<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Lesch–Nyhan syndrome and can you explain it in depth? [/INST] Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.The HGPRT deficiency causes a build-up of uric acid in all body fluids. The combination of increased synthesis and decreased utilization of purines leads to high levels of uric acid production. This results in both high levels of uric acid in the blood and urine, associated with severe gout and kidney problems. Neurological signs include poor muscle control and moderate intellectual disability. These complications usually appear in the first year of life. Beginning in the second year of life, a particularly striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntingtons disease. The cause of the neurological abnormalities remains unknown. Because a lack of HGPRT causes the body to poorly utilize vitamin B12, some males may develop megaloblastic anemia.LNS is inherited in an X-linked recessive manner; the gene mutation is usually carried by the mother and passed on to her son, although one-third of all cases arise de novo (from new mutations) and do not have a family history. LNS is present at birth in baby boys. Most, but not all, persons with this deficiency have severe mental and physical problems throughout life. Cases in females are very rare.The symptoms caused by the buildup of uric acid (gout and kidney symptoms) respond well to treatment with medications such as allopurinol that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond well to treatment. There is no cure, but many affected people live to adulthood. Several new experimental treatments may alleviate symptoms.

Signs and symptoms
LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes affected individuals to adopt a characteristic fencing stance due to the nature of the lesion. Some may also have macrocytic anemia due to the faulty DNA synthesis, most likely due to deficient purine synthesis that leads to a lag of  cell division with respect to increases in cell mass. Virtually all patients are male; males experience delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis but are usually otherwise unaffected.

Overproduction of uric acid
One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant. Overproduction of uric acid may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder. Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness. The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine. The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones or distinct large stones that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some affected people have kidney damage due to such kidney stones. Stones may be the presenting feature of the disease, but can go undetected for months or even years.

Nervous system impairment
The periods before and surrounding birth are typically normal in individuals with LNS. The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals are late in sitting up, while most never crawl or walk. Lack of speech is also a very common trait associated with LNS.Irritability is most often noticed along with the first signs of nervous system impairment. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia), writhing motions (choreoathetosis), and arching of the spine (opisthotonus). Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. As a result, most individuals are initially diagnosed as having cerebral palsy. The motor disability is so extensive that most individuals never walk, and become lifelong wheelchair users.

Self-injuring behavior
Persons affected are cognitively impaired and have behavioral disturbances that emerge between two and three years of age. The uncontrollable self-injury associated with LNS also usually begins at three years of age. The self-injury begins with biting of the lips and tongue; as the disease progresses, affected individuals frequently develop finger biting and headbanging. The self-injury can increase during times of stress. Self-harm is a distinguishing characteristic of the disease and is apparent in 85% of affected males.The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms because of the behavioral disturbances and motor deficits associated with the syndrome. In many ways, the behaviors may be seen as a psychological extension of the compulsion to cause self-injury, and include rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed, and provoking anger from caregivers when affection is desired.Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and coprolalia (involuntary swearing). The development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life.

LNS in females
While carrier females are generally an asymptomatic condition, they do experience an increase in uric acid excretion, and some may develop symptoms of hyperuricemia, and experience gout in their later years. Testing in this context has no clinical consequence, but it may reveal the possibility of transmitting the trait to male children. Women may also require testing if a male child develops LNS. In this instance, a negative test means the sons disease is the result of a new mutation, and the risk in siblings is not increased.Females who carry one copy of the defective gene are carriers with a 50% chance of passing the disease on to their sons. In order for a female to be affected, she would need to have two copies of the mutated gene, one of which would be inherited from her father. Males affected with LNS do not usually have children due to the debilitating effects of the disease. It is possible for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HGPRT gene. Under these circumstances, a girl could be born with LNS, and though there are a few reports of this happening, it is very rare. The overwhelming majority of patients with LNS are male.

Less severe forms
A less severe, related disease, partial HPRT deficiency, is known as Kelley–Seegmiller syndrome (Lesch–Nyhan syndrome involves total HPRT deficiency). Symptoms generally involve less neurological involvement but the disease still causes gout and kidney stones.

Genetics
LNS is due to mutations in the HPRT1 gene, so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT, EC 2.4.2.8). This enzyme is involved in the biochemical pathways the body uses to produce purines, one of the components of DNA and RNA. Defects of this enzyme lead to increased production of uric acid. Since the HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease.The father of an affected male will not be the carrier of the mutant allele, and will not have the disease. An obligate carrier would be a woman who has an affected son and one other affected relative in the maternal line.If a woman is the first in her family with an affected son, Haldanes rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation.The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female.Males with LNS do not reproduce due to the characteristics of the disease. However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected.

Pathophysiology
As in other X-linked diseases, males are affected because they only have one copy of the X chromosome. In Lesch–Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a participant in the recycling of purine nucleotides. Female carriers have a second X chromosome, which contains a "normal" copy of HPRT, preventing the disease from developing, though they may have increased risk of hyperuricemia.A large number of mutations of HPRT are known. Mutations that only mildly decrease the enzymes function do not normally cause the severe form of LNS, but do produce a milder form of the disease which still features purine overproduction accompanied by susceptibility to gout and uric acid nephrolithiasis.Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthetized de novo from amino acids and other precursors. A small part, however, is recycled from degraded DNA of broken-down cells. This is termed the "salvage pathway".HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:
Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
The de novo pathway is stimulated due to an excess of PRPP (5-phospho-D-ribosyl-1-pyrophosphate or simply phosphoribosyl-pyrophosphate).It was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotides during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.Importantly, evidence suggests that one or more lesions in striatal dopaminergic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation. 6-hydroxydopamine toxicity in rodents may be a useful animal model for the syndrome, although this is not proven.
However, the link between dopamine and purine synthesis is a nucleotide called guanosine triphosphate or GTP. The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency.Another animal model for LNS has been proposed to arise from oxidative damage, caused by the hyperuricemia accompanying LNS.  This is based on the theory that uric acid is a powerful reducing agent and likely an important human antioxidant, in high concentration in blood. Thus, it has been suggested that free radicals, oxidative stress, and reactive oxygen species may play some role in the neuropathology of LNS.However, some evidence suggests against a role for uric acid in the neuropathology of Lesch–Nyhan syndrome:

Hyperuricemia associated with classic primary gout, which is caused by low uric acid renal clearance rather than uric acid overproduction, is not associated with neuropathology.
Hypouricemia occurs in a number of purine disorders, in particular xanthinuria. Despite having complete absence of blood uric acid, xanthinuria patients do not have any neuropathology, nor any other disease states – other than the kidney stones caused by accumulation of insoluble xanthine in lieu of uric acid.Similarly,  uric acid does not penetrate the blood–brain barrier well. However, oxidative stress due to uric acid is now thought to figure in metabolic syndrome, atherosclerosis, and stroke, all syndromes associated with high uric acid levels.  Similarly, Superoxide dismutase ( "SOD" ) and SOD-mimetics such as TEMPOL ameliorate the effects of hyperuricemia. Likewise, 6-hydroxydopamine (the putative animal model for Lesch–Nyhans neuropathy) apparently acts as a neurotoxin by generation of reactive oxygen species. It may be that oxidative stress induced by some other oxypurine such as xanthine causes the disease.

