<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 Amyloid and can you explain it in depth? [/INST] Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits in amyloid plaques around cells which can disrupt the healthy function of tissues and organs.
Such amyloids have been associated with (but not necessarily as the cause of) more than 50 human diseases, known as amyloidosis, and may play a role in some neurodegenerative diseases. Some of these diseases are mainly sporadic and only a few cases are familial. Others are only familial. Some are iatrogenic as they result from medical treatment. Prions are an infectious form of amyloids that can act as a template to convert other non-infectious forms. Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.Amyloids have been known to arise from many different proteins. These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.An unusual secondary structure named alpha sheet has been proposed as the toxic constituent of amyloid precursor proteins. This idea is not widely accepted at present, but a fair amount of evidence has accumulated, especially recently, in its favor.

Definition
The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch (amylumcode: lat promoted to code: la  in Latin, from Ancient Greek: ἄμυλον, romanized: amylon), based on crude iodine-staining techniques.  For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumoid proteinaceous material.
The classical, histopathological definition of amyloid is an extracellular, proteinaceous fibrillar deposit exhibiting β-sheet secondary structure and identified by apple-green birefringence when stained with congo red under polarized light. These deposits often recruit various sugars and other components such as serum amyloid P component, resulting in complex, and sometimes inhomogeneous structures. Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.
A more recent, biophysical definition is broader, including any polypeptide that polymerizes to form a cross-β structure, in vivo or in vitro, inside or outside cells. Microbiologists, biochemists, biophysicists, chemists and physicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.

Proteins forming amyloids in diseases
To date, 37 human proteins have been found to form amyloid in pathology and be associated with well-defined diseases. The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by TTR). A table is included below.

Non-disease and functional amyloids
Many examples of non-pathological amyloid with a well-defined physiological role have been identified in various organisms, including human. These may be termed as functional or physiological or native amyloid.
Functional amyloid in Homo sapiens:
Intralumenal domain of melanocyte protein PMEL
Peptide/protein hormones stored as amyloids within endocrine secretory granules
Receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3)
Fragments of prostatic acid phosphatase and semenogelinsFunctional amyloid in other organisms:
Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla. This suggest that many more bacteria may express curli fibrils.
GvpA, forming the walls of particular Gas vesicles, i.e. the buoyancy organelles of aquatic archaea and eubacteria
Fap fibrils in various species of Pseudomonas
Chaplins from Streptomyces coelicolor
Spidroin from Trichonephila edulis (spider) (Spider silk)
Hydrophobins from Neurospora crassa and other fungi
Fungal cell adhesion proteins forming cell surface amyloid regions with greatly increased binding strength
Environmental biofilms according to staining with amyloid specific dyes and antibodies.
Tubular sheaths encasing Methanosaeta thermophila filamentsFunctional amyloid acting as prions
Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] or [RNQ+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
Prion HET-s from Podospora anserina
Neuron-specific isoform of CPEB from Aplysia californica (marine snail)

Structure
Amyloids are formed of long unbranched fibers that are characterized by an extended beta-sheet secondary structure in which individual beta strands (β-strands) (coloured arrows in the adjacent figure) are arranged in an orientation perpendicular to the long axis of the fiber. Such a structure is known as cross-β structure. Each individual fiber may be 7–13 nanometres in width and a few micrometres in length. The main hallmarks recognised by different disciplines to classify protein aggregates as amyloid is the presence of a fibrillar morphology with the expected diameter, detected using transmission electron microscopy (TEM) or atomic force microscopy (AFM), the presence of a cross-β secondary structure, determined with circular dichroism, FTIR, solid-state nuclear magnetic resonance (ssNMR), X-ray crystallography, or X-ray fiber diffraction (often considered the "gold-standard" test to see whether a structure contains cross-β fibres), and an ability to stain with specific dyes, such as Congo red, thioflavin T or thioflavin S.The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. The "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned β-strands.  The cross-β pattern is considered a diagnostic hallmark of amyloid structure.Amyloid fibrils are generally composed of 1–8 protofilaments (one protofilament also corresponding to a fibril is shown in the figure), each 2–7 nm in diameter, that interact laterally as flat ribbons that maintain the height of 2–7 nm (that of a single protofilament) and are up to 30 nm wide; more often protofilaments twist around each other to form the typically 7–13 nm wide fibrils. Each protofilament possesses the typical cross-β structure and may be formed by 1–6 β-sheets (six are shown in the figure) stacked on each other. Each individual protein molecule can contribute one to several β-strands in each protofilament and the strands can be arranged in antiparallel β-sheets, but more often in parallel β-sheets. Only a fraction of the polypeptide chain is in a β-strand conformation in the fibrils, the remainder forms structured or unstructured loops or tails.
For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods, including solid-state NMR spectroscopy and Cryo-Electron Microscopy. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid, although only for simplified peptides having a length remarkably shorter than that of peptides or proteins involved in disease. The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface. There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets. A limitation of X-ray crystallography for solving amyloid structure is represented by the need to form microcrystals, which can be achieved only with peptides shorter than those associated with disease.
Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a β-sandwich, or a β-solenoid which may be either β-helix or β-roll. Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed.One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations. This phenomenon is typically described as amyloid polymorphism.  It has notable biological consequences given that it is thought to explain the prion strain phenomenon.

Formation
Amyloid is formed through the polymerization of hundreds to thousands of monomeric peptides or proteins into long fibers. Amyloid formation involves a lag phase (also called nucleation phase), an exponential phase (also called growth phase) and a plateau phase (also called saturation phase), as shown in the figure. Indeed, when the quantity of fibrils is plotted versus time, a sigmoidal time course is observed reflecting the three distinct phases.
In the simplest model of nucleated polymerization (marked by red arrows in the figure below), individual unfolded or partially unfolded polypeptide chains (monomers) convert into a nucleus (monomer or oligomer) via a thermodynamically unfavourable process that occurs early in the lag phase. Fibrils grow subsequently from these nuclei through the addition of monomers in the exponential phase.A different model, called nucleated conformational conversion and marked by blue arrows in the figure below, was introduced later on to fit some experimental observations: monomers have often been found to convert rapidly into misfolded and highly disorganized oligomers distinct from nuclei. Only later on, will these aggregates reorganise structurally into nuclei, on which other disorganised oligomers will add and reorganise through a templating or induced-fit mechanism (this nucleated conformational conversion model), eventually forming fibrils.Normally folded proteins have to unfold partially before aggregation can take place through one of these mechanisms. In some cases, however, folded proteins can aggregate without crossing the major energy barrier for unfolding, by populating native-like conformations as a consequence of thermal fluctuations, ligand release or local unfolding occurring in particular circumstances. In these native-like conformations, segments that are normally buried or structured in the fully folded and possessing a high propensity to aggregate become exposed to the solvent or flexible, allowing the formation of native-like aggregates, which convert subsequently into nuclei and fibrils. This process is called native-like aggregation (green arrows in the figure) and is similar to the nucleated conformational conversion model.
A more recent, modern and thorough model of amyloid fibril formation involves the intervention of secondary events, such as fragmentation, in which a fibril breaks into two or more shorter fibrils, and secondary nucleation, in which fibril surfaces (not fibril ends) catalyze the formation of new nuclei. Both secondary events increase the number of fibril ends able to recruit new monomers or oligomers, therefore accelerating fibril formation through a positive feedback mechanism. These events add to the well recognised steps of primary nucleation (formation of the nucleus from the monomers through one of models described above), fibril elongation (addition of monomers or oligomers to growing fibril ends) and dissociation (opposite process).
Such a new model is described in the figure on the right and involves the utilization of a master equation that includes all steps of amyloid fibril formation, i.e. primary nucleation, fibril elongation, secondary nucleation and fibril fragmentation. The rate constants of the various steps can be determined from a global fit of a number of time courses of aggregation (for example ThT fluorescence emission versus time) recorded at different protein concentrations. The general master equation approach to amyloid fibril formation with secondary pathways has been developed by Knowles, Vendruscolo, Cohen, Michaels and coworkers and considers the time evolution of the concentration

        f
        (
        t
        ,
        j
        )

