Younger people may complain about not being able to do push-ups anymore because of a painful hand.

There are a number of tests and actions that can be performed when a patient is suspected of having osteoarthritis caused by SLAC or SNAC.SLAC:

Tenderness 1 cm above Lister’s tubercleTests:

Watsons test
Finger extension testSNAC:

Tenderness at the anatomical snuff box
Painful pronation and supination when performed against resistance
Pain during axial pressure

X-rays
Osteoarthritis between the radius bone and the carpals is indicated by a radiocarpal joint space of less than 2mm.SLAC

Because SLAC results from scapholunate ligament rupture, there is a larger space between the two bones, also known as the Terry Thomas sign. Osteoarthritis and a space larger than 3 mm is suspicious and a space larger than 5 mm is a proven SLAC pathology. Scaphoid instability due to the ligament rupture can be stactic or dynamic. When the X-ray is diagnostic and there is a convincing Terry Thomas sign it is a static scaphoid instability. When the scaphoid is made unstable by either the patient or by manipulation by the examining physician it is a dynamic instability.SNAC
In order to diagnose a SNAC wrist you need a PA view X-ray and a lateral view X-ray. As in SLAC, the lateral view X-ray is performed to see if there is a DISI.Computed tomography (CT) or Magnetic Resonance Imaging (MRI) are rarely used to diagnose SNAC or SLAC wrist osteoarthritis because there is no additional value. Also, these techniques are much more expensive than a standard X-ray. CT or MRI may be used if there is a strong suspicion for another underlying pathology or disease.

Treatment
Post-traumatic wrist osteoarthritis can be treated conservatively or with a surgical intervention. In many patients, a conservative (non-surgical) approach is sufficient. Because osteoarthritis is progressive and symptoms may get worse, surgical treatment is advised in any stage.

Stage I
For stage I, normally, nonsurgical treatment is sufficient. This type of therapy includes the use of splint or cast immobilization, injections of corticosteroid in the pain causing joints and the use of a systemic non-steroidal anti-inflammatory drug to reduce pain and improve the functional use of the affected joint. However, the amount of pain that can be suppressed by nonsurgical therapy is limited and with the progression of the wrist osteoarthritis surgical treatment is inevitable.In stage I surgical treatment often consists of neurectomy of the posterior interosseous nerve and is often combined with other procedures. In the case of a SLAC, the scapholunate ligament can be reconstructed in combination with a radial styloidectomy, in which the radial styloid is surgically removed from the distal radius. In the case of a SNAC, the scaphoid can be reconstructed by fixating the scaphoid with a screw or by placing a bone graft (Matti-Russe procedure) to increase the stability of the scaphoid.

Stage II
In the treatment of stage II wrist osteoarthritis, there are two treatment options that have proved to be most successful.
The first treatment option is proximal row carpectomy. During this surgical intervention the proximal row of the carpal bones is removed (scaphoid, lunate, triquetrum, pisiform). It is important that the radioscaphocapitate ligament is left intact, because if the ligament is not preserved the capitate bone will translate to the ulnar side of the wrist and move away from the distal radius. The new formed joint between the capitate and the lunate fossa of the distal radius is not as congruent as the former scaphoid-lunate-radius joint, however the results of proximal row carpectomy are generally excellent. In patients older than 40 years proximal row carpectomy is preferred because these patients have a small chance of developing osteoarthritis in the new formed capitate-radial joint during their remaining life.Patients younger than 40 years have a big chance to develop osteoarthritis in the radiocapitate joint. These patients have longer to live, therefore the incongruence of the joint will exist for a longer time. Thus, in this patient population four-corner arthrodesis is the treatment of first choice. The capitate, lunate, hamate and triquetrum are bounded together in this procedure and the scaphoid is excised. Before the arthrodesis is executed, the lunate must be reduced out of DISI position. Because the radiolunate joint is typically preserved in stage II SLAC and SNAC wrists, this joint can be the only remaining joint of the proximal wrist.
Both procedures are often combined with wrist denervation, as described in the text of treatment stage I.

Stage III
The only treatment option for stage III wrist osteoarthritis is four-corner arthrodesis, as described above in stage II. Proximal row carpectomy is not an option, because in stage III patients the capitate is already affected by the osteoarthritis. So, this procedure would merely lead to a new painful joint.

Stage IV
In this stage there are two surgical treatment options; total wrist arthroplasty and total wrist arthrodesis.
Total wrist arthrodesis has become the standard surgical treatment for patients with stage IV wrist osteoarthritis </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 Fabry disease and can you explain it in depth? [/INST] Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin.  Fabry disease is one of a group of conditions known as lysosomal storage diseases.  The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids, leading to these substances building up in the walls of blood vessels and other organs.  It is  inherited in an X-linked manner.
Fabry disease is sometimes diagnosed using a blood test that measures the activity of the affected enzyme called alpha-galactosidase, but genetic testing is also sometimes used, particularly in females.
The treatment for Fabry disease varies depending on the organs affected by the condition, and the underlying cause can be addressed by replacing the enzyme that is lacking.
The first descriptions of the condition were made simultaneously by  dermatologist Johannes Fabry and the surgeon William Anderson in 1898.