Diagnosis
When an affected individual has fully developed the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. Diagnosis is less easy in the early stages, when the three features are not yet obvious. Signs of self-injurious behavior (SIB), results of pedigree analysis and novel molecular biology with genetic testing (called as Diagnostic triad for LNS), often confirms the diagnosis. Suspicion often comes about when the developmental delay of the individual is associated with hyperuricemia. Otherwise, the diagnosis should be alleged when developmental delay is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), caused by uric acid stones. For the most part, Lesch–Nyhan syndrome is first suspected when self-inflicted injury behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch–Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence. Biting the fingers and lips is a definitive feature of Lesch–Nyhan syndrome; in other syndromes associated with self-injury, the behaviors usually consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers. Lesch–Nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction.

Diagnostic approach
The urate to creatinine (breakdown product of creatine phosphate in muscle) concentration ratio in urine is elevated. This is a good indicator of acid overproduction. For children under ten years of age with LNS, a urate to creatinine ratio above two is typically found. Twenty-four-hour urate excretion of more than 20 mg/kg is also typical but is not diagnostic. Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis. Activity of the HGPRT enzyme in cells from any type of tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome. Molecular genetic studies of the HPRT gene mutations may confirm diagnosis, and are particularly helpful for subsequent carrier testing in at-risk females such as close family relatives on the female side.

Testing
The use of biochemical testing for the detection of carriers is technically demanding and not often used. Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both false positive and false negative outcomes. If only a suspected carrier female is available for mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only HGPRT-deficient cells to survive. A mutant frequency of 0.5–5.0 × 10−2 is found in carrier females, while a non-carrier female has a frequency of 1–20 × 10−6. This frequency is usually diagnostic by itself.Molecular genetic testing is the most effective method of testing, as HPRT1 is the only gene known to be associated with LNS. Individuals who display the full Lesch–Nyhan phenotype all have mutations in the HPRT1 gene. Sequence analysis of mRNA is available clinically and can be utilized in order to detect HPRT1 mutations in males affected with Lesch–Nyhan syndrome. Techniques such as RT-PCR, multiplex genomic PCR, and sequence analysis (cDNA and genomic DNA), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests result in cDNA showing the absence of an entire exon or exons, then multiplex genomic PCR testing is performed. Multiplex genomic PCR testing amplifies the nine exons of the HPRT1 gene as eight PCR products. If the exon in question is deleted, the corresponding band will be missing from the multiplex PCR. However, if the exon is present, the exon is sequenced to identify the mutation, therefore causing exclusion of the exon from cDNA. If no cDNA is created by RT-PCR, then multiplex PCR is performed on the notion that most or all of the gene is obliterated.

Treatment
Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.It is essential that the overproduction of uric acid be controlled in order to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis. The drug allopurinol is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi (produced after having chronic gout), kidney stones, and nephropathy, the resulting kidney disease. Allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day. The dose is then adjusted to bring the uric acid level down into the normal range (<3 mg/dL). Most affected individuals can be treated with allopurinol all through life.No medication is effective in controlling the extrapyramidal motor features of the disease. Spasticity, however, can be reduced by the administration of baclofen or benzodiazepines.There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. Even children treated from birth with allopurinol develop behavioral and neurologic problems, despite never having had high serum concentrations of uric acid. Self-injurious and other behaviors are best managed by a combination of medical, physical, and behavioral interventions. The self-mutilation is often reduced by using restraints. Sixty percent of individuals have their teeth extracted in order to avoid self-injury, which families have found to be an effective management technique. Because stress increases self-injury, behavioral management through aversive techniques (which would normally reduce self-injury) actually increases self-injury in individuals with LNS. Nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time. This is often at their own request, and occasionally involves restraints that would appear to be ineffective, as they do not physically prevent biting. Families report that affected individuals are more at ease when restrained.The Matheny Medical and Educational Center [2] in Peapack, NJ, has six Lesch–Nyhan syndrome patients, believed to be the largest concentration of LNS cases in one location, and is recognized as the leading source of information on care issues.
Treatment for LNS patients, according to Gary E. Eddey, MD, medical director, should include: 1) Judicious use of protective devices; 2) Utilization of a behavioral technique commonly referred to as selective ignoring with redirection of activities; and 3) Occasional use of medications.An article in the August 13, 2007 issue of The New Yorker magazine, written by Richard Preston, discusses "deep-brain stimulation" as a possible treatment. It has been performed on a few patients with Lesch–Nyhan syndrome by Dr. Takaomi Taira in Tokyo and by a group in France led by Dr. Philippe Coubes </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Allergy and can you explain it in depth? [/INST] Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note: food intolerances and food poisoning are separate conditions.Common allergens include pollen and certain foods. Metals and other substances may also cause such problems. Food, insect stings, and medications are common causes of severe reactions. Their development is due to both genetic and environmental factors. The underlying mechanism involves immunoglobulin E antibodies (IgE), part of the bodys immune system, binding to an allergen and then to a receptor on mast cells or basophils where it triggers the release of inflammatory chemicals such as histamine. Diagnosis is typically based on a persons medical history. Further testing of the skin or blood may be useful in certain cases. Positive tests, however, may not necessarily mean there is a significant allergy to the substance in question.Early exposure of children to potential allergens may be protective. Treatments for allergies include avoidance of known allergens and the use of medications such as steroids and antihistamines. In severe reactions, injectable adrenalin (epinephrine) is recommended. Allergen immunotherapy, which gradually exposes people to larger and larger amounts of allergen, is useful for some types of allergies such as hay fever and reactions to insect bites. Its use in food allergies is unclear.Allergies are common. In the developed world, about 20% of people are affected by allergic rhinitis, about 6% of people have at least one food allergy, and about 20% have or have had atopic dermatitis at some point in time. Depending on the country, about 1–18% of people have asthma. Anaphylaxis occurs in between 0.05–2% of people. Rates of many allergic diseases appear to be increasing. The word "allergy" was first used by Clemens von Pirquet in 1906.