    {\displaystyle f(t,j)}
   of fibrils of length

        j

    {\displaystyle j}
   (here

        j

    {\displaystyle j}
   represents the number of monomers in an aggregate). where

          δ

            i
            ,
            j

    {\displaystyle \delta _{i,j}}
   denotes the Kronecker delta. The physical interpretation of the various terms in the above master equation is straight forward: the terms on the first line describe the growth of fibrils via monomer addition with rate constant

          k

            +

    {\displaystyle k_{+}}
   (elongation). The terms on the second line describe monomer dissociation, i.e. the inverse process of elongation.

          k

              o
              f
              f

    {\displaystyle k_{\rm {off}}}
   is the rate constant of monomer dissociation. The terms on the third line describe the effect of fragmentation, which is assumed to occur homogeneously along fibrils with rate constant

          k

            −

    {\displaystyle k_{-}}
  . Finally, the terms on the last line describe primary and secondary nucleation respectively. Note that the rate of secondary nucleation is proportional to the mass of aggregates, defined as

        M
        (
        t
        )
        =

          ∑

            j
            =

              n

                1

            ∞

        j
        f
        (
        t
        ,
        j
        )

    {\displaystyle M(t)=\sum _{j=n_{1}}^{\infty }jf(t,j)}
  .
Following this analytical approach, it has become apparent that the lag phase does not correspond necessarily to only nucleus formation, but rather results from a combination of various steps. Similarly, the exponential phase is not only fibril elongation, but results from a combination of various steps, involving primary nucleation, fibril elongation, but also secondary events. A significant quantity of fibrils resulting from primary nucleation and fibril elongation may be formed during the lag phase and secondary steps, rather than only fibril elongation, can be the dominant processes contributing to fibril growth during the exponential phase. With this new model, any perturbing agents of amyloid fibril formation, such as putative drugs, metabolites, mutations, chaperones, etc., can be assigned to a specific step of fibril formation.

Amino acid sequence and amyloid formation
In general, amyloid polymerization (aggregation or non-covalent polymerization) is sequence-sensitive, that is mutations in the sequence can induce or prevent self-assembly. For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur.  Studies comparing synthetic to recombinant β amyloid peptide in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant β amyloid peptide has a faster fibrillation rate and greater toxicity than synthetic β amyloid peptide.There are multiple classes of amyloid-forming polypeptide sequences.  Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as trinucleotide repeat disorders including Huntingtons disease. When glutamine-rich polypeptides are in a β-sheet conformation, glutamines can brace the structure by forming inter-strand hydrogen bonding between its amide carbonyls and nitrogens of both the backbone and side chains. The onset age for Huntingtons disease shows an inverse correlation with the length of the polyglutamine sequence, with analogous findings in a C. elegans model system with engineered polyglutamine peptides.Other polypeptides and proteins such as amylin and the β amyloid peptide do not have a simple consensus sequence and are thought to aggregate through the sequence segments enriched with hydrophobic residues, or residues with high propensity to form β-sheet structure. Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.Cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo. This phenomenon is important, since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimers and type 2 diabetes. In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" that prevent polymerization.

Amyloid toxicity
The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves.Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes. Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signalling pathway leading to apoptosis. There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntingtons disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.All these mechanisms of toxicity are likely to play a role </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 Familial encephalopathy with neuroserpin inclusion bodies and can you explain it in depth? [/INST] Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive disorder of the nervous system that is characterized by a loss of intellectual functioning (dementia) and seizures. At first, affected individuals may have difficulty sustaining attention and concentrating. Their judgment, insight, and memory become impaired as the condition progresses. Over time, they lose the ability to perform the activities of daily living, and most people with this condition eventually require comprehensive care.The signs and symptoms of familial encephalopathy with neuroserpin inclusion bodies vary in their severity and age of onset. In severe cases, the condition causes seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a persons teens. Less severe cases are characterized by a progressive decline in intellectual functioning beginning in a persons forties or fifties.Mutations in the SERPINI1 gene cause familial encephalopathy with neuroserpin inclusion bodies </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 Cooks syndrome and can you explain it in depth? [/INST] Cooks syndrome is a hereditary disorder which is characterized in the hands by bilateral nail hypoplasia on the thumb, index finger, and middle finger, absence of fingernails (anonychia) on the ring finger and little finger, lengthening of the thumbs, and bulbousness of the fingers </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 Aspirin exacerbated respiratory disease and can you explain it in depth? [/INST] Aspirin exacerbated respiratory disease (AERD),  also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.

Signs and symptoms
The various non-allergic NSAID hypersensitivity syndromes affect 0.5–1.9% of the general population, with AERD affecting about 7% of all asthmatics and about 14% of adults with severe asthma. AERD, which is slightly more prevalent in women, usually begins in young adulthood (twenties and thirties are the most common onset times, although children are affected by it and present a diagnostic problem in pediatrics) and may not include any other allergies. Most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion. The disorder typically progresses to asthma, then nasal polyposis, with aspirin sensitivity coming last. Anosmia (lack of smell) also is common, as inflammation within the nose and sinuses likely reaches the olfactory receptors.The respiratory reactions to NSAIDs vary in severity, ranging from mild nasal congestion and eye watering to lower respiratory symptoms including wheezing, coughing, an asthma attack, and in rare cases, anaphylaxis. In addition to the typical respiratory reactions, about 10% of patients with AERD manifest skin symptoms such as urticaria and/or gastrointestinal symptoms such as abdominal pain or vomiting during their reactions to aspirin.In addition to aspirin, patients also react to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses is generally considered safe. NSAIDs that are highly selective in blocking COX-2 and do not block its closely related paralog, COX-1, such as the COX-2 inhibitors celecoxib and rofecoxib, also are regarded as safe. Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors. In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients.

