<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Polysubstance dependence and explain in detail? [/INST] Polysubstance dependence refers to a type of substance use disorder in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that alcohol is commonly used with another substance. This is supported by one study on polysubstance use that separated participants who used multiple substances into groups based on their preferred substance. The results of a longitudinal study on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance.

Common combinations
The three substances were cocaine, alcohol, and heroin, which implies that those three are very popular. Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants and benzodiazepines are often used in combination as well.

Presentation
Associated cognitive impairments
Cognition refers to what happens in the mind, such as mental functions like "perception, attention, memory, language, problem solving, reasoning, and decision making." Although many studies have looked at cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies.

Learning ability
The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the Benton Visual Retention Test (BVRT) and the California Verbal Learning Test (CVLT) to look at visual memory and verbal ability. This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition.

Memory, reasoning and decision making
Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in rave parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing, working memory, knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances.Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to cannabis, cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups performance levels on executive function, or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. In general, this meant that multiple substances negatively affected the polysubstance groups cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately.Alcohols negative effects on learning, spatial abilities and memory has been shown in many studies. This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. The California Verbal Learning Test (CVLT) was used due to its ability to "quantify small changes in verbal learning and memory" by evaluating errors made during the test and the strategies used to make those errors. The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain.

Length of abstinence matter
To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the Wechsler Adult Intelligence Scale vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the Stroop Neuropsychological Screening task for inhibition, and the Trail Making Test for attention. The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year.

Causes
Biological
There is data to support that some genes contribute to substance dependence. Some studies have focused on finding genes that predispose the person to be dependent on marijuana, cocaine, or heroin by studying genes that control a persons dopamine and opioid receptors, but no conclusive findings were reported. Other researchers found a connection between dopamine receptor genes and dependency on a substance. A potential problem with this study was that alcohol is commonly used with another substance, so the results of the study may not have been caused by dependency on a single substance. This means that multiple substances may have been contributing to the results, but the researchers suggested that further research should be done.However, there are studies that have found evidence of the influence of genes on vulnerability to substance dependence. These studies often use genotype, or the genetic information found on a persons chromosomes, and phenotype, which consists of the visible features of a person, to look at genetic patterns. One study examined the phenotype and genotype of 1,858 participants from 893 families to look at differences in three nicotinic acetylcholine receptor genes found within these individuals. The experimenters found significant connections between receptor genes for nicotine and polysubstance dependence, which indicated that differences in these genes can create the risk of being dependent on multiple substances.

Psychological
A 1989 study conducted by Khantzian and Treece found that nearly 60% of their opioid-dependent sample met criteria for an Axis II diagnosis. In the same study, 93% of the sample had a comorbid disorder, implying that the comorbid disorder plays some role in the addiction. It has also been shown that depression and polysubstance dependence are often both present at the same time. If a person is genetically predisposed to be depressed then they are at a higher risk of having polysubstance dependence.Possibly the most widely accepted cause of addictions is the self-medication hypothesis, that views substance addiction as a form of coping with stress through negative reinforcement, by temporarily alleviating awareness of or concerns over the stressor. People who use substances learn that the effects of each type of substance works to relieve or better painful states. They use substances as a form of self-medication to deal with difficulties of self-esteem, relationships, and self-care. Individuals with substance use disorders often are overwhelmed with emotions and painful situations and turn to substances as a coping method.

Sociocultural
The sociocultural causes are areas in a persons life that might have influenced their decision to start and continue using multiple substances. Sociocultural causes can be divided into social causes and cultural causes.

Social Causes: Some studies have shown that adolescents have one of the highest rates of polysubstance dependence. According to one study this population, ages 12–25, represents about half of the nations population that uses illicit substances. Of these individuals, half of them have started using substances by the end of 12th grade. This could be attributed to social expectations of peers, peer pressure to fit it, or a way of numbing their emotions. Some of these young kids start trying different substances initially to fit in, but then after a while they start to develop a tolerance for these substances and experience withdrawal if they dont have enough substances in their system and eventually become dependent on having the effects of substance dependence. With tolerance comes the craving for additional substances to get high, this constant need for that feeling is polysubstance dependence.In the older generations, polysubstance dependence had been linked to additional considerations such as personality disorder, homelessness, bipolar disorder, major depressive disorder and so on. Medical care being so expensive and difficult to get long term has been linked to polysubstance dependence. Those who need psychological help sometimes use multiple substances as a type of self medication to help manage their mental illnesses.

Comorbidity of mental disorders
For most of these disorders, in relation to polysubstance dependence, there is a vicious cycle that those with a dependence go through. First, Ingesting the substance creates a need for more, which creates a dopamine surge, which then creates pleasure. As the dopamine subsides, the pleasure adds to the emotional and physical pain and triggers stress transmitters, which in turn creates a craving, which must then be medicated, and thus the cycle begins again. However, the next time they use, more of the substance will need to be used to get to the same degree of intoxication .

Depression
Scientists have hypothesized that the use of a substance either causes a mood disorder such as depression or at least attributes to a pre-existing one. Additionally, the substances that people with depression use can be a misguided method of self-medication in order to manage their depression. This is the classic chicken or egg hypothesis, does the pre-existing condition cause dependence or does dependence cause the condition? The underlying mental illness needs to be identified and treated in conjunction with treating the polysubstance dependence in order to increase the success rate of treatment and decrease the probability of relapse. One specific study focused on alcohol and depression, because they are so commonly inter-related. Researchers have discovered that depression continues for several weeks after a patient had been rehabilitated and those who relapsed developed depression again. This means that the onset of depression happens after alcohol dependence occurs, which means that alcohol is a major contributor to depression.

Eating disorders
One study showed that patients who are recovering from an addiction, who have had an eating disorder in the past, often use food to try to replace the substance that they are no longer getting. Or they obsess over controlling their weight and appearance. Some rehabilitation centers have licensed nutritionists to help patients develop healthy eating habits to help them cope while recovering from their addictions. It is important that those who have a former eating disorder be taught how to eat healthfully, so they dont continuously switch from one addiction back to another.

Diagnosis
According to the DSM-IV, a diagnosis of polysubstance dependence must include a person who has used at least three different substances (not including caffeine or nicotine) indiscriminately, but does not have a preference to any specific one. In addition they must show a minimum of three of the following symptoms listed below, all within the past twelve months. There is a distinct difference between a person having three separate dependence issues and having Polysubstance dependence the main difference is polysubstance dependence means that they are not specifically addicted to one particular substance. This is often confused with multiple specific dependences present at the same time. To elaborate, if a person is addicted to three separate substance such as cocaine, methamphetamines and alcohol and is dependent on all three then they would be diagnosed with three separate dependence disorders existing together (cocaine dependence, methamphetamine dependence and alcohol dependence,) not polysubstance dependence. In addition to using three different substances without a preference to one, there has to be a certain level of dysfunction in a persons life to qualify for a diagnosis of polysubstance dependence. One of the bigger challenges that often occurs when trying to diagnose is the fact that people dont always report what they are taking because they are afraid of getting into legal trouble. When coding polysubstance Dependence in a DSM-IV it would be a multiaxial diagnosis 304.80- Polysubstance Dependence", next to the classification, it is accompanied by a list of other types of Substance dependence (e.g. "305.00 Alcohol Abuse" or "305.60 Cocaine Abuse").The DSM-IV requires at least three of the following symptoms present during a 12-month period for a diagnoses of polysubstance dependence.
Tolerance: Use of increasingly high amounts of a substance or they find the same amount less and less effective ( the amount has to be at least 50% more of the original amount needed.)
Withdrawal: Either withdrawal symptoms when the substance stops being used or the substance is used to prevent withdrawal symptoms.
Loss of control: Repeated use of more substance than was initially planned or use of the substances over longer periods of time than was planned.
Inability to stop using: Either unsuccessfully attempted to cut down or stop using the substances or a persistent desire to stop using.
Time: Spending a lot of time studying substances, obtaining substances, using substances, being under the influence of substances, and recovering from the effects of substances.
Interference with activities: Give up or reduce the amount of time involved in recreational activities, social activities, and/or occupational activities because of the use of substances.
Harm to self: Continuous use of substances despite having a physical or psychological problem caused by or made worse by the use of substances.DSM-5 eliminated polysubstance disorder; there the substances must be specified, among other related changes.