Signs and symptoms
Many allergens such as dust or pollen are airborne particles. In these cases, symptoms arise in areas in contact with air, such as the eyes, nose, and lungs. For instance, allergic rhinitis, also known as hay fever, causes irritation of the nose, sneezing, itching, and redness of the eyes. Inhaled allergens can also lead to increased production of mucus in the lungs, shortness of breath, coughing, and wheezing.Aside from these ambient allergens, allergic reactions can result from foods, insect stings, and reactions to medications like aspirin and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and hives. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis. Insect stings, food, antibiotics, and certain medicines may produce a systemic allergic response that is also called anaphylaxis; multiple organ systems can be affected, including the digestive system, the respiratory system, and the circulatory system. Depending on the severity, anaphylaxis can include skin reactions, bronchoconstriction, swelling, low blood pressure, coma, and death. This type of reaction can be triggered suddenly, or the onset can be delayed. The nature of anaphylaxis is such that the reaction can seem to be subsiding but may recur throughout a period of time.

Skin
Substances that come into contact with the skin, such as latex, are also common causes of allergic reactions, known as contact dermatitis or eczema. Skin allergies frequently cause rashes, or swelling and inflammation within the skin, in what is known as a "weal and flare" reaction characteristic of hives and angioedema.With insect stings, a large local reaction may occur in the form of an area of skin redness greater than 10 cm in size that can last one to two days. This reaction may also occur after immunotherapy.

Cause
Risk factors for allergies can be placed in two broad categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. However, there have been recent increases in the incidence of allergic disorders that cannot be explained by genetic factors alone. Four major environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.

Dust mites
Dust mite allergy, also known as house dust allergy, is a sensitization and allergic reaction to the droppings of house dust mites. The allergy is common and can trigger allergic reactions such as asthma, eczema, or itching. It is the manifestation of a parasitosis. The mites gut contains potent digestive enzymes (notably peptidase 1) that persist in their feces and are major inducers of allergic reactions such as wheezing. The mites exoskeleton can also contribute to allergic reactions. Unlike scabies mites or skin follicle mites, house dust mites do not burrow under the skin and are not parasitic.

Foods
A wide variety of foods can cause allergic reactions, but 90% of allergic responses to foods are caused by cows milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish. Other food allergies, affecting less than 1 person per 10,000 population, may be considered "rare". The use of hydrolyzed milk baby formula versus standard milk baby formula does not appear to affect the risk.The most common food allergy in the US population is a sensitivity to crustacea. Although peanut allergies are notorious for their severity, peanut allergies are not the most common food allergy in adults or children. Severe or life-threatening reactions may be triggered by other allergens and are more common when combined with asthma.Rates of allergies differ between adults and children. Children can sometimes outgrow peanut allergies. Egg allergies affect one to two percent of children but are outgrown by about two-thirds of children by the age of 5. The sensitivity is usually to proteins in the white, rather than the yolk.Milk-protein allergies are most common in children. Approximately 60% of milk-protein reactions are immunoglobulin E-mediated, with the remaining usually attributable to inflammation of the colon. Some people are unable to tolerate milk from goats or sheep as well as from cows, and many are also unable to tolerate dairy products such as cheese. Roughly 10% of children with a milk allergy will have a reaction to beef. Beef contains small amounts of proteins that are present in greater abundance in cows milk. Lactose intolerance, a common reaction to milk, is not a form of allergy at all, but due to the absence of an enzyme in the digestive tract.Those with tree nut allergies may be allergic to one or to many tree nuts, including pecans, pistachios, pine nuts, and walnuts. In addition, seeds, including sesame seeds and poppy seeds, contain oils in which protein is present, which may elicit an allergic reaction.Allergens can be transferred from one food to another through genetic engineering; however genetic modification can also remove allergens. Little research has been done on the natural variation of allergen concentrations in unmodified crops.

Latex
Latex can trigger an IgE-mediated cutaneous, respiratory, and systemic reaction. The prevalence of latex allergy in the general population is believed to be less than one percent. In a hospital study, 1 in 800 surgical patients (0.125 percent) reported latex sensitivity, although the sensitivity among healthcare workers is higher, between seven and ten percent. Researchers attribute this higher level to the exposure of healthcare workers to areas with significant airborne latex allergens, such as operating rooms, intensive-care units, and dental suites. These latex-rich environments may sensitize healthcare workers who regularly inhale allergenic proteins.The most prevalent response to latex is an allergic contact dermatitis, a delayed hypersensitive reaction appearing as dry, crusted lesions. This reaction usually lasts 48–96 hours. Sweating or rubbing the area under the glove aggravates the lesions, possibly leading to ulcerations. Anaphylactic reactions occur most often in sensitive patients who have been exposed to a surgeons latex gloves during abdominal surgery, but other mucosal exposures, such as dental procedures, can also produce systemic reactions.Latex and banana sensitivity may cross-react.  Furthermore, those with latex allergy may also have sensitivities to avocado, kiwifruit, and chestnut. These people often have perioral itching and local urticaria. Only occasionally have these food-induced allergies induced systemic responses. Researchers suspect that the cross-reactivity of latex with banana, avocado, kiwifruit, and chestnut occurs because latex proteins are structurally homologous with some other plant proteins.

Medications
About 10% of people report that they are allergic to penicillin; however, 90% turn out not to be. Serious allergies only occur in about 0.03%.

Insect stings
Typically, insects which generate allergic responses are either stinging insects (wasps, bees, hornets and ants) or biting insects (mosquitoes, ticks). Stinging insects inject venom into their victims, whilst biting insects normally introduce anti-coagulants.

Toxins interacting with proteins
Another non-food protein reaction, urushiol-induced contact dermatitis, originates after contact with poison ivy, eastern poison oak, western poison oak, or poison sumac. Urushiol, which is not itself a protein, acts as a hapten and chemically reacts with, binds to, and changes the shape of integral membrane proteins on exposed skin cells. The immune system does not recognize the affected cells as normal parts of the body, causing a T-cell-mediated immune response. Of these poisonous plants, sumac is the most virulent. The resulting dermatological response to the reaction between urushiol and membrane proteins includes redness, swelling, papules, vesicles, blisters, and streaking.Estimates vary on the percentage of the population that will have an immune system response. Approximately 25 percent of the population will have a strong allergic response to urushiol. In general, approximately 80 percent to 90 percent of adults will develop a rash if they are exposed to .0050 milligrams (7.7×10−5 gr) of purified urushiol, but some people are so sensitive that it takes only a molecular trace on the skin to initiate an allergic reaction.