Cause
The disorder is thought to be caused by an anomaly in the arachidonic acid metabolizing cascade that leads to increased production of pro-inflammatory cysteinyl leukotrienes, a series of chemicals involved in the bodys inflammatory response. When medications such as NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma, this results in the overproduction of pro-inflammatory leukotrienes, which can cause severe exacerbations of asthma and allergy-like symptoms. The underlying cause of the disorder is not fully understood, but there have been several important findings:

Abnormally low levels of prostaglandin E2 (PGE2), which is protective for the lungs, has been found in patients with aspirin-induced asthma and may worsen their lung inflammation.
In addition to the overproduction of cystinyl leukotrienes, overproduction of 15-lipoxygenase-derived arachidonic acid metabolites viz., 15-hydroxyicosatetraenoic acid and eoxins by the eosinophils isolated from the blood of individuals with AERD; certain of these products may help promote the inflammatory response.
Overexpression of both the cysteinyl leukotriene receptor 1 and the leukotriene C4 synthase enzyme has been shown in respiratory tissue from patients with aspirin-induced asthma, which likely relates to the increased response to leukotrienes and increased production of leukotrienes seen in the disorder.
The attachment of platelets to certain leukocytes in the blood of patients with aspirin-sensitive asthma also has been shown to contribute to the overproduction of leukotrienes.
There may be a relationship between aspirin-induced asthma and TBX21, PTGER2, and LTC4S.
Eosinophils isolated from the blood of aspirin-induced asthma subjects (as well as severe asthmatic patients) greatly overproduce 15-hydroxyicosatetraenoic acid and eoxin C4 when challenged with arachidonic acid or calcium ionophore A23187, compared to the eosinophils taken from normal or mildly asthmatic subjects; aspirin treatment of eosinophils from aspirin intolerant subjects causes the cells to mount a further increase in eoxin production. These results suggest that 15-lipoxygenase and certain of its metabolites, perhaps eoxin C4, is contributing to aspirin-induced asthma in a fashion similar to 5-lipoxygenase and its leukotriene metabolites.

Treatment
Medication
Avoidance of NSAID medications will not stop the progression of the disease. The preferred treatment for many patients is desensitization to aspirin, undertaken at a clinic or hospital specializing in such treatment. Patients who are desensitized then take a maintenance dose of aspirin daily to maintain their desensitization. The recommended maintenance dose for symptom control is 650 mg to 1300 mg aspirin daily. While on daily aspirin, most patients have reduced need for supporting medications, fewer asthma and sinusitis symptoms than previously, and an improved sense of smell. Desensitization to aspirin reduces the chance of nasal polyp recurrence and may slow the regrowth of nasal polyps. Once desensitized to aspirin, most patients can safely take other NSAID medications again.Even patients desensitized to aspirin may continue to need other medications including nasal steroids, inhaled steroids, and leukotriene antagonists. Leukotriene antagonists and inhibitors (montelukast, zafirlukast, and zileuton) often are helpful in treating the symptoms of AERD. In a large survey of AERD patients, it was reported that Zyflo (zileuton) was significantly more effective at controlling the symptoms of the disease than Singulair (montelukast).Biologic medications such as dupilumab, mepolizumab, and omalizumab may also be of benefit. In a 2021 survey of biologics, dupilumab was found to be most effective in treating symptoms of AERD.Despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion.

Surgery
Often surgery is required to remove nasal polyps, although they typically recur, particularly if aspirin desensitization is not undertaken. 90% of patients have been shown to have recurrence of nasal polyps within five years after surgery, with 47% requiring revision surgery in the same time period. A complete endoscopic sinus surgery followed by aspirin desensitization has been shown to reduce the need for revision surgeries. Exact cause of nasal polyp formation is unknown. However, Differential gene expression analysis of AERD nasal polyp epithelial cells versus AERD non polyp nasal mucosa revealed DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps.

Diet
The majority of those with aspirin exacerbated respiratory disease experience respiratory reactions to alcohol. One study found that 83% reported such reactions. Of those who had reactions, 75% had a sinus reaction (runny nose, nasal congestion) and 51% had a lower respiratory reaction (wheezing, shortness of breath). The current theory on the cause of these reactions is that they may be related to polyphenols found in alcoholic beverages. A 2017 study found that alcohol sensitive patients reacted to catechins in red wine, but not to resveratrol. It has been suggested that steel fermented white wines and clear liquors may cause less of a reaction than other alcoholic beverages. Desensitization to aspirin has been found to reduce reactions to alcohol.Some people have reported relief of symptoms by following a low-salicylate diet such as the Feingold diet. Aspirin is quickly converted in the body to salicylic acid, also known as 2-Hydroxybenzoic 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 Barodontalgia and can you explain it in depth? [/INST] Barodontalgia, commonly known as tooth squeeze, is a pain in a tooth caused by a change in ambient pressure. The pain usually ceases at ground level. Dental barotrauma is a condition in which such changes in barometric pressure changes cause damage to the dentition.

Description
The most common victims are underwater divers because in deep dives pressures can increase by several atmospheres, and military pilots because of rapid changes.
In pilots, barodontalgia may be severe enough to cause premature cessation of flights.Most of the available data regarding barodontalgia is derived from high-altitude chamber simulations rather than actual flights. Barodontalgia prevalence was between 0.7% and 2% in the 1940s, and 0.3% in the 1960s.Similarly, cases of barodontalgia were reported in 0.3% of high altitude-chamber simulations in the Luftwaffe.The rate of barodontalgia was about 1 case per 100 flight-years in the Israeli Air Force. During World War II, about one-tenth of American aircrews had one or more episodes of barodontalgia. In a recent study, 8.2% of 331 Israeli Air Force aircrews, reported at least one episode of barodontalgia.In addition, a large epidemiologic study suggested that changes in barometric pressure were the reason for the initiation and/or exacerbation of various oral pains observed in dental emergency departments.Barodontalgia is a symptom of dental disease, for example inflammatory cyst in the mandible.
Indeed, most of the common oral pathologies have been reported as possible sources of barodontalgia: dental caries, defective tooth restoration, pulpitis, pulp necrosis, apical periodontitis, periodontal pockets, impacted teeth, and mucous retention cysts. One exception is barodontalgia manifested as referred pain from barosinusitis or barotitis-media. The latter two conditions are generated from pressure changes rather than pressure-related flare-up of pre-existing conditions. A meta-analysis of studies conducted between 2001 and 2010 revealed a rate of 5 episodes/1,000 flight-years </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 Symblepharon and can you explain it in depth? [/INST] A symblepharon is a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball </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 Hypoalphalipoproteinemia 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 Calcinosis cutis 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 Autosomal recessive polycystic kidney disease and can you explain it in depth? [/INST] Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.

Signs and symptoms
Symptoms and signs include abdominal discomfort, polyuria, polydipsia, incidental discovery of hypertension, and abdominal mass. The classic presentation for ARPKD is systemic hypertension with progression to end-stage kidney disease (ESKD) by the age of 15. In a typical presentation, a small number of individuals with ARPKD live to adulthood with some kidney function; but with significant deterioration in liver function. This outcome is postulated to result from expression of the polycystic kidney and hepatic disease gene PKHD1, which is located on chromosome 6p. In severe cases, a fetus will present with oligohydramnios and as a result, may present with Potter sequence.