Treatment
Treatment for polysubstance dependence has many critical aspects. Substance rehabilitation is a lengthy and difficult process. Treatment must be individualized and last a sufficient amount of time to ensure the patient has kicked the addictions and to ensure the prevention of relapse. The most common forms of treatment for polysubstance dependence include: inpatient and outpatient treatment centers, counseling and behavioral treatments, and medications. It is important that treatments be carried on throughout the patients life in order to prevent relapse. It is a good idea that recovering addicts continue to attend social support groups or meet with counselors to ensure they do not relapse.

Inpatient treatment center
Inpatient treatment centers are treatment centers where addicts move to the facility while they are undergoing treatment. Inpatient treatment centers offer a safe environment where patients will not be exposed to potentially harmful situations during their treatments as they would on the outside. Inpatients usually undergo the process of detoxification. Detox involves withdrawing the user (usually medically) from all substances of concern. During their stay in the treatment facility, patients often are learning to manage and identify their substance addictions and to find alternate ways to cope with whatever is the cause of their addiction.

Outpatient treatments
Outpatient treatments include many of the same activities offered in an inpatient treatment facility, but the patient is not protected by the secure and safe environment of an inpatient treatment center. For this reason, they are significantly less effective. The patient usually continues to hold a job and goes to treatment nightly.

Twelve-step programs
Both in-patient and out-patient treatments can offer introductions to 12-step programs. Suggested 12-step programs are Alcoholics Anonymous (AA) and Narcotics Anonymous (NA). They offer regular meetings where members can discuss their experiences in a non-judgmental and supportive place.

Cognitive behavioral therapy
Also offered to patients are one-on-one counseling sessions and cognitive behavioral therapy(CBT). When looked at through a cognitive-behavioral perspective, addictions are the result of learned behaviors developed through positive experiences. In other words, when an individual uses a substance and receives desired results (happiness, reduced stress, etc.) it may become the preferred way of attaining those results, leading to addictions. The goal of CBT is to identify the needs that the addictions are being used to meet and to develop skills and alternative ways of meeting those needs. The therapist will work with the patient to educate them on their addictions and give them the skills they need to change their cognitions and behaviors.Addicts will learn to identify and correct problematic behavior. They will be taught how to identify harmful thoughts and substance cravings. CBT is an effective treatment for addictions.

Medications
Medications can be very helpful in the long-term treatment of polysubstance dependence. Medications are a useful aid in helping to prevent or reducing substance cravings. Another benefit of medications is helping to preventing relapse. Since substance use disorders affect brain functioning, medications assist in returning to normal brain functioning. People who use multiple substances require medications for each substance they use, as the current medications do not treat all substance use disorders simultaneously. Medications are a useful aid in treatments, but are not effective when they are the sole treatment method.

Substance use Disorder Medications
Methadone treatment for heroin addiction.
Naltrexone: Reduces opiates and alcohol cravings.
Disulfiram: induces intense nausea after drinking alcohol.
Acamprosate: normalizes brain chemistry disrupted by alcohol withdrawal and aids alcohol abstinence.
Buprenorphine/naloxone: The two medications together reduce cravings and block the pleasure from opiates.

Epidemiology
There are not very many studies that have examined how often polysubstance dependence occurs or how many people are dependent on multiple substances. However, according to a study that analyzed the results from the National Epidemiological Survey on Alcohol and Related Conditions, approximately 215.5 out of a total of 43,093 individuals in the United States (0.5%) met the requirements for polysubstance use disorder. Another study suggested that the number of new cases of polysubstance dependence has been going up. This idea was supported by a study that took place in Munich, Germany. A group of researchers chose to look at responses to a survey using the M-Composite International Diagnostic Interview (M-CIDI). The M-CIDI is a version of the Composite International Diagnostic Interview (CIDI). The researchers collected data from 3,021 participants, all between the ages of 14 and 24, to estimate the prevalence, or total number of cases, of substance use and of polysubstance use/dependence. The results of this study indicated that of the 17.3% who said that they regularly used substances, 40% said that they used more than one substance, but 3.9% specifically reported using three or more substances, indicating that there is a lot of overlap in the use of different substances </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vascular malformation and explain in detail? [/INST] A vascular malformation is a blood vessel or lymph vessel abnormality. Vascular malformations are one of the classifications of vascular anomalies, the other grouping is vascular tumors. They may cause aesthetic problems as they have a growth cycle, and can continue to grow throughout life.
Vascular malformations of the brain (VMBs) include those involving capillaries, and those involving the veins and arteries. Capillary malformations in the brain are known as cerebral cavernous malformations or capillary cavernous malformations (CCMs). Those involving the mix of vessels are known as cerebral arteriovenous malformations (AVMs or cAVMs). The arteriovenous type is the most common in the brain.

Types
A simple division of the vascular malformations is made into low-flow and high-flow types. Low-flow malformations involve a single type of blood or lymph vessel, and are known as simple vascular malformations; high-flow malformations involve an artery. There are also malformations that are of mixed-flow involving more than one type of vessel, such as an arteriovenous malformation.Low-flow vascular malformations include capillary malformations, venous malformations, and lymphatic malformations.

Capillary malformation
Capillary malformations involve the capillaries, and are the most common type. They used to refer only to port-wine stains but now include others. Capillary malformations are limited to the superficial layers of the skin but they can thicken, become nodular, and sometimes become disfiguring.
It has been proposed that the category of capillary malformations, also called vascular stains, be classified into seven major clinical types including nevus flammeus nuchae also known as nevus simplex, commonly known as stork bite or salmon patch.A capillary malformation is also a feature of the disorder macrocephaly-capillary malformation.

Venous malformation
Venous malformations are typically ill-defined masses, coloured from pale to dark blue. They can affect any tissue in the body </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Perichondritis and explain in detail? [/INST] Perichondritis  is inflammation of the perichondrium, a layer of connective tissue which surrounds cartilage </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Neuronal ceroid lipofuscinosis and explain in detail? [/INST] Neuronal ceroid lipofuscinosis  is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the bodys tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

Signs and symptoms
The classic characterization of the group of neurodegenerative, lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins, with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes.In the early infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. Adult variant NCL (ANCL or Kufs disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later.All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins.

Genetics
Childhood NCLs are generally autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein.Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an autosomal dominant (Parrys) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected.Many authorities refer to the NCLs collectively as Batten disease.

Diagnosis
Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patients medical history and information from various laboratory tests.Diagnostic tests used for NCLs include:

Skin or tissue sampling: The doctor can examine a small piece of tissue under a  microscope to spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively.
Electroencephalogram or EEG: An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brains electrical activity that suggest a patient has seizures.
Electrical studies of the eyes: These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs.
Brain scans: Imaging can help doctors look for changes in the brains appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brains tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.
Enzyme assay: A recent development in diagnosis of NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test.