Genetics
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins. Allergic parents are more likely to have allergic children, and those childrens allergies are likely to be more severe than those in children of non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. The likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk. Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years. The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.Ethnicity may play a role in some allergies; however, racial factors have been difficult to separate from environmental influences and changes due to migration. It has been suggested that different genetic loci are responsible for asthma, to be specific, in people of European, Hispanic, Asian, and African origins.

Hygiene hypothesis
Allergic diseases are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response. Many bacteria and viruses elicit a TH1-mediated immune response, which down-regulates TH2 responses. The first proposed mechanism of action of the hygiene hypothesis was that insufficient stimulation of the TH1 arm of the immune system leads to an overactive TH2 arm, which in turn leads to allergic disease. In other words, individuals living in too sterile an environment are not exposed to enough pathogens to keep the immune system busy. Since our bodies evolved to deal with a certain level of such pathogens, when they are not exposed to this level, the immune system will attack harmless antigens, and thus normally benign microbial objects—like pollen—will trigger an immune response.The hygiene hypothesis was developed to explain the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were, it is presumed, exposed to more infectious agents through their siblings, than in children from families with only one child. The hygiene hypothesis has been extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of allergic disorders. It is used to explain the increase in allergic diseases that have been seen since industrialization, and the higher incidence of allergic diseases in more developed countries. The hygiene hypothesis has now expanded to include exposure to symbiotic bacteria and parasites as important modulators of immune system development, along with infectious agents.Epidemiological data support the hygiene hypothesis. Studies have shown that various immunological and autoimmune diseases are much less common in the developing world than the industrialized world, and that immigrants to the industrialized world from the developing world increasingly develop immunological disorders in relation to the length of time since arrival in the industrialized world. Longitudinal studies in the third world demonstrate an increase in immunological disorders as a country grows more affluent and, it is presumed, cleaner. The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases. The use of antibacterial cleaning products has also been associated with higher incidence of asthma, as has birth by Caesarean section rather than vaginal birth.

Stress
Chronic stress can aggravate allergic conditions. This has been attributed to a T helper 2 (TH2)-predominant response driven by suppression of interleukin 12 by both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. Stress management in highly susceptible individuals may improve symptoms.

Other environmental factors
Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined. Historically, the trees planted in urban areas were predominantly male to prevent litter from seeds and fruits, but the high ratio of male trees causes high pollen counts, a phenomenon that horticulturist Tom Ogren has called "botanical sexism".Alterations in exposure to microorganisms is another plausible explanation, at present, for the increase in atopic allergy. Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood. Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies. Recent research has shown that some common parasites, such as intestinal worms (e.g., hookworms), secrete chemicals into the gut wall (and, hence, the bloodstream) that suppress the immune system and prevent the body from attacking the parasite. This gives rise to a new slant on the hygiene hypothesis theory—that co-evolution of humans and parasites has led to an immune system that functions correctly only in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive. In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants. However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms. Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies. It may be that the term parasite could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work. For more information on this topic, see Helminthic therapy.

Pathophysiology
Acute response
In the initial stages of allergy, a type I hypersensitivity reaction against an allergen encountered for the first time and presented by a professional antigen-presenting cell causes a response in a type of immune cell called a TH2 lymphocyte, a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage, are sensitized to the allergen.If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis) or localized to specific body systems. Asthma is localized to the respiratory system and eczema is localized to the dermis.

Late-phase response
After the chemical mediators of the acute response subside, late-phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial site. The reaction is usually seen 2–24 hours after the original reaction. Cytokines from mast cells may play a role in the persistence of long-term effects. Late-phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils and are still dependent on activity of TH2 cells.

Allergic contact dermatitis
Although allergic contact dermatitis is termed an "allergic" reaction (which usually refers to type I hypersensitivity), its pathophysiology involves a reaction that more correctly corresponds to a type IV hypersensitivity reaction. In type IV hypersensitivity, there is activation of certain types of T cells (CD8+) that destroy target cells on contact, as well as activated macrophages that produce hydrolytic enzymes.

Diagnosis
Effective management of allergic diseases relies on the ability to make an accurate diagnosis. Allergy testing can help confirm or rule out allergies. Correct diagnosis, counseling, and avoidance advice based on valid allergy test results reduce the incidence of symptoms and need for medications, and improve quality of life. To assess the presence of allergen-specific IgE antibodies, two different methods can be used: a skin prick test, or an allergy blood test. Both methods are recommended, and they have similar diagnostic value.Skin prick tests and blood tests are equally cost-effective, and health economic evidence shows that both tests were cost-effective compared with no test. Early and more accurate diagnoses save cost due to reduced consultations, referrals to secondary care, misdiagnosis, and emergency admissions.Allergy undergoes dynamic changes over time. Regular allergy testing of relevant allergens provides information on if and how patient management can be changed to improve health and quality of life. Annual testing is often the practice for determining whether allergy to milk, egg, soy, and wheat have been outgrown, and the testing interval is extended to 2–3 years for allergy to peanut, tree nuts, fish, and crustacean shellfish. Results of follow-up testing can guide decision-making regarding whether and when it is safe to introduce or re-introduce allergenic food into the diet.

Skin prick testing
Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny punctures or pricks made into the patients skin. Tiny amounts of suspected allergens and/or their extracts (e.g., pollen, grass, mite proteins, peanut extract) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patients skin, with a needle and syringe. Common areas for testing include the inside forearm and the back.
If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients similar to a mosquito bite. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/− meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature. Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.If a serious life-threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines in the last several days.

Patch testing
Patch testing is a method used to determine if a specific substance causes allergic inflammation of the skin. It tests for delayed reactions. It is used to help ascertain the cause of skin contact allergy or contact dermatitis. Adhesive patches, usually treated with several common allergic chemicals or skin sensitizers, are applied to the back. The skin is then examined for possible local reactions at least twice, usually at 48 hours after application of the patch, and again two or three days later.

Blood testing
An allergy blood test is quick and simple and can be ordered by a licensed health care provider (e.g., an allergy specialist) or general practitioner. Unlike skin-prick testing, a blood test can be performed irrespective of age, skin condition, medication, symptom, disease activity, and pregnancy. Adults and children of any age can get an allergy blood test. For babies and very young children, a single needle stick for allergy blood testing is often gentler than several skin pricks.
An allergy blood test is available through most laboratories. A sample of the patients blood is sent to a laboratory for analysis, and the results are sent back a few days later. Multiple allergens can be detected with a single blood sample. Allergy blood tests are very safe since the person is not exposed to any allergens during the testing procedure.
The test measures the concentration of specific IgE antibodies in the blood. Quantitative IgE test results increase the possibility of ranking how different substances may affect symptoms. A rule of thumb is that the higher the IgE antibody value, the greater the likelihood of symptoms. Allergens found at low levels that today do not result in symptoms cannot help predict future symptom development. The quantitative allergy blood result can help determine what a patient is allergic to, help predict and follow the disease development, estimate the risk of a severe reaction, and explain cross-reactivity.A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with allergy tests for specific IgE antibodies for a carefully chosen of allergens is often warranted.
Laboratory methods to measure specific IgE antibodies for allergy testing include enzyme-linked immunosorbent assay (ELISA, or EIA), radioallergosorbent test (RAST) and fluorescent enzyme immunoassay (FEIA).