Genetics
The cause of ARPKD is linked to mutations in the PKHD1 gene. PKHD1 gene codes forfibrocystin.  Fibrocystin is found in the epithelial cells of both the renal tubule and the bile ducts; deficiency leads to the characteristic polycystic dilation of both structures

ARPKD is a significant hereditary renal disease in that appears in childhood. The prevalence is estimated to be of 1 in 20,000 live births, with a reported carrier frequency of up to 1:70. The single gene mutation called PKHD1 is fully responsible for the disease presentation of ARPKD. This PKHD1 is located on the human chromosome region 6p21.1–6p12.2. It is also one of the largest genes in the genome as it occupies approximately 450 kb of DNA, and contains at least 86 exons.It is capable of producing multiple alternatively spliced transcripts. The largest known transcript encodes fibrocystin /polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. The structure of the FPC consist of a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. The FPC protein is found on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, and show similarity to polycystins and several other ciliopathy proteins. FPC is also found to be expressed on the basal body and plasma membrane. It is presumed that the large extracellular domain of FPC binds to a ligand(s) that is yet unknown and that is also involved in cell-cell and cell-matrix interactions.It is known that FPC interacts with ADPKD protein PC2 and may also participate in this regulation pathway of the mechanosensory function of the primary cilia, calcium signaling, and PCP. This is suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. The FPC protein is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and mitotic spindle assembly during cell division. There have been a large number of various single-gene mutations found throughout PKHD1 and are unique to individual families. Most of the patients are compound heterozygotes for PKHD1 mutations. Patients with two nonsense mutations appear to have an earlier onset of the disease.

Diagnosis
Ultrasonography is the primary method to evaluate autosomal recessive polycystic kidney disease, particularly in the perinatal and neonatal stages.

Differential diagnosis
The differential diagnoses of this condition include:
Glomerulocystic kidney disease
Autosomal dominant polycystic kidney disease
Diffuse cystic dysplasia

Treatment
The treatment options for autosomal recessive polycystic kidney disease, given there is no current cure, are:
Medications for hypertension
Medications and/or surgery for pain
Antibiotics for infection
Dialysis (if kidney failure is present)
Kidney transplantation(in serious cases)

References
Further reading
Lonergan, Gael J.; Rice, Roy R.; Suarez, Eric S. (2000-05-01). "Autosomal Recessive Polycystic Kidney Disease: Radiologic-Pathologic Correlation". RadioGraphics. 20 (3): 837–855 </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 Rheumatoid nodulosis 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 Parathyroidectomy and can you explain it in depth? [/INST] Parathyroidectomy is the surgical removal of one or more of the (usually) four parathyroid glands. This procedure is used to remove an adenoma or hyperplasia of these glands when they are producing excessive parathyroid hormone (PTH): hyperparathyroidism. The glands are usually four in number and located adjacent to the posterior surface of the thyroid gland, but their exact location is variable. When an elevated PTH level is found, a sestamibi scan or an ultrasound may be performed in order to confirm the presence and location of abnormal parathyroid tissue.

Indications
The main indication for parathyroidectomy is primary hyperparathyroidism, a condition in which one or more of the parathyroid glands produce excessive parathyroid hormone. Not all cases of primary hyperparathyroidism require surgery, but it is recommended if the condition causes significant symptoms or if it affects the kidneys (nephrocalcinosis) or bone health (osteoporosis), and also in people under 50 even if they do not have symptoms. It is not always possible to anticipate if a parathyroid tumor is malignant (i.e. capable of invading other tissues or spreading elsewhere). Any suspicion of parathyroid carcinoma is therefore also an indication for surgery.Parathyroidectomy may also be required in secondary hyperparathyroidism. This situation arises mainly in people with severe chronic kidney disease in which the parathyroid glands are overactive to compensate for the low calcium and vitamin D levels often present in CKD. In many cases, the parathyroid hormone production improves when these abnormalities are treated with medication. A small proportion, however, have persistently raised hormone levels six months after treatment has started, thought to be autonomous production of hormone by the glands and loss of feedback mechanisms. In this situation surgical parathyroidectomy may be required, especially if calcium and phosphate levels remain elevated, there is calcium deposition in the wall of blood vessels (calciphylaxis in severe cases) or there is worsening bone disease. In people on dialysis, parathyroidectomy can improve their survival. It does appear that the procedure may be underused.

Procedure
The operation requires a general anesthetic (unconscious and pain free) or a local anesthetic (pain free). The surgeon makes an incision around an inch long in the neck just under the larynx (Adams apple), and locates the offending parathyroid glands. Preoperative testing using sestamibi scanning can help identify the location of glands. It can also be used to limit the extent of surgical exploration when used in conjunction with intraoperative PTH hormone monitoring.  The particular problem or disease process will determine how many of the parathyroid glands are removed. Some parathyroid tissue must be left in place to help prevent hypoparathyroidism.
Recovery after the operation tends to be swift. The PTH level is back to normal within 10–15 minutes, and can be confirmed by intraoperative rapid assessment during the operation.  However, the remaining parathyroid glands may take hours to several weeks to return to their normal functioning levels (as they may have become dormant).  Calcium supplements are therefore often required to prevent symptoms of hypocalcemia and to restore lost bone mass.The patient is placed in a semi-Fowler position and the neck is extended. An abbreviated Kocher incision is made and the platysma muscle is dissected horizontally. The strap muscles are released off of the thyroid gland. Then the thyroid gland is mobilized and the parathyroid arterial blood supply is suture ligated. The entire parathyroid adenoma is identified and dissected out. Intraoperative PTH monitoring can begin at this time and will show falling PTH levels if the entire adenoma has been resected.

Complications
While mild hypocalcemia is common after partial parathyroidectomy, some people experience persistently prolonged low calcium levels. This is called hungry bone syndrome. Despite the reactivation of unresected parathyroid glands producing normal to elevated levels of PTH, serum calcium continues to be low </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 Arginine:glycine amidinotransferase deficiency and can you explain it in depth? [/INST] Arginine:glycine amidinotransferase deficiency  or AGAT deficiency is an autosomal recessive cerebral creatine deficiency caused by a deficiency of the enzyme arginine:glycine amidinotransferase.  This enzyme deficiency results in decreased creatine synthesis, and is caused by biallelic pathogenic variants in GATM.  Individuals with AGAT deficiency are intellectually disabled and have muscle weakness.  The symptoms of AGAT deficiency are caused by the lack of creatine in specific tissues, most notably muscle and brain.  Oral creatine supplementation can be used to treat AGAT deficiency, with early intervention providing the best results.  All creatine deficiencies are rare, and there have been fewer than 20 individuals reported in medical literature with AGAT deficiency.  This disorder was first described in 2000.

Signs and symptoms
As with other cerebral creatine deficiency syndromes, individuals affected with AGAT deficiency are intellectually disabled and can have seizures.  They can often have muscle weakness.  These symptoms are caused by the lack of creatine in skeletal muscles and in the brain.  AGAT deficiency was first identified in 2000, in a pair of sisters aged 4 and 6.  Both sisters had severe intellectual disability.