Types
The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.

Mutations
Infantile form
Nonsense and frameshift mutations in the CLN1 gene (located at
1p32) always induce classical INCL, while some missense mutations have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a lysosomal enzyme called palmitoyl protein thioesterase 1 (PPT1).The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum (ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9, eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase  and eventual apoptosis.

Late infantile form
The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device).

Juvenile form
All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or frameshift mutations. The wild-type CLN3 gene codes for a protein with no known function, but studies of the yeast CLN3 ortholog, the product of which is called battenin (after its apparent connections to Battens disease, or JNCL), have suggested that the protein may play a role in lysosomal pH homeostasis. Furthermore, recent studies have also implied the proteins role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.

Adult dominant form
Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase.Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.

Treatment
Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. Several experimental treatments are under investigation.

Cystagon
In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to be  useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL.Currently, two drug trials are underway for infantile NCL, both using Cystagon.

Gene therapy
A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. The trial was conducted by Weill Medical College of Cornell University and sponsored by the Nathans Battle Foundation. In May 2008,  the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the diseases progression during the 18-month follow-up period" and "suggested that higher doses and a better delivery system may provide greater benefit".A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly".A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects.

Flupirtine
A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, or the Hospital for Sick Children in Toronto.

Stem cells
On October 20, 2005, the Food and Drug Administration approved a phase-I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon.Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or stem-cell transplants for this condition. A bone-marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.Trials testing the effectiveness of bone-marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.

Immunosuppressants
In late 2007,  Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone-marrow transplants, may be useful in slowing down the progress of juvenile NCL.

Enzyme replacement therapy
On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL.

Epidemiology
Incidence can vary greatly from type-to-type, and from country-to-country.In Germany, one study reported an incidence of 1.28 per 100,000.A study in Italy reported an incidence of 0.56 per 100,000.A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.

History
19th century
The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Gender dysphoria and explain in detail? [/INST] Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identity—their personal sense of their own gender—and their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used until 2013 with the release of the diagnostic manual DSM-5. The condition was renamed to remove the stigma associated with the term disorder.People with gender dysphoria commonly identify as transgender. Gender nonconformity is not the same thing as gender dysphoria and does not always lead to dysphoria or distress. According to the American Psychiatric Association, not all transgender people experience dysphoria; the critical element of gender dysphoria is "clinically significant distress".The causes of gender dysphoria are unknown but a gender identity likely reflects genetic, biological, environmental, and cultural factors. Treatment for gender dysphoria may include supporting the individuals gender expression or their desire for hormone therapy or surgery. Treatment may also include counseling or psychotherapy.Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender. Without the classification of gender dysphoria as a medical disorder, HRT and gender affirming surgery may be viewed as cosmetic treatments by health insurance, as opposed to medically necessary treatment, and may not be covered.

Signs and symptoms
Distress arising from an incongruence between a persons felt gender and assigned sex/gender (usually at birth) is the cardinal symptom of gender dysphoria.Gender dysphoria in those assigned male at birth (AMAB) tends to follow one of two broad trajectories: early-onset or late-onset. Early-onset gender dysphoria is behaviorally visible in childhood. Sometimes gender dysphoria will stop for a while in this group and they will identify as gay or homosexual for a period of time, followed by recurrence of gender dysphoria. This group is usually sexually attracted to members of their natal sex in adulthood, commonly identifying as heterosexual. Late-onset gender dysphoria does not include visible signs in early childhood, but some report having had wishes to be the opposite sex in childhood that they did not report to others. Transgender people assigned male at birth who experience late-onset gender dysphoria will usually be attracted to women and may identify as lesbians or bisexual, while those with early-onset will usually be attracted to men. A similar pattern occurs in those assigned female at birth (AFAB), with those experiencing early-onset GD being most likely to be attracted to women and those with late-onset being most likely to be attracted to men and identify as gay.Symptoms of GD in children include preferences for opposite sex-typical toys, games, or activities; great dislike of their own genitalia; and a strong preference for playmates of the opposite sex.  Some children may also experience social isolation from their peers, anxiety, loneliness, and depression.  In adolescents and adults, symptoms include the desire to be and to be treated as a different gender. Adults with GD are at increased risk for stress, isolation, anxiety, depression, poor self-esteem, and suicide.  Transgender people are also at heightened risk for eating disorders and substance abuse.

Causes
The specific causes of gender dysphoria remain unknown, and treatments targeting the etiology or pathogenesis of gender dysphoria do not exist. Evidence from studies of twins suggests that genetic factors play a role in the development of gender dysphoria. Gender identity is thought to likely reflect a complex interplay of biological, environmental, and cultural factors.

Diagnosis
The American Psychiatric Association permits a diagnosis of gender dysphoria in adolescents or adults if two or more of the following criteria are experienced for at least six months duration:
A strong desire to be of a gender other than ones assigned gender
A strong desire to be treated as a gender other than ones assigned gender
A significant incongruence between ones experienced or expressed gender and ones sexual characteristics
A strong desire for the sexual characteristics of a gender other than ones assigned gender
A strong desire to be rid of ones sexual characteristics due to incongruence with ones experienced or expressed gender
A strong conviction that one has the typical reactions and feelings of a gender other than ones assigned genderIn addition, the condition must be associated with clinically significant distress or impairment.The DSM-5 moved this diagnosis out of the sexual disorders category and into a category of its own. The diagnosis was renamed from gender identity disorder to gender dysphoria, after criticisms that the former term was stigmatizing. Subtyping by sexual orientation was deleted. The diagnosis for children was separated from that for adults, as "gender dysphoria in children". The creation of a specific diagnosis for children reflects the lesser ability of children to have insight into what they are experiencing, or ability to express it if they have insight. Other specified gender dysphoria or unspecified gender dysphoria can be diagnosed if a person does not meet the criteria for gender dysphoria but still has clinically significant distress or impairment. Intersex people are now included in the diagnosis of GD.The International Classification of Diseases (ICD-10) lists several disorders related to gender identity:
Transsexualism (F64.0): Desire to live and be accepted as a member of the opposite sex, usually accompanied by a desire for surgery and hormonal treatment
Gender identity disorder of childhood (F64.2): Persistent and intense distress about ones assigned gender, manifested prior to puberty
Other gender identity disorders (F64.8)
Gender identity disorder, unspecified (F64.9)
Sexual maturation disorder (F66.0): Uncertainty about ones gender identity or sexual orientation, causing anxiety or distressThe ICD-11, which came into effect on 1 January 2022, significantly revised classification of gender identity-related conditions. Under "conditions related to sexual health", the ICD-11 lists "gender incongruence", which is coded into three conditions:
Gender incongruence of adolescence or adulthood (HA60): replaces F64.0
Gender incongruence of childhood (HA61): replaces F64.2
Gender incongruence, unspecified (HA6Z): replaces F64.9In addition, sexual maturation disorder has been removed, along with dual-role transvestism. ICD-11 defines gender incongruence as "a marked and persistent incongruence between an individuals experienced gender and the assigned sex", with no requirement for significant distress or impairment.