Other testing
Challenge testing: Challenge testing is when tiny amounts of a suspected allergen are introduced to the body orally, through inhalation, or via other routes. Except for testing food and medication allergies, challenges are rarely performed. When this type of testing is chosen, it must be closely supervised by an allergist.
Elimination/challenge tests: This testing method is used most often with foods or medicines. A patient with a suspected allergen is instructed to modify his diet to totally avoid that allergen for a set time. If the patient experiences significant improvement, he may then be "challenged" by reintroducing the allergen, to see if symptoms are reproduced.
Unreliable tests: There are other types of allergy testing methods that are unreliable, including applied kinesiology (allergy testing through muscle relaxation), cytotoxicity testing, urine autoinjection, skin titration (Rinkel method), and provocative and neutralization (subcutaneous) testing or sublingual provocation.

Differential diagnosis
Before a diagnosis of allergic disease can be confirmed, other plausible causes of the presenting symptoms should be considered. Vasomotor rhinitis, for example, is one of many illnesses that share symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis. Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.

Prevention
Giving peanut products early may decrease the risk of allergies while only breastfeeding during at least the first few months of life may decrease the risk of dermatitis. There is no good evidence that a mothers diet during pregnancy or breastfeeding affects the risk of allergies, nor is there evidence that delayed introduction of certain foods is useful. Early exposure to potential allergens may actually be protective.Fish oil supplementation during pregnancy is associated with a lower risk. Probiotic supplements during pregnancy or infancy may help to prevent atopic dermatitis.

Management
Management of allergies typically involves avoiding the allergy trigger and taking medications to improve the symptoms. Allergen immunotherapy may be useful for some types of allergies.

Medication
Several medications may be used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, and antileukotriene agents are common treatments of allergic diseases. Anticholinergics, decongestants, and other compounds thought to impair eosinophil chemotaxis are also commonly used. Although rare, the severity of anaphylaxis often requires epinephrine injection, and where medical care is unavailable, a device known as an epinephrine autoinjector may be used.

Immunotherapy
Allergen immunotherapy is useful for environmental allergies, allergies to insect bites, and asthma. Its benefit for food allergies is unclear and thus not recommended. Immunotherapy involves exposing people to larger and larger amounts of allergen in an effort to change the immune systems response.Meta-analyses have found that injections of allergens under the skin is effective in the treatment in allergic rhinitis in children and in asthma. The benefits may last for years after treatment is stopped. It is generally safe and effective for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insects.To a lesser extent, the evidence also supports the use of sublingual immunotherapy for rhinitis and asthma. For seasonal allergies the benefit is small. In this form the allergen is given under the tongue and people often prefer it to injections. Immunotherapy is not recommended as a stand-alone treatment for asthma.

Alternative medicine
An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective. EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favoring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases, but evidence does not show effectiveness.A review found no effectiveness of homeopathic treatments and no difference compared with placebo. The authors concluded that based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of homeopathic treatments.According to the National Center for Complementary and Integrative Health, U.S., the evidence is relatively strong that saline nasal irrigation and butterbur are effective, when compared to other alternative medicine treatments, for which the scientific evidence is weak, negative, or nonexistent, such as honey, acupuncture, omega 3s, probiotics, astragalus, capsaicin, grape seed extract, Pycnogenol, quercetin, spirulina, stinging nettle, tinospora, or guduchi.

Epidemiology
The allergic diseases—hay fever and asthma—have increased in the Western world over the past 2–3 decades. Increases in allergic asthma and other atopic disorders in industrialized nations, it is estimated, began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s, although some suggest that a steady rise in sensitization has been occurring since the 1920s. The number of new cases per year of atopy in developing countries has, in general, remained much lower.

Changing frequency
Although genetic factors govern susceptibility to atopic disease, increases in atopy have occurred within too short a period to be explained by a genetic change in the population, thus pointing to environmental or lifestyle changes. Several hypotheses have been identified to explain this increased rate. Increased exposure to perennial allergens may be due to housing changes and increased time spent indoors, and a decreased activation of a common immune control mechanism may be caused by changes in cleanliness or hygiene, and exacerbated by dietary changes, obesity, and decline in physical exercise. The hygiene hypothesis maintains that high living standards and hygienic conditions exposes children to fewer infections. It is thought that reduced bacterial and viral infections early in life direct the maturing immune system away from TH1 type responses, leading to unrestrained TH2 responses that allow for an increase in allergy.Changes in rates and types of infection alone, however, have been unable to explain the observed increase in allergic disease, and recent evidence has focused attention on the importance of the gastrointestinal microbial environment. Evidence has shown that exposure to food and fecal-oral pathogens, such as hepatitis A, Toxoplasma gondii, and Helicobacter pylori (which also tend to be more prevalent in developing countries), can reduce the overall risk of atopy by more than 60%, and an increased rate of parasitic infections has been associated with a decreased prevalence of asthma. It is speculated that these infections exert their effect by critically altering TH1/TH2 regulation. Important elements of newer hygiene hypotheses also include exposure to endotoxins, exposure to pets and growing up on a farm.

History
Some symptoms attributable to allergic diseases are mentioned in ancient sources. Particularly, three members of the Roman Julio-Claudian dynasty (Augustus, Claudius and Britannicus) are suspected to have a family history of atopy. The concept of "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noticed that patients who had received injections of horse serum or smallpox vaccine usually had quicker, more severe reactions to second injections. Pirquet called this phenomenon "allergy" from the Ancient Greek words ἄλλος allos meaning "other" and ἔργον ergon meaning "work".All forms of hypersensitivity used to be classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with a common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity. With this new classification, the word allergy, sometimes clarified as a true allergy, was restricted to type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions involving IgE antibodies.A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE). IgE was simultaneously discovered in 1966–67 by two independent groups: Ishizakas team at the Childrens Asthma Research Institute and Hospital in Denver, USA, and by Gunnar Johansson and Hans Bennich in Uppsala, Sweden. Their joint paper was published in April 1969.