Signs and symptoms
Symptoms are typically first experienced in early childhood and can be very difficult to diagnose; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.

Pain
Full-body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI-tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract, which obstructs blood flow and causes pain.

Kidney
Kidney complications are common and serious effects of the disease; chronic kidney disease and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life, and is a common cause of death due to the disease.

Heart
Fabry disease can affect the heart in several ways.  The accumulation of sphingolipids within heart muscle cells causes abnormal thickening of the heart muscle or hypertrophy.  This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a restrictive cardiomyopathy causing shortness of breath.Fabry disease can also affect the way in which the heart conducts electrical impulses, leading to both abnormally slow heart rhythms such as complete heart block, and abnormally rapid heart rhythms such as ventricular tachycardia.  These abnormal heart rhythms can cause blackouts, palpitations, or even sudden cardiac death.Sphingolipids can also build up within the heart valves, thickening the valves and affecting the way they open and close.  If severe, this can cause the valves to leak (regurgitation) or to restrict the forward flow of blood (stenosis).  The aortic and mitral valves are more commonly affected than the valves on the right side of the heart.

Skin
Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the navel, buttocks, lower abdomen, and groin) are common.Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).Additionally, patients can exhibit Raynauds disease-like symptoms with neuropathy (in particular, burning extremity pain).Ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic patients, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision.Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataract. Visual reduction from these manifestations is uncommon.

Other manifestations
Fatigue, neuropathy (in particular, burning extremity pain, red hands and feet on and off), cerebrovascular effects leading to an increased risk of stroke - early strokes, mostly vertebrobasilar system tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.

Causes
Fabry disease is caused by a DNA sequence (gene) that is not functioning as it should. A person who inherits this gene does not have enough of a functioning enzyme known as alpha-galactosidase A. The lack of alpha-galactosidase  leads to Fabry disease. A deficiency of alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper functions.At least 443 disease-causing mutations in the GLA gene have been discovered. The DNA mutations that cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all non-intersex males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms.  Research suggests many women experience severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure.  This variability is thought to be due to X-inactivation patterns during embryonic development of the female.

Mechanism
Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. This enzyme deficiency is a result of an accumulation of glycosphingolipids found in the lysosomes and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis. In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients. Fabry disease is X-linked and manifests mostly in homozygous males but also in heterozygous females. Cardiac involvement is recurrent in Fabry patients. Patients have developed hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Deficient activity of lysosomal alpha-galactosidase results in progressive accumulation of globotriaosylceramide (GL-3) within lysosomes, that is believed to trigger a cascade of cellular events. The demonstration of marked alpha-galactosidase deficiency is the conclusive method for the diagnosis in homozygous males. It may be detected in heterozygotous females, but it is often inconclusive due to random X-chromosomal inactivation, so molecular testing (genotyping) of females is mandatory.

Diagnosis
Fabry disease is suspected based on the individuals clinical presentation, and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity.  An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members.  Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease. All immediate and extended family members in the same family have the same family mutation, so if one member of a family has a DNA sequence analysis performed, other members of the family can be diagnosed by performing a targeted sequence analysis instead of testing the entire gene. Targeted sequencing is quicker and less expensive to perform. One study reported that for every first diagnosis in a family, on average five more family members (immediate and extended) are also diagnosed.MRI is accurate in accessing left ventricular mass and thickness and hypertrophy. Late gadolinium enhancement shows increased signal of the midwall at the inferolateral wall of the base of the left ventricle, usually in the non-hypertrophic ventricle. T1-weighted imaging can show low T1 signal due to sphingolipid storage in the heart even without ventricular hypertrophy in 40% of the those affected by the disease. Thus, MRI is a useful way of diagnosing the disease early. T2 signal is increased in inflammation and oedema.

Treatment
The treatments available for Fabry disease can be divided into therapies that aim to correct the underlying problem of decreased activity of the alpha galactosidase A enzyme and thereby reduce the risk of organ damage, and therapies to improve symptoms and life expectancy once organ damage has already occurred.