Treatment
Treatment for a person diagnosed with GD may include psychological counseling, supporting the individuals gender expression, or hormone therapy or surgery. This may involve physical transition resulting from medical interventions such as hormonal treatment, genital surgery, electrolysis or laser hair removal, chest/breast surgery, or other reconstructive surgeries.  The goal of treatment may simply be to reduce problems resulting from the persons transgender status, for example, counseling the patient in order to reduce guilt associated with cross-dressing.Guidelines have been established to aid clinicians. The World Professional Association for Transgender Health (WPATH) Standards of Care are used by some clinicians as treatment guidelines. Others use guidelines outlined in Gianna Israel and Donald Tarvers Transgender Care. Guidelines for treatment generally follow a "harm reduction" model.

Children
Medical, scientific, and governmental organizations have opposed conversion therapy, defined as treatment viewing gender nonconformity as pathological and something to be changed, instead supporting approaches that affirm childrens diverse gender identities. People are more likely to keep having gender dysphoria the more intense their gender dysphoria, cross-gendered behavior, and verbal identification with the desired/experienced gender are (i.e. stating that they are a different gender rather than wish to be a different gender).Professionals who treat gender dysphoria in children sometimes prescribe puberty blockers to delay the onset of puberty until a child is believed to be old enough to make an informed decision on whether hormonal or surgical gender reassignment is in their best interest.A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.A review commissioned by the UK Department of Health found that there was very low certainty of quality of evidence about puberty blocker outcomes in terms of mental health, quality of life and impact on gender dysphoria. The Finnish government commissioned a review of the research evidence for treatment of minors and the Finnish Ministry of Health concluded that there are no research-based health care methods for minors with gender dysphoria. Nevertheless, they recommend the use of puberty blockers for minors on a case-by-case basis, and the American Academy of Pediatrics state that "pubertal suppression in children who identify as TGD [transgender and gender diverse] generally leads to improved psychological functioning in adolescence and young adulthood.".In the United States, several states have introduced or are considering legislation that would prohibit the use of puberty blockers in the treatment of transgender children. The American Medical Association, the Endocrine Society, the American Psychological Association, the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics oppose bans on puberty blockers for transgender children. In the UK, in the case of Bell v Tavistock, an appeal court, overturning the original decision, ruled that children under 16 could give consent to receiving puberty blockers.

Psychological treatments
Until the 1970s, psychotherapy was the primary treatment for gender dysphoria and generally was directed to helping the person adjust to their assigned sex. Psychotherapy is any therapeutic interaction that aims to treat a psychological problem. Psychotherapy may be used in addition to biological interventions, although some clinicians use only psychotherapy to treat gender dysphoria. Psychotherapeutic treatment of GD involves helping the patient to adapt to their gender incongruence or to explorative investigation of confounding co-occurring mental health issues. Attempts to alleviate GD by changing the patients gender identity to reflect assigned sex have been ineffective and are regarded as conversion therapy by most health organizations.: 1741

Biological treatments
Biological treatments physically alter primary and secondary sex characteristics to reduce the discrepancy between an individuals physical body and gender identity. Biological treatments for GD are typically undertaken in conjunction with psychotherapy; however, the WPATH Standards of Care state that psychotherapy should not be an absolute requirement for biological treatments.Hormonal treatments have been shown to reduce a number of symptoms of psychiatric distress associated with gender dysphoria. A WPATH commissioned systematic review of the outcomes of hormone therapy "found evidence that gender-affirming hormone therapy may be associated with improvements in [quality of life] scores and decreases in depression and anxiety symptoms among transgender people." The strength of the evidence was low due to methodological limitations of the studies undertaken. Some literature suggests that gender-affirming surgery is associated with improvements in quality of life and decreased incidence of depression. Those who choose to undergo sex reassignment surgery report high satisfaction rates with the outcome, though these studies have limitations including risk of bias (lack of randomization, lack of controlled studies, self-reported outcomes) and high loss to follow up.For adolescents, much is unknown, including persistence. Disagreement among practitioners regarding treatment of adolescents is in part due to the lack of long-term data. Young people qualifying for biomedical treatment according to the Dutch model (including having GD from early childhood on which intensifies at puberty and absence of psychiatric comorbidities that could challenge diagnosis or treatment) found reduction in gender dysphoria, although limitations to these outcome studies have been noted, such as lack of controls or considering alternatives like psychotherapy.In its position statement published December 2020, the Endocrine Society stated that there is durable evidence for a biological underpinning to gender identity and that pubertal suppression, hormone therapy, and medically indicated surgery are effective and relatively safe when monitored appropriately and have been established as the standard of care. They noted a decrease in suicidal ideation among youth who have access to gender-affirming care and comparable levels of depression to cisgender peers among socially transitioned pre-pubertal youth. In its 2017 guideline on treating those with gender dysphoria, it recommends puberty blockers be started when the child has started puberty (Tanner Stage 2 for breast or genital development) and cross-sex hormones be started at 16, though they note "there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/gender incongruence". They recommend a multidisciplinary team of medical and mental health professionals manage the treatment for those under 18. They also recommend "monitoring clinical pubertal development every 3 to 6 months and laboratory parameters every 6 to 12 months during sex hormone treatment".A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.More rigorous studies are needed to assess the effectiveness, safety, and long-term benefits and risks of hormonal and surgical treatments. For instance, a 2020 Cochrane review found insufficient evidence to determine whether feminizing hormones were safe or effective. Several studies have found significant long-term psychological and psychiatric pathology after surgical treatments.In 2021, a review published in Plastic And Reconstructive Surgery found that less than 1% of people who undergo gender-affirming surgery regret the decision.

Comorbidities
Among youth, around 20% to 30% of individuals attending gender clinics meet the DSM criteria for an anxiety disorder. Gender dysphoria is also associated with an increased risk of eating disorders in transgender youth.A widely held view among clinicians is that there is an over-representation of neurodevelopmental conditions amongst individuals with GD, although this view has been questioned due to the low quality of evidence. Studies on children and adolescents with gender dysphoria have found a high prevalence of autism spectrum disorder (ASD) traits or a confirmed diagnosis of ASD. Adults with gender dysphoria attending specialist gender clinics have also been shown to have high rates of ASD traits or an autism diagnosis as well. It has been estimated that children with ASD were over four times as likely to be diagnosed with GD, with ASD being reported from 6% to over 20% of teens referring to gender identity services.

Epidemiology
Different studies have arrived at different conclusions about the prevalence of gender dysphoria. The DSM-5 estimates that about 0.005% to 0.014% of people assigned male at birth and 0.002% to 0.003% of people assigned female at birth are diagnosable with gender dysphoria.According to Blacks Medical Dictionary, gender dysphoria "occurs in one in 30,000 male births and one in 100,000 female births." Studies in European countries in the early 2000s found that about 1 in 12,000 natal male adults and 1 in 30,000 natal female adults seek out sex reassignment surgery. Studies of hormonal treatment or legal name change find higher prevalence than sex reassignment, with, for example a 2010 Swedish study finding that 1 in 7,750 adult natal males and 1 in 13,120 adult natal females requested a legal name change to a name of the opposite gender.Studies that measure transgender status by self-identification find even higher rates of gender identity different from sex assigned at birth (although some of those who identify as transgender or gender nonconforming may not experience clinically significant distress and so do not have gender dysphoria). A study in New Zealand found that 1 in 3,630 natal males and 1 in 22,714 natal females have changed their legal gender markers.  A survey of Massachusetts adults found that 0.5% identify as transgender. A national survey in New Zealand of 8,500 randomly selected secondary school students from 91 randomly selected high schools found 1.2% of students responded "yes" to the question "Do you think you are transgender?". Outside of a clinical setting, the stability of transgender or non-binary identities is unknown.Research indicates people who transition in adulthood are up to three times more likely to be male assigned at birth, but that among people transitioning in childhood the sex ratio is close to 1:1. The prevalence of gender dysphoria in children is unknown due to the absence of formal prevalence studies.