Diagnosis
Radiometric assays include the radioallergosorbent test (RAST test) method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood. Other, newer methods use colorimetric or fluorescence-labeled technology in the place of radioactive isotopes.The RAST methodology was invented and marketed in 1974 by Pharmacia Diagnostics AB, Uppsala, Sweden, and the acronym RAST is actually a brand name. In 1989, Pharmacia Diagnostics AB replaced it with a superior test named the ImmunoCAP Specific IgE blood test, which uses the newer fluorescence-labeled technology.American College of Allergy Asthma and Immunology (ACAAI) and the American Academy of Allergy Asthma and Immunology (AAAAI) issued the Joint Task Force Report "Pearls and pitfalls of allergy diagnostic testing" in 2008, and is firm in its statement that the term RAST is now obsolete:

The term RAST became a colloquialism for all varieties of (in vitro allergy) tests.  This is unfortunate because it is well recognized that there are well-performing tests and some that do not perform so well, yet they are all called RASTs, making it difficult to distinguish which is which. For these reasons, it is now recommended that use of RAST as a generic descriptor of these tests be abandoned.
The updated version, the ImmunoCAP Specific IgE blood test, is the only specific IgE assay to receive Food and Drug Administration approval to quantitatively report to its detection limit of 0.1kU/L.

Medical specialty
An allergist is a physician specially trained to manage and treat allergies, asthma, and the other allergic diseases.
In the United States physicians holding certification by the American Board of Allergy and Immunology (ABAI) have successfully completed an accredited educational program and evaluation process, including a proctored examination to demonstrate knowledge, skills, and experience in patient care in allergy and immunology. Becoming an allergist/immunologist requires completion of at least nine years of training. After completing medical school and graduating with a medical degree, a physician will undergo three years of training in internal medicine (to become an internist) or pediatrics (to become a pediatrician). Once physicians have finished training in one of these specialties, they must pass the exam of either the American Board of Pediatrics (ABP), the American Osteopathic Board of Pediatrics (AOBP), the American Board of Internal Medicine (ABIM), or the American Osteopathic Board of Internal Medicine (AOBIM) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Flood and can you explain it in depth? [/INST] A flood is an overflow of water (or rarely other fluids) that submerges land that is usually dry. In the sense of "flowing water", the word may also be applied to the inflow of the tide. Floods are an area of study of the discipline hydrology and are of significant concern in agriculture, civil engineering and public health.   Human changes to the environment often increase the intensity and frequency of flooding, for example land use changes such as deforestation and removal of wetlands, changes in waterway course or flood controls such as with levees, and larger environmental issues such as climate change and sea level rise. In particular climate changes increased rainfall and extreme weather events increases the severity of other causes for flooding, resulting in more intense floods and increased flood risk.Flooding may occur as an overflow of water from water bodies, such as a river, lake, or ocean, in which the water overtops or breaks levees, resulting in some of that water escaping its usual boundaries, or it may occur due to an accumulation of rainwater on saturated ground in an areal flood. While the size of a lake or other body of water will vary with seasonal changes in precipitation and snow melt, these changes in size are unlikely to be considered significant unless they flood property or drown domestic animals.
Floods can also occur in rivers when the flow rate exceeds the capacity of the river channel, particularly at bends or meanders in the waterway. Floods often cause damage to homes and businesses if they are in the natural flood plains of rivers.  While riverine flood damage can be eliminated by moving away from rivers and other bodies of water, people have traditionally lived and worked by rivers because the land is usually flat and fertile and because rivers provide easy travel and access to commerce and industry. Flooding can lead to secondary consequences in addition to damage to property, such as long-term displacement of residents and creating increased spread of waterborne diseases and vector-bourne disesases transmitted by mosquitos.

Types
Areal
Floods can happen on flat or low-lying areas when water is supplied by rainfall or snowmelt more rapidly than it can either infiltrate or run off. The excess accumulates in place, sometimes to hazardous depths. Surface soil can become saturated, which effectively stops infiltration, where the water table is shallow, such as a floodplain, or from intense rain from one or a series of storms. Infiltration also is slow to negligible through frozen ground, rock, concrete, paving, or roofs. Areal flooding begins in flat areas like floodplains and in local depressions not connected to a stream channel, because the velocity of overland flow depends on the surface slope. Endorheic basins may experience areal flooding during periods when precipitation exceeds evaporation.

Riverine (Channel)
Floods occur in all types of river and stream channels, from the smallest ephemeral streams in humid zones to normally-dry channels in arid climates to the worlds largest rivers. When overland flow occurs on tilled fields, it can result in a muddy flood where sediments are picked up by run off and carried as suspended matter or bed load. Localized flooding may be caused or exacerbated by drainage obstructions such as landslides, ice, debris, or beaver dams.
Slow-rising floods most commonly occur in large rivers with large catchment areas. The increase in flow may be the result of sustained rainfall, rapid snow melt, monsoons, or tropical cyclones. However, large rivers may have rapid flooding events in areas with dry climate, since they may have large basins but small river channels and rainfall can be very intense in smaller areas of those basins.
Rapid flooding events, including flash floods, more often occur on smaller rivers, rivers with steep valleys, rivers that flow for much of their length over impermeable terrain, or normally-dry channels. The cause may be localized convective precipitation (intense thunderstorms) or sudden release from an upstream impoundment created behind a dam, landslide, or glacier. In one instance, a flash flood killed eight people enjoying the water on a Sunday afternoon at a popular waterfall in a narrow canyon. Without any observed rainfall, the flow rate increased from about 50 to 1,500 cubic feet per second (1.4 to 42 m3/s) in just one minute. Two larger floods occurred at the same site within a week, but no one was at the waterfall on those days. The deadly flood resulted from a thunderstorm over part of the drainage basin, where steep, bare rock slopes are common and the thin soil was already saturated.
Flash floods are the most common flood type in normally-dry channels in arid zones, known as arroyos in the southwest United States and many other names elsewhere. In that setting, the first flood water to arrive is depleted as it wets the sandy stream bed. The leading edge of the flood thus advances more slowly than later and higher flows. As a result, the rising limb of the hydrograph becomes ever quicker as the flood moves downstream, until the flow rate is so great that the depletion by wetting soil becomes insignificant.

Estuarine and coastal
Flooding in estuaries is commonly caused by a combination of storm surges caused by winds and low barometric pressure and large waves meeting high upstream river flows.
Coastal areas may be flooded by storm surges combining with high tides and large wave events at sea, resulting in waves over-topping flood defenses or in severe cases by tsunami or tropical cyclones. A storm surge, from either a tropical cyclone or an extratropical cyclone, falls within this category. Research from the NHC (National Hurricane Center) explains: "Storm surge is an additional rise of water generated by a storm, over and above the predicted astronomical tides. Storm surge should not be confused with storm tide, which is defined as the water level rise due to the combination of storm surge and the astronomical tide. This rise in water level can cause extreme flooding in coastal areas particularly when storm surge coincides with spring tide, resulting in storm tides reaching up to 20 feet or more in some cases."