Therapies targeting enzyme activity
Enzyme replacement therapy is designed to provide the enzyme the patient is missing as a result of a genetic malfunction. This treatment is not a cure, but can partially prevent disease progression, and potentially reverse some symptoms. As of March 2022, two medical drugs based on enzyme replacement therapy are available for Fabry disease:
Agalsidase alfa, sold under the brand name Replagal by the company Takeda (since its acquisition of the company Shire), is a recombinant form of alpha-galactosidase A It received approval in the EU in 2001. FDA approval was applied for the United States.  However, Shire withdrew their application for approval in the United States in 2012, citing that the agency will require additional clinical trials before approval. As of March 2022, Replagal has not received FDA approval.
Agalsidase beta, sold under the brand name Fabrazyme by the company Sanofi Genzyme, is another recombinant form of alpha-galactosidase. Like replagal, it received approval in the EU in 2001. In 2003, it was the first treatment for Fabry disease to be approved by the FDA.Clinically, the two treatments are generally similar in effectiveness and safety, however they have never been compared directly in a randomized trial. Both are given by intravenous infusion every two weeks. They are available in Europe and in many other parts of the world, but treatment costs remain very high.Pharmacological chaperone therapy is another strategy to maintain enzyme activity. It does so by assisting correct folding of alpha-galactosidase despite the mutations that cause Fabry disease. As of March 2022, one medical drug based on pharmacological chaperone therapy is available for Fabry disease:
Migalastat, sold under the brand name Galafold by the company Amicus Therapeutics, is a pharmacological chaperone that can stabilize many mutant forms of alpha-galactosidase. It is taken by mouth. In a randomized trial comparing Migalastat with enzyme replacement therapy, the efficacy and safety of both treatments were similar. The US Food and Drug Administration (FDA) granted Galafold orphan drug status in 2004, and the European Commission followed in 2006. The European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP) granted the drug a marketing approval under the name Galafold in May 2016. FDA approval followed in 2018.
Experimental therapies that are currently not approved for treatment as of March 2022 include the following:
A gene therapy treatment that is in early-phase clinical trials, with the technology licensed to AvroBio.
Plant-based ERT (pegunigalsidase alfa) under development by the company Protalix
The substrate reduction therapy Venglustat (Ibiglustat) under development by Sanofi-Genzyme
Bio-better ERT (CDX-6311) under pre-clinical development by the company Codexis
A gene therapy (ST-920) under development by the company Sangamo.

Organ-specific treatment
Pain associated with Fabry disease may be partially alleviated by enzyme replacement therapy in some patients, but pain management regimens may also include analgesics, anticonvulsants, and nonsteroidal anti-inflammatory drugs, though the latter are usually best avoided in kidney disease.  The kidney failure seen in some of those with Fabry disease sometimes requires haemodialysis. The cardiac complications of Fabry disease include abnormal heart rhythms, which may require a pacemaker or implantable cardioverter-defibrillator, while the restrictive cardiomyopathy often seen may require diuretics.

Prognosis
Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements.

Epidemiology
Fabry disease is panethnic, but due to its rarity, determining an accurate disease frequency is difficult. Reported incidences, ranging from one in 476,000 to one in 117,000 in the general population, may largely underestimate the true prevalence. Newborn screening initiatives have found an unexpectedly high prevalence of the disease, as high as one in about 3,100 newborns in Italy and have identified a surprisingly high frequency of newborn males around one in 1,500 in Taiwan.

Research
Enzyme replacement therapy: Replacement of the missing enzyme to clear the lipids (GL-3) from the cells
Substrate synthesis inhibition, also called substrate reduction therapy: Inhibits the production of the lipid (GL-3) that accumulates in the cells
Chaperone therapy: Uses small-molecule drugs that bind to the defective enzyme and stabilize it to increase enzyme activity and increase cellular function
Gene editing: Technology that can potentially cut and fix a broken gene in a cell
Gene therapy: Genetically modifies the affected cells to produce the missing enzyme.

History
Fabry disease was first described by  dermatologist Johannes Fabry and  surgeon William Anderson independently in 1898. It was recognised to be due to abnormal storage of lipids in 1952.  In the 1960s, the inheritance pattern was established as being X-linked, as well as the molecular defect responsible for causing the accumulation of glycolipids.Ken Hashimoto published his classic paper on his electron microscopic findings in Fabry disease in 1965.The first specific treatment for Fabry disease was approved in 2001.

Society and culture
House ("Epic Fail", season six, episode three) centers on a patient with Fabry disease.
Scrubs ("My Catalyst", season three, episode 12) features a Fabry disease diagnosis.
Crossing Jordan ("Theres No Place Like Home", season two, episode one) features a patient who died from Fabry disease.
The Village (Korean drama): "Achiaras Secret" features daughters of a serial rapist who find each other because they share Fabry disease.
Doctor John (Korean drama): In episode two, a prisoner is diagnosed with Fabry disease.
In Lincoln Rhyme: Hunt for the Bone Collector, a copycat of the titular Bone Collector has Fabry disease and takes Galafold, which allows the detectives to learn his identity.
Partners for Justice 2  (Korean drama), features Doctor K, who had Fabry disease.
 Doc (Italian drama): Series two features an episode with a tennis player who is diagnosed with Fabry disease

See also
Migalastat

References
Further reading
James, William D.; Berger, Timothy G.; Elston, Dirk (2006). Andrews Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
Schiffmann, Raphael; Kopp, Jeffrey B.; Austin, Howard A.; Sabnis, Sharda; Moore, David F.; Weibel, Thais; Balow, James E.; Brady, Roscoe O. (June 2001). "Enzyme replacement therapy in Fabry disease: a randomized controlled trial". JAMA </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 Sorsbys fundus dystrophy and can you explain it in depth? [/INST]  </s>