History
Neither the DSM-I (1952) nor the DSM-II (1968) contained a diagnosis analogous to gender dysphoria. Gender identity disorder first appeared as a diagnosis in the DSM-III (1980), where it appeared under "psychosexual disorders" but was used only for the childhood diagnosis. Adolescents and adults received a diagnosis of transsexualism (homosexual, heterosexual, or asexual type). The DSM-III-R (1987) added "Gender Identity Disorder of Adolescence and Adulthood, Non-Transsexual Type" (GIDAANT). DSM-V (2013) replaced gender identity disorder (GID) with gender dysphoria (GD) to avoid the stigma of the term disorder.

Society and culture
Researchers disagree about the nature of distress and impairment in people with GD. Some authors have suggested that people with GD suffer because they are stigmatized and victimized; and that, if society had less strict gender divisions, transgender people would suffer less.Some controversy surrounds the creation of the GD diagnosis, with Davy et al. stating that although the creators of the diagnosis state that it has rigorous scientific support, "it is impossible to scrutinize such claims, since the discussions, methodological processes, and promised field trials of the diagnosis have not been published."Some cultures have three or more defined genders.  The existence of accepted social categories other than man or woman may alleviate the distress associated with cross-gender identity. For example, in Samoa, the faafafine, a group of feminine males, are mostly socially accepted. The faafafine appear similar to transgender women in terms of their lifelong identities and gendered behavior, but experience far less distress than do transgender women in Western cultures. This suggests that the distress of gender dysphoria is mostly not caused by the cross-gender identity itself, but by difficulties encountered from social disapproval by ones culture. Overall, it is unclear whether or not gender dysphoria persists in cultures with third gender categories.

Classification as a disorder
The psychiatric diagnosis of gender identity disorder (now gender dysphoria) was introduced in DSM-III in 1980. Arlene Istar Lev and Deborah Rudacille have characterized the addition as a political maneuver to re-stigmatize homosexuality. (Homosexuality was declassified as a mental disorder in the DSM-II in 1974.) By contrast, Kenneth Zucker and Robert Spitzer argue that gender identity disorder was included in DSM-III because it "met the generally accepted criteria used by the framers of DSM-III for inclusion." Some researchers, including Spitzer and Paul J. Fink, contend that the behaviors and experiences seen in transsexualism are abnormal and constitute a dysfunction. The American Psychiatric Association stated that gender nonconformity is not the same thing as gender dysphoria, and that "gender nonconformity is not in itself a mental disorder. The critical element of gender dysphoria is the presence of clinically significant distress associated with the condition."Individuals with gender dysphoria may or may not regard their own cross-gender feelings and behaviors as a disorder. Advantages and disadvantages exist to classifying gender dysphoria as a disorder. Because gender dysphoria had been classified as a disorder in medical texts (such as the previous DSM manual, the DSM-IV-TR, under the name "gender identity disorder"), many insurance companies are willing to cover some of the expenses of sex reassignment therapy. Without the classification of gender dysphoria as a medical disorder, sex reassignment therapy may be viewed as a cosmetic treatment, rather than medically necessary treatment, and may not be covered. In the United States, transgender people are less likely than others to have health insurance, and often face hostility and insensitivity from healthcare providers. Gender dysphoria being a disorder also means it is covered by the Americans with Disabilities Act, which may aid transgender people in accessing legal protections they otherwise may be unable to. Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender.An analysis of the Samoan third gender faafafine suggests that the DSM-IV-TR diagnostic component of distress is not inherent in the cross-gender identity; rather, it is related to social rejection and discrimination suffered by the individual. Psychology professor Darryl Hill insists that gender dysphoria is not a mental disorder, but rather that the diagnostic criteria reflect psychological distress in children that occurs when parents and others have trouble relating to their childs gender variance. Transgender people have often been harassed, socially excluded, and subjected to discrimination, abuse and violence, including murder.In December 2002, the British Lord Chancellors office published a Government Policy Concerning Transsexual People document that categorically states, "What transsexualism is not ... It is not a mental illness." In May 2009, the government of France declared that a transsexual gender identity will no longer be classified as a psychiatric condition, but according to French trans rights organizations, beyond the impact of the announcement itself, nothing changed. Denmark made a similar statement in 2016.In the ICD-11, GID is reclassified as "gender incongruence", a condition related to sexual health. The working group responsible for this recategorization recommended keeping such a diagnosis in ICD-11 to preserve access to health services.

Gender euphoria
Gender euphoria (GE) is a proposed term for the opposite of gender dysphoria. It is the satisfaction, enjoyment, or relief felt by trans people when they feel their body matches their personal gender identity. Healthline defines it as "feelings of alignment or joy about [ones] gender identity or expression," while Psych Centrals definition is "deep joy when your internal gender identity matches your gender expression."In 1986, the term was first published in a trans context, as part of an interview with a trans person: "gender dysphoria, and a term of which he seems inordinately proud, gender euphoria." Similar uses were published in 1988. (The same term had been used as early as 1979, but to describe male privilege present in Black men.)In a 1988 interview with a trans man, the subject states, "I think that day [Dr. Charles Ilhenfeld] administered my first shot of the wonder-drug must have been one of the peak-experiences of my life -- talk about gender euphoria!" The interview indicates he is referring to testosterone.In 1989, Mariette Pathy Allen published an unnamed transgender persons quote in her photography book Transformations: "The shrinks may call it gender dysphoria, but for some of us, its gender euphoria, and were not going to apologize anymore!"In 1990, Virginia Prince used the phrase in trans magazine Femme Mirror, ending an article with, "...from here on you can enjoy GENDER EUPHORIA - HAVE A GOOD LIFE!"Starting in 1991, a monthly newsletter named Gender Euphoria was released, featuring articles about transgender topics; Leslie Feinberg read the newsletter to better understand the transgender community. In 1993, the blurb of Nan Goldins The Other Side read, "The pictures in this book are not of people suffering dysphoria but rather expressing gender euphoria."In 1994, Scottish "TV/TS" periodical The Tartan Skirt wrote, "Lets accentuate the positive, discard the negative, and promote the new condition of Gender Euphoria."In 1997, Patrick Califia described transgender activists picketing using signs that read "Gender Euphoria NOT Gender Dysphoria" and handing out "thousands of leaflets" at protests.
The following year, in 1998, Second Skins: The Body Narratives of Transsexuality reported:The transactivist group Transexual Menace is campaigning to have the diagnosis "Gender Identity Disorder" removed entirely from the Diagnostic and Statistical Manual of Mental Disorders. "Gender Euphoria NOT Gender Dysphoria"; its slogans invert the pathologizing of transgender, offering pride in queer difference as an alternative to the psychiatric story.Transgender congruence is also used to ascribe transgender individuals feeling genuine, authentic, and comfortable with their gender identity and external appearance.In 2019, the Midsumma festival in Australia hosted "Gender Euphoria," a cabaret focusing on "bliss" in transgender experiences, including musical, ballet, and burlesque performances. A reviewer described it as "triumphant – honest, unpretentious, touching, and a vital celebration."