Urban flooding
Catastrophic
Catastrophic riverine flooding is usually associated with major infrastructure failures such as the collapse of a dam, but they may also be caused by drainage channel modification from a landslide, earthquake or volcanic eruption. Examples include outburst floods and lahars. Tsunamis can cause catastrophic coastal flooding, most commonly resulting from undersea earthquakes.

Causes
Upslope factors
The amount, location, and timing of water reaching a drainage channel from natural precipitation and controlled or uncontrolled reservoir releases determines the flow at downstream locations.  Some precipitation evaporates, some slowly percolates through soil, some may be temporarily sequestered as snow or ice, and some may produce rapid runoff from surfaces including rock, pavement, roofs, and saturated or frozen ground.  The fraction of incident precipitation promptly reaching a drainage channel has been observed from nil for light rain on dry, level ground to as high as 170 percent for warm rain on accumulated snow.Most precipitation records are based on a measured depth of water received within a fixed time interval.  Frequency of a precipitation threshold of interest may be determined from the number of measurements exceeding that threshold value within the total time period for which observations are available.  Individual data points are converted to intensity by dividing each measured depth by the period of time between observations. This intensity will be less than the actual peak intensity if the duration of the rainfall event was less than the fixed time interval for which measurements are reported.  Convective precipitation events (thunderstorms) tend to produce shorter duration storm events than orographic precipitation. Duration, intensity, and frequency of rainfall events are important to flood prediction.  Short duration precipitation is more significant to flooding within small drainage basins.The most important upslope factor in determining flood magnitude is the land area of the watershed upstream of the area of interest.  Rainfall intensity is the second most important factor for watersheds of less than approximately 30 square miles or 80 square kilometres.  The main channel slope is the second most important factor for larger watersheds.  Channel slope and rainfall intensity become the third most important factors for small and large watersheds, respectively.Time of Concentration is the time required for runoff from the most distant point of the upstream drainage area to reach the point of the drainage channel controlling flooding of the area of interest. The time of concentration defines the critical duration of peak rainfall for the area of interest. The critical duration of intense rainfall might be only a few minutes for roof and parking lot drainage structures, while cumulative rainfall over several days would be critical for river basins.

Downslope factors
Water flowing downhill ultimately encounters downstream conditions slowing movement. The final limitation in coastal flooding lands is often the ocean or some coastal flooding bars which form natural lakes. In flooding low lands, elevation changes such as tidal fluctuations are significant determinants of coastal and estuarine flooding. Less predictable events like tsunamis and storm surges may also cause elevation changes in large bodies of water. Elevation of flowing water is controlled by the geometry of the flow channel and, especially, by depth of channel, speed of flow and amount of sediments in it  Flow channel restrictions like bridges and canyons tend to control water elevation above the restriction. The actual control point for any given reach of the drainage may change with changing water elevation, so a closer point may control for lower water levels until a more distant point controls at higher water levels.
Effective flood channel geometry may be changed by growth of vegetation, accumulation of ice or debris, or construction of bridges, buildings, or levees within the flood channel.

Coincidence
Extreme flood events often result from coincidence such as unusually intense, warm rainfall melting heavy snow pack, producing channel obstructions from floating ice, and releasing small impoundments like beaver dams. Coincident events may cause extensive flooding to be more frequent than anticipated from simplistic statistical prediction models considering only precipitation runoff flowing within unobstructed drainage channels. Debris modification of channel geometry is common when heavy flows move uprooted woody vegetation and flood-damaged structures and vehicles, including boats and railway equipment. Recent field measurements during the 2010–11 Queensland floods showed that any criterion solely based upon the flow velocity, water depth or specific momentum cannot account for the hazards caused by velocity and water depth fluctuations. These considerations ignore further the risks associated with large debris entrained by the flow motion.Some researchers have mentioned the storage effect in urban areas with transportation corridors created by cut and fill. Culverted fills may be converted to impoundments if the culverts become blocked by debris, and flow may be diverted along streets.  Several studies have looked into the flow patterns and redistribution in streets during storm events and the implication on flood modelling.

Climate change
Intentional flooding
The intentional flooding of land that would otherwise remain dry may take place for military, agricultural, or river-management purposes. This is a form of hydraulic engineering.
Agricultural flooding may occur in preparing paddy fields for the growing of semi-aquatic rice in many countries.
Flooding for river management may occur in the form of diverting flood waters in a river at flood stage upstream from areas that are considered more valuable than the areas that are sacrificed in this way. This may be done ad hoc, as in the 2011 intentional breach of levees by the United States Army Corps of Engineers in Missouri, or permanently, as in the so-called overlaten (literally "let-overs"), an intentionally lowered segment in Dutch riparian levees, like the Beerse Overlaat in the left levee of the Meuse between the villages of Gassel and Linden, North Brabant.
Military inundation creates an obstacle in the field that is intended to impede the movement of the enemy. This may be done both for offensive and defensive purposes. Furthermore, in so far as the methods used are a form of hydraulic engineering, it may be useful to differentiate between controlled inundations (as in most historic inundations in the Netherlands under the Dutch Republic and its successor states in that area and exemplified in the two Hollandic Water Lines, the Stelling van Amsterdam, the Frisian Water Line, the IJssel Line, the Peel-Raam Line, and the Grebbe line in that country) and uncontrolled ones (as in the second Siege of Leiden during the first part of the Eighty Years War, and the Inundation of Walcheren, and the Inundation of the Wieringermeer during the Second World War). To count as controlled, a military inundation has to take the interests of the civilian population into account, by allowing them a timely evacuation, by making the inundation reversible, and by making an attempt to minimize the adverse ecological impact of the inundation. That impact may also be adverse in a hydrogeological sense if the inundation lasts a long time.

Effects
Floods can also be a huge destructive power. When water flows, it has the ability to demolish all kinds of buildings and objects, such as  bridges, structures, houses, trees, cars...  For example, in Bangladesh in 2007, a flood was responsible for the destruction of more than one million houses. And yearly in the United States, floods cause over $7 billion in damage.

Primary effects
The primary effects of flooding include loss of life and damage to buildings and other structures, including bridges, sewerage systems, roadways, and canals.