Genetics
AGAT deficiency is caused by deficient activity of arginine:glycine amidinotransferase, which is coded for by GATM, located on the long arm of chromosome 15. AGAT deficiency is inherited in an autosomal recessive manner, which means pathogenic variants must be inherited from each parent.  This enzyme catalyzes the first step in creatine biosynthesis, the combination of arginine and glycine to form guanidinoacetate, which also results in the formation or ornithine as a by product.  These reactions take place primarily in the kidney and pancreas.  The clinical manifestations of AGAT deficiency are caused by the decreased amounts of creatine produced.

Diagnosis
AGAT deficiency can be suspected from clinical findings, although there is significant phenotypic overlap with the most common presenting symptoms of intellectual disability and muscle weakness.  Laboratory testing of plasma and urine will show decreased levels of creatine and guanidinoacetate.  Non-specific elevations of metabolites on urine testing that are normalized to creatinine may appear falsely elevated.  Magnetic resonance spectroscopy (MRS) of the brain will also show an absence of creatine, which is normally present.  This finding is not specific to AGAT deficiency, it can be observed in all three cerebral creatine deficiencies.  The combination of biochemical testing and MRS findings can be strongly suggestive of AGAT deficiency.  Confirmation would most often be done with molecular testing of GATM.  Identification of biallelic pathogenic variants in GATM would be confirmation of a diagnosis of AGAT deficiency </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 Adenosine deaminase deficiency and can you explain it in depth? [/INST] Adenosine deaminase deficiency (ADA deficiency)  is a  metabolic disorder that causes immunodeficiency. It is caused by  mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) among non-inbred populations.ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder. It occurs in fewer than one in 100,000 live births worldwide.

Signs and symptoms
The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.An association with polyarteritis nodosa has been reported.

Genetics
The enzyme adenosine deaminase is encoded by the ADA gene on chromosome 20 </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 Fryns syndrome and can you explain it in depth? [/INST] Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period. Fryns (1987) reviewed the syndrome.

Presentation
Usually associated with diaphragmatic hernia,
pulmonary hypoplasia,
imperforate anus,
micropenis,
bilateral cryptorchidism,
cerebral ventricular dilation,
camptodactyly,
agenesis of sacrum,
low-set ear.

Cytogenetics
In a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2. They suggested that the gene for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15, chromosome 6, chromosome 8 and chromosome 22, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder.By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400).

Diagnosis
Prenatal Diagnosis:

Aymé, et al. (1989) reported prenatal diagnosis of Fryns syndrome by sonography between 24 and 27 weeks.
Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisors; natal teeth had not been mentioned in other cases of Fryns syndrome.Differential Diagnosis:

McPherson et al. (1993) noted the phenotypic overlap between Fryns syndrome and the Pallister–Killian syndrome (601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.
Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister–Killian syndrome, noting that differentiation is important to genetic counseling because Fryns syndrome is an autosomal recessive disorder and Pallister–Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with coarse face, acral hypoplasia, and internal anomalies, the initial diagnosis of Fryns syndrome had to be changed because mosaicism of isochromosome 12p was detected in fibroblast cultures or kidney tissue. Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister–Killian syndrome by Veldman et al. (2002).
Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta, dilatation of the ureters, proximal thumbs, and broad clavicles.

Epidemiology
In France, Aymé, et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live births and perinatal deaths).

Cases
Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies.
Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.
Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features.
Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins.
Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Post-mortem examination showed Dandy–Walker malformation, ventricular septal defect, and renal cystic dysplasia.
Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct.
Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome.
Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but had severe intellectual disability. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older siblings had died in utero. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. Nevertheless, intellectual disability has been present in all surviving patients.
Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients.
Aymé, et al. (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy–Walker anomaly and/or agenesis of the corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane.
Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.
In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age.
Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment </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 Persistent Müllerian duct syndrome and can you explain it in depth? [/INST] Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives (fallopian tubes, uterus, and/or the upper part of the vagina)  in what would be considered a genetically and otherwise physically normal male animal by typical human based standards.  In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives.Typical features include undescended testes (cryptorchidism) and the presence of a small, underdeveloped uterus in an XY infant or adult. This condition is usually caused by deficiency of fetal anti-Müllerian hormone (AMH) effect due to mutations of the gene for AMH or the anti-Müllerian hormone receptor, but may also be as a result of insensitivity to AMH of the target organ.PMDS can also present in non-human animals.

Presentation
The first visible signs of PMDS after birth is cryptorchidism (undescended testes) either unilaterally or bilaterally. Along with cryptorchidism, is also inguinal hernias which may be presented unilaterally (affects one testicle) or bilaterally (affects both testicles).  Adults who have been oblivious to this condition may be presented with haematuria, which is when blood appears in urine because of hormonal imbalances. PMDS Type I, is also referred to as hernia uteri inguinalis, which exhibits one descended testis that has also pulled the fallopian tube and sometimes uterus, through the inguinal canal. The descended testes, fallopian tube and uterus all fall in the same inguinal canal, causing an inguinal hernia. Altogether when the aforementioned conditions occur, it is called transverse testicular ectopia.Under the microscope, some samples taken for biopsies displayed results where testicular tissue was at a stage of immaturity, and showed dysplasia.

Genetics
Mutation in AMH gene (PMDS Type 1) or AMHR2 gene (PMDS Type 2) are the primary causes of PMDS. AMH, or sometimes referred to as Müllerian inhibiting substance (MIS), is secreted by Sertoli cells during an individuals whole life. It is essential during the foetal period as it functions to regress the Müllerian ducts. However, AMH also functions in the last trimester of pregnancy, after birth, and even during adulthood in minimal amounts. The Sertoli cells in males secrete AMH, through the presence of a Y chromosome.The role of the AMH gene in reproductive development, is the production of a protein that contributes to male sex differentiation. During development of male foetuses, the AMH protein is secreted by cells within the testes. AMHs bind to the AMH Type 2 Receptors, which are present on cells on the surface of the Müllerian duct. The binding of AMH to its receptors on the Müllerian duct induces the apoptosis of the Müllerian duct cells, thus the regression of the Müllerian duct within males. However, for females who originally do not produce AMH proteins during foetal development, the Müllerian duct eventually becomes the uterus and fallopian tubes as normal. With the AMH gene mutation (PMDS Type 1), the AMH is either not produced, produced in deficient amounts, defective, secreted at the wrong critical period for male differentiation or the Müllerian ducts manifested a resistance to AMH.AMHR2 contains the instructions for generating the receptors that AMH binds to. If there if a mutation in the AMHR2 gene, the response to AMH molecules binding to the receptor cannot be properly reciprocated. Other possibilities include an absence of the receptors, such that the AMH molecules cannot induce differentiation. Mutation in the AMHR2 is critical to proper male sex differentiation. The genetic mutational cause of PMDS, is a 27 base-pair deletion of the Anti-Müllerian Type 2 Receptor gene. The 27-base-pair deletion that occurs PMDS is in exon 10 on one allele.PMDS is inherited in an autosomal recessive manner. The male individuals inherit mutated copies of the X chromosomes from the maternal and paternal genes, implying the parents are carriers and do not show symptoms. Females inheriting two mutated genes do not display symptoms of PMDS, though remain as carriers. Males are affected genotypically with the karyotype (46, XY) and phenotypically.