See also
List of transgender-related topics
Transmedicalism
Gender transitioning
Detransition
Rapid-onset gender dysphoria controversy
ICD-11 § Gender incongruence

References
Further reading
Conway, Lynn (June 26, 2014). "Successful TransMen: Links and Photos". ai.eecs.umich.edu. Retrieved December 2, 2014.
Conway, Lynn (February 5, 2011). "Transsexual Womens Successes: Links and Photos". ai.eecs.umich.edu </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Barraquer–Simons syndrome and explain in detail? [/INST] Barraquer–Simons syndrome is a rare form of lipodystrophy,
which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to LMNB2.

Causes
The etiology of this condition has not been fully elucidated.  Lipodystrophy is often associated with glomerulonephritis, low C3 serum complement levels, and the presence of a C3 nephritic factor. C3 nephritic factor is a serum immunoglobulin G that interacts with the C3bBb alternative pathway convertase to activate C3. C3 nephritic factor induces the lysis of adipocytes that secrete adipsin, a product identical to complement factor D. The distribution of the lipoatrophy is postulated to be dictated by the variable amounts of adipsin secreted by the adipocytes at different locations.Human PTRF mutations may cause secondary deficiency of caveolins, resulting in generalized lipodystrophy in association with in muscular dystrophy. Complement dysfunction may predispose some patients to bacterial infections.

Diagnosis
The diagnosis of the disease is mainly clinical (see diagnostic criteria). A laboratory workup is needed primarily to investigate for the presence of associated disorders (metabolic, autoimmune, and renal diseases).
Every patient should have a fasting blood glucose and lipid profile, creatinine evaluation, and urinalysis for protein content at the first visit, after which he/she should have these tests on a regular basis.
Although uncommon, lipid abnormalities can occur in the form of raised triglyceride levels and low high-density lipoprotein cholesterol levels.
Patients usually have decreased serum C3 levels, normal levels of C1 and C4, and high levels of C3NeF (autoantibody), which may indicate the presence of renal involvement.
Antinuclear antibodies (ANA) and antidouble-stranded deoxyribonucleic acid (DNA) antibodies have reportedly been observed in some patients with acquired partial lipodystrophy.
A genetic workup should be performed if the familial form of lipodystrophy is suggested.Laboratory work for associated diseases includes:
Metabolic disease - fasting glucose, glucose tolerance test, lipid profile, and fasting insulin to characterize the insulin resistance state; free testosterone (in women) to look for polycystic ovary syndrome.
Autoimmune disease - ANA, antidouble-stranded DNA, rheumatoid factor, thyroid antibodies, C3, and C3NeF.As a confirmatory test, whole-body MRI usually clearly demonstrates the extent of lipodystrophy. MRI is not recommended on a routine basis.

Diagnostic criteria
A review published in 2004, which was based on 35 patients seen by the respective authors over 8 years and also a literature review of 220 cases of acquired partial lipodystrophy (APL), proposed an essential diagnostic criterion. Based on the review and the authors experience, they proposed that APL presents as a gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. The median age of the onset of lipodystrophy was seven years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Around 83% of APL patients had low complement 3 (C3) levels and the presence of polyclonal immunoglobulin C3 nephritic factor. About 22% of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of about 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 ± 10.3 yr vs 7.7 ± 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02).The adipose stores of the gluteal regions and lower extremities (including soles) tend to be either preserved or increased, particularly among women.  Variable fat loss of the palms, but no loss of intramarrow or retro-orbital fat, has been demonstrated.

Treatment
In general, treatment for acquired partial lipodystrophy is limited to cosmetic, dietary, or medical options. Currently, no effective treatment exists to halt its progression.
Diet therapy has been shown to be of some value in the control of metabolic problems.  The use of small, frequent feedings and partial substitution of medium-chain triglycerides for polyunsaturated fats appears to be beneficial.Plastic surgery with implants of monolithic silicon rubber for correction of the deficient soft tissue of the face has been shown to be effective.  False teeth may be useful in some cases for cosmetic reasons.  Long-term treatment usually involves therapy for kidney and endocrine dysfunction.Data on medications for APL are very limited.  Thiazolidinediones have been used in the management of various types of lipodystrophies. They bind to peroxisome proliferator-activator receptor gamma (PPAR-gamma), which stimulates the transcription of genes responsible for growth and differentiation of adipocytes. A single report has suggested a beneficial effect from treatment with rosiglitazone on fat distribution in acquired partial lipodystrophy; however, preferential fat gain was in the lower body.Direct drug therapy is administered according to the associated condition. Membranoproliferative glomerulonephritis and the presence of renal dysfunction largely determine the prognosis of acquired partial lipodystrophy. Standard guidelines for the management of renal disease should be followed. The course of membranoproliferative glomerulonephritis in acquired partial lipodystrophy has not been significantly altered by treatment with corticosteroids or cytotoxic medications.  Recurrent bacterial infections, if severe, might be managed with prophylactic antibiotics.

Prognosis
Estimating the mortality rate based on the available literature is difficult.  Several case reports have revealed an association between acquired partial lipodystrophy and other diseases.Nephropathy, in the form of membranoproliferative glomerulonephritis, occurs in about 20% of patients. Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Nager acrofacial dysostosis and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Nontuberculous mycobacteria and explain in detail? [/INST] Nontuberculous mycobacteria (NTM), also known as environmental mycobacteria, atypical mycobacteria and mycobacteria other than tuberculosis (MOTT), are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansens disease). NTM do cause pulmonary diseases that resemble tuberculosis. Mycobacteriosis is any of these illnesses, usually meant to exclude tuberculosis. They occur in many animals, including humans and are commonly found in soil and water.

Introduction
Mycobacteria are a family of small, rod-shaped bacilli that can be classified into three main groups for the purpose of diagnosis and treatment:

Mycobacterium tuberculosis complex, which can cause tuberculosis: M. tuberculosis, M. bovis, M. africanum, M. microti and M. canetti
M. leprae and M. lepromatosis,  which cause Hansens disease, also called leprosy
Nontuberculous mycobacteria (NTM) are all the other mycobacteria that can cause pulmonary disease resembling tuberculosis, lymphadenitis, skin disease, or disseminated disease. Although over 150 different species of NTM have been described, pulmonary infections are most commonly due to Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus (see image).

Taxonomy
In 1959, botanist Ernest Runyon put these human disease-associated bacteria into four groups (Runyon classification):
Photochromogens develop pigments in or after being exposed to light. Examples include M. kansasii, M. simiae, and M. marinum.
Scotochromogens become pigmented in darkness. Examples include M. scrofulaceum and M. szulgai.
Nonchromogens include a group of prevalent opportunistic pathogens called M. avium complex (MAC). Other examples are M. ulcerans, M. xenopi, M. malmoense, M. terrae, M. haemophilum, and M. genavense.
Rapid growers include four well-recognized, pathogenic, rapidly growing, nonchromogenic species: M. chelonae, M. abscessus, M. fortuitum, and M. peregrinum. Other examples cause disease rarely, such as M. smegmatis and M. flavescens.The number of identified and cataloged NTM species has been increasing rapidly, from about 50 in 1997 to over 125 by January 2007. The surge is mainly due to improved isolation and identification techniques.Even with these new techniques, though, the Runyon classification is still sometimes used to organize the mycobacteria into categories.

Epidemiology
NTM are widely distributed in the environment, particularly in wet soil, marshland, streams, rivers and estuaries. Different species of NTM prefer different types of environment. Human disease is believed to be acquired from environmental exposures. Unlike tuberculosis and leprosy, animal-to-human or human-to-human transmission of NTM rarely occurs.NTM diseases have been seen in most industrialized countries, where incidence rates vary from 1.0 to 1.8 cases per 100,000 persons. Recent studies, including one done in Ontario, Canada, suggest that incidence is much higher.  Pulmonary NTM is estimated by some experts in the field to be at least ten times more common than TB in the U.S., with at least 150,000 cases per year.
Most NTM disease cases involve the species known as Mycobacterium avium complex or MAC for short, M. abscessus, M. fortuitum and M. kansasii. M. abscessus is being seen with increasing frequency and is particularly difficult to treat.Mayo Clinic researchers found a three-fold increased incidence of cutaneous NTM infection between 1980 and 2009 in a population-based study of residents of Olmsted County, Minnesota. The most common species were M. marinum, accounting for 45% of cases and M. chelonae and M. abscessus, together accounting for 32% of patients. M. chelonae infection outbreaks, as a consequence of tattooing with infected ink, have been reported in the United Kingdom and the United States.Rapidly growing NTMs are implicated in catheter infections, post-LASIK, skin and soft tissue (especially post-cosmetic surgery) and pulmonary infections.

Pathogenesis
The most common clinical manifestation of NTM disease is lung disease, but lymphatic, skin/soft tissue, and disseminated diseases are also important.Pulmonary disease caused by NTM is most often seen in postmenopausal women and patients with underlying lung disease such as cystic fibrosis, bronchiectasis, and prior tuberculosis. It is not uncommon for alpha 1-antitrypsin deficiency, Marfan syndrome, and primary ciliary dyskinesia patients to have pulmonary NTM colonization and/or infection.  Pulmonary NTM can also be found in individuals with AIDS and malignant disease. It can be caused by many NTM species, which depends on region, but most frequently MAC and M. kansasii.Clinical symptoms vary in scope and intensity, but commonly include chronic cough, often with purulent sputum. Hemoptysis may also be present. Systemic symptoms include malaise, fatigue, and weight loss in advanced disease. The diagnosis of M. abscessus pulmonary infection requires the presence of symptoms, radiologic abnormalities, and microbiologic cultures.
Lymphadenitis can be caused by various species that differ from one place to another, but again, MAC is the main cause worldwide. Most patients are aged less than 5 years, but the incidence is rare for children having BCG vaccine. The disease has a high curability.Soft-tissue disease due to NTM infection include post-traumatic abscesses (caused by rapid growers), swimming pool granuloma (caused by M. marinum) and Buruli ulcer (caused by M. ulcerans or M. shinshuense). Post-traumatic abscesses most commonly occur after injection.Disseminated mycobacterial disease was common in US and European AIDS patients in the 1980s and early 1990s, though the incidence has declined in developed nations since the introduction of highly active antiretroviral therapy. It can also occur in individuals after having renal transplantation.

Diagnosis
Diagnosis of opportunistic mycobacteria is made by repeated isolation and identification of the pathogen with compatible clinical and radiological features. Similar to M. tuberculosis, most nontuberculous mycobacteria can be detected microscopically and grow on Löwenstein-Jensen medium. Many reference centres now use a nucleic acid-based method such as sequence differences detection in the gene coding for 16S ribosomal RNA to identify the species.Pulmonary NTM disease diagnosis requires both identification of the mycobacterium in the patients lung(s), as well as a high-resolution CT scan of the lungs.

Research
French researchers finalized the genome sequence of M. abscessus in March 2008.  The genome is available at https://www.ncbi.nlm.nih.gov/sites/entrez?db=genome&cmd=search&term=abscessus.

References
Further reading
Griffith David E.; Aksamit Timothy; Brown-Elliott Barbara;  et al. (2007). "American Thoracic Society Guidelines: Diagnosis, Treatment and Prevention of Nontuberculous Mycobacterial Diseases". American Journal of Respiratory and Critical Care Medicine. 175 (4): 367–417. doi:10.1164/rccm.200604-571st. PMID 17277290.
New BTS Guideline has been published in 2017, https://www.brit-thoracic.org.uk/standards-of-care/guidelines/bts-guidelines-for-non-tuberculous-mycobacteria/
Grange, J. M. (2007). "Environmental mycobacteria". In Greenwood, David; Slack, Richard; Peitherer, John; & Barer, Mike (Eds.), Medical Microbiology (17th ed.), pp. 221–227 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Fetal hydantoin syndrome and explain in detail? [/INST] Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to  teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, commonly used in the treatment of epilepsy.
It may also be called congenital hydantoin syndrome, fetal hydantoin syndrome, dilantin embryopathy, or phenytoin embryopathy.
Association with EPHX1 has been suggested.

Signs and symptoms
About one third of children whose mothers are taking this drug during pregnancy typically have intrauterine growth restriction with a small head and develop minor dysmorphic craniofacial features (microcephaly and intellectual disability) and limb defects including hypoplastic nails and distal phalanges (birth defects). Heart defects including ventricular septal defect, atrial septal defect, patent ductus arteriosus and coarctation of the aorta may occur in these children. A smaller population will have growth problems and developmental delay, or intellectual disability.
Heart defects and cleft lip may also be featured.

Diagnosis
There is no diagnostic testing that can identify fetal hydantoin syndrome. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of phenytoin exposure during gestation. It is important to note that the majority of infants born to women who take phenytoin during pregnancy will not develop fetal hydantoin syndrome.

Treatment
The treatment of fetal hydantoin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, neurologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected childs treatment. Infants with fetal hydantoin syndrome can benefit from early developmental intervention to ensure that affected children reach their potential </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Thyroid storm and explain in detail? [/INST] Thyroid storm  is a rare but severe and potentially life-threatening complication of hyperthyroidism (overactivity of the thyroid gland). It is characterized by a high fever (temperatures often above 40 °C/104 °F), fast and often irregular heart beat, elevated blood pressure, vomiting, diarrhea, and agitation. Hypertension with a wide pulse pressure occurs in early to mid crisis, with hypotension accompanying shock occurring in the late stage. Heart failure and heart attack may occur. Death may occur despite treatment. Most episodes occur either in those with known hyperthyroidism whose treatment has been stopped or become ineffective, or in those with untreated mild hyperthyroidism who have developed an intercurrent illness (such as an infection).The primary treatment of thyroid storm is with inorganic iodine and antithyroid drugs (propylthiouracil or methimazole) to reduce synthesis and release of thyroid hormone. Temperature control and intravenous fluids are also mainstays of management. Beta blockers are often used to reduce the effects of thyroid hormone. Patients often require admission to the intensive care unit.

Signs and symptoms
Thyroid storm is characterized by an acute onset of symptoms of hyperthyroidism (fast heart rate, restlessness, agitation) accompanied by other features such as fever (temperatures often above 40 °C/104 °F), hypertension, mental status changes, diarrhea, and vomiting.Individuals can exhibit varying signs of organ dysfunction. Patients may experience liver dysfunction, and jaundice (yellowing of the skin), which is considered a poor prognostic sign. Cardiac (heart) symptoms include abnormal heart rhythms, myocardial infarction (heart attack), and congestive heart failure, which may lead to cardiovascular collapse. Mortality can be as high as 20-30%.In some situations, individuals may not experience the classic signs of restlessness and agitation, but instead present with apathetic signs of weakness and confusion.