Mechanism
AMH (anti Müllerian hormone) is produced by the primitive Sertoli cells as one of the earliest Sertoli cell products and induces regression of the Müllerian ducts. Fetal Müllerian ducts are only sensitive to AMH action around the 7th or 8th week of gestation, and Müllerian regression is completed by the end of the 9th week. The AMH induced regression of the Müllerian duct occurs in cranio-caudal direction via apoptosis. The AMH receptors are on the Müllerian duct mesenchyme and transfer the apoptotic signal to the Müllerian epithelial cell, presumably via paracrine actors. The Wolffian ducts differentiate into epididymides, vasa deferentia and seminal vesicles under the influence of testosterone, produced by the fetal Leydig cells.

Diagnosis
Persistent Müllerian duct syndrome (PMDS), also known as persistent oviduct syndrome, is a congenital disorder related to male sexual development. PMDS usually affects phenotypically normal male individuals with the karyotype (46, XY) and is a form of pseudohermaphroditism.The condition occurs in males and consists of normal-functioning reproductive organs and gonads, but also female reproductive organs such as the uterus and the fallopian tubes. The fetus has two sets of tubes which give rise to accessory reproductive organs - the (Wolffian) mesonephric ducts and the (Müllerian) paramesonephric ducts. Usually, the Wolffian duct gives rise to male reproductive organs (specifically the testicle, epididymis and vas deferens) while the Müllerian to female (the fallopian tubes, the uterus and the vagina), while the other duct regresses. In PMDS, an abnormality in the anti-Müllerian hormone signalling pathway causes the in-males-redundant Müllerian duct to persist and give rise to variously developed female reproductive organs.PMDS has various causes related to AMH or receptor abnormalities. For example, AMH has failed to synthesize, failed to release or was secreted at the wrong time. Normally, both the Müllerian and Wolffian ducts are present during the 7th week of gestation. At approximately the end of the 7th and the beginning of the 8th week of gestation, the Sertoli cells secretion of AMH occurs, causing male sex differentiation during fetal development. The AMH molecules bind to AMHRII (anti-Müllerian hormone receptor type II) regressing the Müllerian duct. The Leydig cells secrete testosterone to aid the male differentiation process by inducing structures such as the epididymis, vas deferens and seminal vesicles. However, with PMDS individuals, the Müllerian duct persists instead of regressing, either due to AMH secretion (PMDS Type I) or AMH receptors (PMDS Type II). PMDS is usually coincidentally found during surgery for inguinal hernia, or when searching for adult male infertility causes.

Other diagnostic tests
Genetic
Another method for the confirmation of PMDS is genetic testing. It is not usually preferred because of its processing period and cost. With image screenings such as ultrasound and MRI, the condition can be efficiently confirmed. Genetic tests can identify those who hold the mutated gene, identify the family members chances and risks, and advise those who are trying to get pregnant. Genetic counseling and further genetic testing is offered to confirm the chances and risks of an individuals offspring obtaining the pair of mutated genes. Further research into the family tree and inheritance is possible as well.

ELISA
An ELISA test is a form of immunoassay, a technique which uses an antibody or antigen to identify the presence of particular substances. For PMDS, ELISA tests can be used to determine the levels of AMH within the male individuals serum, but this is only effective before the individual reaches puberty as it normally increases during this period. PMDS patients display low levels of AMH within the serum, and low levels of testosterone.

Treatment
The main form of treatment is laparotomy, a modern and minimally invasive type of surgery. Laparotomy properly positions the testes within the scrotum (orchidopexy) and remove Müllerian structures, the uterus and fallopian tubes. Occasionally they are unsalvageable if located high in the retroperitoneum. During this surgery, the uterus is usually removed and attempts made to dissect away Müllerian tissue from the vas deferens and epididymis to improve the chance of fertility. If the person has male gender identity and the testes cannot be retrieved, testosterone replacement will be usually necessary at puberty should the affected individual choose to pursue medical attention. Recently, laparoscopic hysterectomy is offered to patients as a solution to both improve the chances of fertility and to prevent the occurrence of neoplastic tissue formation. The surgery is recommended to be performed when the individual is between one and two years old, but usually done when less than one year old. Having a target age for surgery reduces the risks of damaging the vas deferens. The vas deferens is in close proximity to the Müllerian structures, and is sometimes lodged in the uterine wall. Overall, the purpose of the treatment improves self-identification of an individual, reduces the increased risk of cancer and reduces the possibility of infertility, if not already present.
PMDS patients have a possibility of infertility in the future if not promptly operated on. When the affected males are adults, those who are not aware of the condition may find the presence of blood in their semen (hematospermia). The Müllerian structures and cryptorchidism can also  develop into cancer if ignored, or if there are pieces of Müllerian structures left from past surgery. If PMDS is found during adulthood, or if Müllerian structures had to be left behind due to risks in surgery, biopsies of the remaining Müllerian structures can be performed. Upon pathohistological observation, the endometrial tissues appear atrophied, and the fallopian tubes have begun to congest showing signs of fibrosis.

Epidemiology
PMDS is a relatively rare congenital disease </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ellis–Van Creveld syndrome and can you explain it in depth? [/INST] Ellis–Van Creveld syndrome (also called  mesoectodermal dysplasia but see Nomenclature section below) is a rare genetic disorder of the skeletal dysplasia type.

Signs and symptoms
It involves numerous anomalies including:

Post-axial polydactyly
Congenital heart defects (most commonly an atrial septal defect producing a common atrium, occurring in 60% of affected individuals)
Teeth present at birth (natal teeth)
Fingernail dysplasia
Short-limbed dwarfism, mesomelic pattern
Short ribs
Cleft palate
Malformation of the wrist bones (fusion of the hamate and capitate bones).

Genetics
Ellis–Van Creveld syndrome often is the result of founder effects in isolated human populations, such as the Amish and some small island inhabitants. Although relatively rare, this disorder does occur with higher incidence within founder-effect populations due to lack of genetic variability. Observation of the inheritance pattern has illustrated that the disease is autosomal recessive, meaning that both parents have to carry the gene in order for an individual to be affected by the disorder.Ellis–Van Creveld syndrome is caused by a mutation in the EVC gene, as well as by a mutation in a nonhomologous gene, EVC2, located close to the EVC gene in a head-to-head configuration. The gene was identified by positional cloning. The EVC gene maps to the chromosome 4 short arm (4p16). The function of a healthy EVC gene is not well understood at this time.

Relation to other rare disorders:  genetic ciliopathy
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related.  As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders.  Ellis–Van Creveld syndrome is one such  disease, part of an emerging class of diseases called ciliopathies.  The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body.  The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases.  Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.Weyers acrofacial dysostosis is due to another mutation in the EVC gene and hence is allelic with Ellis–Van Creveld syndrome.

Treatment
There is no causative / curative therapy. Symptomatic medical treatments are focussing on symptoms caused by orthopaedic, dental or cardiac problems. Regarding perioperative / anesthesiological management, recommendations for medical professionals are published at OrphanAnesthesia.