Causes
The transition from hyperthyroidism to thyroid storm is typically triggered by a non-thyroidal insult including, but not limited to fever, sepsis, dehydration, myocardial infarction, and psychiatric diseases. Individuals are at higher risk of thyroid storm if their hyperthyroidism is incompletely treated or if their anti-thyroid drugs are discontinued. Many of these individuals have underlying primary causes of hyperthyroidism (Graves disease, toxic multi-nodular goiter, solitary toxic adenoma, amiodarone). However, thyroid storm can occur in individuals with unrecognized thyrotoxicosis experiencing non-thyroid surgery, labor, infection, or exposure to certain medications and radiocontrast dyes.

Pathophysiology
The precise mechanism for the development of thyroid storm is poorly understood. In the human body, thyroid hormone may be free (biologically active T3/T4) or bound to thyroid binding hormone (biologically inactive) to be transported. The release of thyroid hormone is tightly regulated by a feedback system involving the hypothalamus, pituitary gland, and thyroid gland. Hyperthyroidism results from a dysregulation of this system that eventually leads to increases in levels of free T3/T4. The transition from simple hyperthyroidism to the medical emergency of thyroid storm may be triggered by conditions (see Causes) that lead to the following:

Increases in free thyroid hormone
Individuals with thyroid storm tend to have increased levels of free thyroid hormone, although total thyroid hormone levels may not be much higher than in uncomplicated hyperthyroidism. The rise in the availability of free thyroid hormone may be the result of manipulating the thyroid gland. In the setting of an individual receiving radioactive iodine therapy, free thyroid hormone levels may acutely increase due to the release of hormone from ablated thyroid tissue.

Decrease in thyroid hormone binding protein
A decrease in thyroid hormone binding protein in the setting of various stressors or medications may also cause a rise in free thyroid hormone.

Increased sensitivity to thyroid hormone
Along with increases in thyroid hormone availability, it is also suggested that thyroid storm is characterized by the bodys heightened sensitivity to thyroid hormone, which may be related to sympathetic activation (see below).

Sympathetic activation
Sympathetic nervous system activation during times of stress may also play a significant role in thyroid storm. Sympathetic activation increases production of thyroid hormone by the thyroid gland. In the setting of elevated thyroid hormone, the density of thyroid hormone receptors (esp. beta-receptors) also increases, which enhances the response to catecholamines. This is likely responsible for several of the cardiovascular symptoms (increased cardiac output, heart rate, stroke volume) seen in thyroid storm.

Thyroid storm as allostatic failure
According to newer theories, thyroid storm results from allostatic failure in a situation where thyrotoxicosis hampers the development of non-thyroidal illness syndrome, which would help to save energy in critical illness and other situations of high metabolic demand.Usually, in critical illness (e.g. sepsis, myocardial infarction and other causes of shock) thyroid function is tuned down to result in low-T3 syndrome and, occasionally, also low TSH concentrations, low-T4 syndrome and impaired plasma protein binding of thyroid hormones. This endocrine pattern is referred to as euthyroid sick syndrome (ESS), non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumours, uraemia and starvation (TACITUS). Although NTIS is associated with significantly worse prognosis, it is also assumed to represent a beneficial adaptation (type 1 allostasis). In cases, where critical illness is accompanied by thyrotoxicosis, this comorbidity prevents the down-regulation of thyroid function. Therefore, the consumption of energy, oxygen and glutathione remains high, which leads to further increased mortality.These new theories imply that thyroid storm results from an interaction of thyrotoxicosis with the specific response of the organism to an oversupply of thyroid hormones.

Diagnosis
The diagnosis of thyroid storm is based on the presence of signs and symptoms consistent with severe hyperthyroidism. Multiple approaches have been proposed to calculate the probability of thyroid storm based on clinical criteria, however, none have been universally adopted by clinicians. For instance, Burch and Wartofsky published the Burch-Wartofsky point scale (BWPS) in 1993, assigning a numerical value based on the presence of specific signs and symptoms organized within the following categories: temperature, cardiovascular dysfunction (including heart rate and presence of atrial fibrillation or congestive heart failure), central nervous system (CNS) dysfunction, gastrointestinal or liver dysfunction and presence of a precipitating event. A Burch-Wartofsky score below 25 is not suggestive of thyroid storm whereas 25 to 45 suggests impending thyroid storm and greater than 45 suggests current thyroid storm. Alternatively, the Japanese Thyroid Association (JTA) criteria, derived from a large cohort of patients with thyroid storm in Japan and published in 2012, provide a qualitative method to determine the probability of thyroid storm. The JTA criteria separate the diagnosis of thyroid storm into definite versus suspected based on the specific combination of signs and symptoms a patient exhibits and require elevated free triiodothyronine (T3) or free thyroxine (T4) for definite thyroid storm.

Laboratory findings
As with hyperthyroidism, TSH is suppressed. Both free and serum (or total) T3 and T4 are elevated. An elevation in thyroid hormone levels is suggestive of thyroid storm when accompanied by signs of severe hyperthyroidism but is not diagnostic as it may also correlate with uncomplicated hyperthyroidism. Moreover, serum T3 may be normal in critically ill patients due to decreased conversion of T4 to T3. Other potential abnormalities include the following:
Hyperglycemia likely due to catecholamine-mediated effects on insulin release and metabolism as well as increased glycogenolysis, evolving into hypoglycemia when glycogen stores are depleted
Elevated aspartate aminotransferase (AST), bilirubin and lactate dehydrogenase (LDH)
Hypercalcemia and elevated alkaline phosphatase due to increased bone resorption
Elevated white blood cell count

Management
The main strategies for the management of thyroid storm are reducing production and release of thyroid hormone, reducing the effects of thyroid hormone on tissues, replacing fluid losses, and controlling temperature. Thyroid storm requires prompt treatment and hospitalization. Often, admission to the intensive care unit is needed.In high fever, temperature control is achieved with fever reducers such as paracetamol/acetaminophen and external cooling measures (cool blankets, ice packs). Dehydration, which occurs due to fluid loss from sweating, diarrhea, and vomiting, is treated with frequent fluid replacement.  In severe cases, mechanical ventilation may be necessary. Any suspected underlying cause is also addressed.

Iodine
Guidelines recommend the administration of inorganic iodide (potassium iodide or Lugols iodine) to reduce the synthesis and release of thyroid hormone. In high dosage, iodine may reduce the synthesis of thyroid hormone via the Wolff-Chaikoff effect and its release via the Plummer effect </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rhinosporidiosis and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sudden acquired retinal degeneration syndrome and explain in detail? [/INST] Sudden acquired retinal degeneration syndrome (SARDS) is a disease in dogs causing sudden blindness.  It can occur in any breed, but female dogs may be predisposed.  Approximately 4000 cases are seen in the United States annually.

Characteristics
Symptoms include sudden permanent blindness, but may occur more slowly over several days, weeks or months, dilated pupils. Pupillary light reflexes  are usually reduced but present; the slow phase mediated by melanopsin in retinal ganglion cells is retained. Other symptoms commonly seen are similar to those seen with Cushings disease and include increased water consumption and urination, weight gain, confusion, restlessness, behavioral changes and lethargy. These symptoms may develop over a few months preceding the onset of SARDS. Clinical signs and disease progression vary markedly among individual animals, depending on the number and type of hormones that are increased, the degree of hormone elevation, and the age of the dog.Some owners notice a more obvious "eye shine" in photographs due to the dilated pupils and retinal atrophy creating what is described as a "hyper-reflective tapetum".

Causes
The cause of SARDS is considered to be idiopathic and the veterinary community is divided as to its cause, but the most common hypotheses on the causes of the disease possibly include autoimmune disease, or exposure to toxins </s>