History
The disorder was described by Richard W. B. Ellis (1902–1966) of Edinburgh and Simon van Creveld (1895–1971) of Amsterdam. Each had a patient with this syndrome, as they had discovered when they met in the same train compartment on the way to a pediatrics conference in England in the late 1930s </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 Akinetic mutism and can you explain it in depth? [/INST] Akinetic mutism is a medical term describing patients tending neither to move (akinesia) nor speak (mutism). Akinetic mutism was first described in 1941 as a mental state where patients lack the ability to move or speak. However, their eyes may follow their observer or be diverted by sound. Patients lack most motor functions such as speech, facial expressions, and gestures, but demonstrate apparent alertness. They exhibit reduced activity and slowness, and can speak in whispered monosyllables.  Patients often show visual fixation on their examiner, move their eyes in response to an auditory stimulus, or move after often repeated commands. Patients with akinetic mutism are not paralyzed, but lack the will to move. Many patients describe that as soon as they "will" or attempt a movement, a "counter-will" or "resistance" rises up to meet them.

Types
Akinetic mutism varies across all patients. Its form, intensity, and clinical features correspond more closely to its functional anatomy rather than to its pathology. However, akinetic mutism most often appears in two different forms: frontal and mesencephalic.

Frontal akinetic mutism
Akinetic mutism can occur in the frontal region of the brain and occurs because of bilateral frontal lobe damage. Akinetic mutism as a result of frontal lobe damage is clinically characterized as hyperpathic.  It occurs in patients with bilateral circulatory disturbances in the supply area of the anterior cerebral artery.

Mesencephalic akinetic mutism
Akinetic mutism can also occur as a result of damage to the mesencephalic region of the brain. Mesencephalic akinetic mutism is clinically categorized as somnolent or apathetic akinetic mutism. It is characterized by vertical gaze palsy and ophthalmoplegia. This state of akinetic mutism varies in intensity, but it is distinguished by drowsiness, lack of motivation, hyper-somnolence, and reduction in spontaneous verbal and motor actions.

Symptoms and signs
Lack of motor function (but not paralysis)
Lack of speech
Apathy
Slowness
Disinhibition

Causes
Akinetic mutism can be caused by a variety of things. It often occurs after brain injury or as a symptom of other diseases.

Frontal lobe damage
Akinetic mutism is often the result of severe frontal lobe injury in which the pattern of inhibitory control is one of increasing passivity and gradually decreasing speech and motion.

Thalamic stroke
Many cases of akinetic mutism occur after a thalamic stroke. The thalamus helps regulate consciousness and alertness.

Ablation of cingulate gyrus
Another cause of both akinesia and mutism is ablation of the cingulate gyrus. Destruction of the cingulate gyrus has been used in the treatment of psychosis. Such lesions result in akinesia, mutism, apathy, and indifference to painful stimuli. The  anterior cingulate cortex is thought to supply a "global energizing factor" that stimulates decision making. When the anterior cingulate cortex is damaged, it can result in akinetic mutism.

Other
Akinetic mutism is a symptom during the final stages of Creutzfeldt–Jakob disease (a rare degenerative brain disease) and can help diagnose patients with this disease. It can also occur in a stroke that affects both anterior cerebral artery territories. Another cause is neurotoxicity due to exposure to certain drugs such as tacrolimus and cyclosporine.
Other causes of akinetic mutism are as follows:

Respiratory arrest and cerebral hypoxia
Acute cases of encephalitis lethargica
Meningitis
Hydrocephalus
Trauma
Tumors
Aneurysms
Olfactory groove meningioma
Cyst in third ventricle
Toxical lesions and infections of central nervous system
Delayed post-hypoxic leukoencephalopathy (DPHL)
Creutzfeldt–Jakob disease (mesencephalic form)

Diagnosis
Akinetic mutism can be misdiagnosed as depression, delirium, or locked-in syndrome, all of which are common following a stroke. Patients with depression can experience apathy, slurring of speech, and body movements similar to akinetic mutism. Similarly to akinetic mutism, patients with locked-in syndrome experience paralysis and can only communicate with their eyes. Correct diagnosis is important to ensure proper treatment.  A variety of treatments for akinetic mutism have been documented, but treatments vary between patients and cases.

Treatment
Magnesium sulfate
Treatments using intravenous magnesium sulfate have shown to reduce the symptoms of akinetic mutism. In one case, a 59-year-old woman was administered intravenous magnesium sulfate in an attempt to resolve her akinetic mutism </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 Hypertensive retinopathy and can you explain it in depth? [/INST] Hypertensive retinopathy is damage to the retina and retinal circulation due to high blood pressure (i.e. hypertension).

Signs and symptoms
Most patients with hypertensive retinopathy have no symptoms. However, some may report decreased or blurred vision, and headaches.

Signs
Signs of damage to the retina caused by hypertension include:

Arteriolar changes, such as generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, changes in the arteriolar wall (arteriosclerosis) and abnormalities at points where arterioles and venules cross. Manifestations of these changes include Copper wire arterioles where the central light reflex occupies most of the width of the arteriole and Silver wire arterioles where the central light reflex occupies all of the width of the arteriole, and "arterio-venular (AV) nicking" or "AV nipping", due to venous constriction and banking.
advanced retinopathy lesions, such as microaneurysms, blot hemorrhages and/or flame hemorrhages, ischemic changes (e.g </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 Hypercholesterolemia and can you explain it in depth? [/INST] Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), and dyslipidemia (any abnormalities of lipid and lipoprotein levels in the blood).Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as type 2 diabetes and an underactive thyroid.Cholesterol is one of three major classes of lipids produced and used by all animal cells to form membranes. Plant cells manufacture phytosterols (similar to cholesterol), but in rather small quantities. Cholesterol is the precursor of the steroid hormones and bile acids. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease. In contrast, higher levels of HDL cholesterol are protective.Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults. In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required. If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed. About 34 million adults in the United States have high blood cholesterol.

Signs and symptoms
Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (hardening of arteries). Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.

Causes
Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include weight, diet, and stress. Loneliness is also a risk factor.

Diet
Diet has an effect on blood cholesterol, but the size of this effect varies between individuals.A diet high in sugar or saturated fats increases total cholesterol and LDL. Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol. As of 2018 there appears to be a modest positive, dose-related relationship between cholesterol intake and LDL cholesterol.

Medical conditions and treatments
A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis therapy, nephrotic syndrome, hypothyroidism, Cushings syndrome and anorexia nervosa. Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics), certain anticonvulsants and medications for HIV as well as interferons.

Genetics
Genetic contributions are usually due to the additive effects of multiple genes ("polygenic"), though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. In familial hypercholesterolemia, mutations may be present in the APOB gene (autosomal dominant), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. Familial hypercholesterolemia affects about one in 250 individuals.

Diagnosis
Cholesterol is measured in milligrams per deciliter (mg/dL) of blood in the United States and some other countries. In the United Kingdom, most European countries and Canada, millimoles per liter of blood (mmol/L) is the measure.For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol is 4 mmol/L, and 2 mmol/L for LDL.In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as "desirable", 200 to 239 mg/dL as "borderline high", and 240 mg/dL or more as "high".There is no absolute cutoff between normal and abnormal cholesterol levels, and values must be considered in relation to other health conditions and risk factors.Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease. Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed. High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction. In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides is composed of VLDL), while LDL was usually estimated by the Friedewald formula:
LDL

        ≈

    {\displaystyle \approx }
   total cholesterol – HDL – (0.2 x fasting triglycerides).However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated (>4.5 mmol/L or >∼400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for measurement of LDL wherever possible. It may be useful to measure all lipoprotein subfractions (VLDL, IDL, LDL, and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value. Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.

Classification
Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis", have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis is found.

Screening method
The U.S. Preventive Services Task Force in 2008 strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease. In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.In Canada, screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels, screening is recommended once every five years. Once people are on a statin further testing provides little benefit except possibly to determine compliance with treatment.

Treatment
Treatment recommendations have been based on four risk levels for heart disease. For each risk level, LDL cholesterol levels representing goals and thresholds for treatment and other action are made. The higher the risk category, the lower the cholesterol thresholds.
For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.

Lifestyle
Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight.Overweight or obese individuals can lower blood cholesterol by losing weight – on average a kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dl.

Diet
Eating a diet with a high proportion of vegetables, fruit, dietary fibre, and low in fats results in a modest decrease in total cholesterol.Eating dietary cholesterol causes a small rise in serum cholesterol, the magnitude of which can be predicted using the Keys and Hegsted equations. Dietary limits for cholesterol were proposed in United States, but not in Canada, United Kingdom, and Australia. However, in 2015 the Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake.A 2020 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol. Other reviews have not found an effect from saturated fats on cardiovascular disease. Trans fats are recognized as a potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended.The National Lipid Association recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25–35% of energy intake, saturated fat to less than 7% of energy intake, and cholesterol to less than 200 mg per day. Changes in total fat intake in low calorie diets do not appear to affect blood cholesterol.Increasing soluble fiber consumption has been shown to reduce levels of LDL cholesterol, with each additional gram of soluble fiber reducing LDL by an average of 2.2 mg/dL (0.057 mmol/L). Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective. Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption. A diet high in fructose can raise LDL cholesterol levels in the blood.

Medication
Statins are the typically used medications, in addition to healthy lifestyle interventions. Statins can reduce total cholesterol by about 50% in the majority of people, and are effective in reducing the risk of cardiovascular disease in both people with and without pre-existing cardiovascular disease. In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heart disease, and strokes. Greater benefit is observed with the use of high-intensity statin therapy. Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention). Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved outcomes and diet is the mainstay of therapy in childhood.Other agents that may be used include fibrates, nicotinic acid, and cholestyramine. These, however, are only recommended if statins are not tolerated or in pregnant women </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 Ocular tilt reaction and can you explain it in depth? [/INST] The ocular tilt reaction (OTR) comprises  skew deviation, head tilt and ocular torsion involving structures of the inner ear responsible for maintenance of balance of the body i.e. the semi-circular canals (SCC), utricle and saccule.
Each anterior semi-circular canals has excitatory projections to the ipsilateral superior rectus muscle and its yoke i.e., the contralateral inferior oblique while simultaneously inhibiting the ipsilateral inferior rectus muscle and its yoke i.e. the contralateral superior oblique. Also, each posterior semi-circular canals has excitatory projections to the ipsilateral superior oblique and its yoke i.e </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 Chemosis and can you explain it in depth? [/INST] Chemosis is the swelling (or edema) of the conjunctiva </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 Peyronies disease and can you explain it in depth? [/INST] Peyronies disease is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis. Specifically, scar tissue forms in the tunica albuginea, the thick sheath of tissue surrounding the corpora cavernosa, causing pain, abnormal curvature, erectile dysfunction, indentation, loss of girth and shortening.It is estimated to affect between .4 to 20% of men. The condition becomes more common with age.

Signs and symptoms
A certain degree of curvature of the penis is considered normal, as many people are born with this benign condition, commonly referred to as congenital curvature. The disease may cause pain; hardened, big, cord-like lesions (scar tissue known as "plaques"); or abnormal curvature of the penis when erect due to chronic inflammation of the tunica albuginea (CITA).Although the popular conception of Peyronies disease is that it always involves curvature of the penis, the scar tissue sometimes causes divots or indentations rather than curvature. The condition may also make sexual intercourse painful and/or difficult, though it is unclear whether some men report satisfactory or unsatisfactory intercourse in spite of the disorder. The disorder is confined to the penis, although a substantial number of men with Peyronies exhibit concurrent connective tissue disorders in the hand, and to a lesser degree, in the feet. About 30 percent of men with Peyronies disease develop fibrosis in other elastic tissues of the body, such as on the hand or foot, including Dupuytrens contracture of the hand. An increased incidence in genetically related males suggests a genetic component. It can affect men of any race and age.

Psychosocial
Peyronies disease can also have psychological effects. While most men will continue to be able to have sexual relations, they are likely to experience some degree of erectile dysfunction. It is not uncommon to exhibit depression or withdrawal from their sexual partners.

Causes
The underlying cause of Peyronies disease is unknown. Although, it is likely due to a buildup of plaque inside the penis due to repeated mild sexual trauma or injury during sexual intercourse or physical activity.Risk factors include diabetes mellitus, Dupuytrens contracture, plantar fibromatosis, penile trauma, smoking, excessive alcohol consumption, genetic predisposition, and European heritage.

Diagnosis
A urologist may be able to diagnose the disease and suggest treatment. An ultrasound can provide conclusive evidence of Peyronies disease, ruling out congenital curvature or other disorders.

Ultrasonography
On penile ultrasonography, the typical appearance is hyperechoic focal thickening of the tunica albuginea. Due to associated calcifications, the imaging of patients with Peyronies disease shows acoustic shadowing, as illustrated in figures below. Less common findings, attributed to earlier stages of the disease (still mild fibrosis), are hypoechoic lesions with focal thickening of the paracavernous tissues, echoic focal thickening of the tunica without posterior acoustic shadowing, retractile isoechoic lesions with posterior attenuation of the beam, and focal loss of the continuity of the tunica albuginea. In the Doppler study, increased flow around the plaques can suggest inflammatory activity and the absence of flow can suggest disease stability. Ultrasound is useful for the identification of lesions and to determine their relationship with the neurovascular bundle. Individuals with Peyronies disease can present with erectile dysfunction, often related to venous leakage, due to insufficient drainage at the site of the plaque. Although plaques are more common on the dorsum of the penis, they can also be seen on the ventral face, lateral face, or septum.

Treatment
Medication and supplements
Many oral treatments have been studied but results so far have been mixed. Some consider the use of nonsurgical approaches to be controversial.Vitamin E supplementation has been studied for decades, and some success has been reported in older trials; those successes have not been reliably repeated in larger, newer studies. The use of Interferon-alpha-2b in the early stages of the disease has been studied; as of 2007, its efficacy was questionable.Collagenase clostridium histolyticum is reported to help by breaking down the excess collagen in the penis </s>