Floods also frequently damage power transmission and sometimes power generation, which then has knock-on effects caused by the loss of power. This includes loss of drinking water treatment and water supply, which may result in loss of drinking water or severe water contamination. It may also cause the loss of sewage disposal facilities. Lack of clean water combined with human sewage in the flood waters raises the risk of waterborne diseases, which can include typhoid, giardia, cryptosporidium, cholera and many other diseases depending upon the location of the flood.
Damage to roads and transport infrastructure may make it difficult to mobilize aid to those affected or to provide emergency health treatment.
Flood waters typically inundate farm land, making the land unworkable and preventing crops from being planted or harvested, which can lead to shortages of food both for humans and farm animals. Entire harvests for a country can be lost in extreme flood circumstances. Some tree species may not survive prolonged flooding of their root systems.

Health effects
Fatalities connected directly to floods are usually caused by drowning; the waters in a flood are very deep and have strong currents. Deaths do not just occur from drowning, deaths are connected with dehydration, heat stroke, heart attack and any other illness that needs medical supplies that cannot be delivered.Injuries can lead to an excessive amount of morbidity when a flood occurs. Injuries are not isolated to just those who were directly in the flood, rescue teams and even people delivering supplies can sustain an injury. Injuries can occur anytime during the flood process; before, during and after. During floods accidents occur with falling debris or any of the many fast moving objects in the water. After the flood rescue attempts are where large numbers injuries can occur.Communicable diseases are increased due to many pathogens and bacteria that are being transported by the water.There are many waterborne diseases such as cholera, hepatitis A, hepatitis E and diarrheal diseases, to mention a few. Gastrointestinal disease and diarrheal diseases are very common due to a lack of clean water during a flood. Most of clean water supplies are contaminated when flooding occurs. Hepatitis A and E are common because of the lack of sanitation in the water and in living quarters depending on where the flood is and how prepared the community is for a flood.When floods hit, people lose nearly their crops, livestock, and food reserves and face starvation.

Urban flooding can cause chronically wet houses, leading to the growth of indoor mold and resulting in adverse health effects, particularly respiratory symptoms. Respiratory diseases are a common after the disaster has occurred. This depends on the amount of water damage and mold that grows after an incident. Research suggests that there will be an increase of 30-50% in adverse respiratory health outcomes caused by dampness and mold exposure for those living in coastal and wetland areas. Fungal contamination in homes is associated with increased allergic rhinitis and asthma.  Vector borne diseases increase as well due to the increase in still water after the floods have settled. The diseases that are vector borne are  malaria, dengue, West Nile, and yellow fever. Floods have a huge impact on victims psychosocial integrity. People suffer from a wide variety of losses and stress. One of the most treated illness in long-term health problems are depression caused by the flood and all the tragedy that flows with one.

Loss of life
Below is a list of the deadliest floods worldwide, showing events with death tolls at or above 100,000 individuals.

Secondary and long-term effects
Economic hardship due to a temporary decline in tourism, rebuilding costs, or food shortages leading to price increases is a common after-effect of severe flooding. The impact on those affected may cause psychological damage to those affected, in particular where deaths, serious injuries and loss of property occur.
Urban flooding also has significant economic implications for affected neighborhoods. In the United States, industry experts estimate that wet basements can lower property values by 10–25 percent and are cited among the top reasons for not purchasing a home. According to the U.S. Federal Emergency Management Agency (FEMA), almost 40 percent of small businesses never reopen their doors following a flooding disaster. In the United States, insurance is available against flood damage to both homes and businesses.

Benefits
Floods (in particular more frequent or smaller floods) can also bring many benefits, such as recharging ground water, making soil more fertile and increasing nutrients in some soils. Flood waters provide much needed water resources in arid and semi-arid regions where precipitation can be very unevenly distributed throughout the year and kills pests in the farming land. Freshwater floods particularly play an important role in maintaining ecosystems in river corridors and are a key factor in maintaining floodplain biodiversity. Flooding can spread nutrients to lakes and rivers, which can lead to increased biomass and improved fisheries for a few years.
For some fish species, an inundated floodplain may form a highly suitable location for spawning with few predators and enhanced levels of nutrients or food. Fish, such as the weather fish, make use of floods in order to reach new habitats. Bird populations may also profit from the boost in food production caused by flooding.Periodic flooding was essential to the well-being of ancient communities along the Tigris-Euphrates Rivers, the Nile River, the Indus River, the Ganges and the Yellow River among others. The viability of hydropower, a renewable source of energy, is also higher in flood prone regions.

Flood safety planning
In the United States, the National Weather Service gives out the advice "Turn Around, Dont Drown" for floods; that is, it recommends that people get out of the area of a flood, rather than trying to cross it. At the most basic level, the best defense against floods is to seek higher ground for high-value uses while balancing the foreseeable risks with the benefits of occupying flood hazard zones.: 22–23  Critical community-safety facilities, such as hospitals, emergency-operations centers, and police, fire, and rescue services, should be built in areas least at risk of flooding. Structures, such as bridges, that must unavoidably be in flood hazard areas should be designed to withstand flooding. Areas most at risk for flooding could be put to valuable uses that could be abandoned temporarily as people retreat to safer areas when a flood is imminent.
Planning for flood safety involves many aspects of analysis and engineering, including:

observation of previous and present flood heights and inundated areas,
statistical, hydrologic, and hydraulic model analyses,
mapping inundated areas and flood heights for future flood scenarios,
long-term land use planning and regulation,
engineering design and construction of structures to control or withstand flooding,
intermediate-term monitoring, forecasting, and emergency-response planning, and
short-term monitoring, warning, and response operations.Each topic presents distinct yet related questions with varying scope and scale in time, space, and the people involved. Attempts to understand and manage the mechanisms at work in floodplains have been made for at least six millennia.In the United States, the Association of State Floodplain Managers works to promote education, policies, and activities that mitigate current and future losses, costs, and human suffering caused by flooding and to protect the natural and beneficial functions of floodplains – all without causing adverse impacts. A portfolio of best practice examples for disaster mitigation in the United States is available from the Federal Emergency Management Agency.

Control
In many countries around the world, waterways prone to floods are often carefully managed. Defenses such as detention basins, levees, bunds, reservoirs, and weirs are used to prevent waterways from overflowing their banks. When these defenses fail, emergency measures such as sandbags or portable inflatable tubes are often used to try to stem flooding. Coastal flooding has been addressed in portions of Europe and the Americas with coastal defenses, such as sea walls, beach nourishment, and barrier islands.
In the riparian zone near rivers and streams, erosion control measures can be taken to try to slow down or reverse the natural forces that cause many waterways to meander over long periods of time. Flood controls, such as dams, can be built and maintained over time to try to reduce the occurrence and severity of floods as well. In the United States, the U.S. Army Corps of Engineers maintains a network of such flood control dams.
In areas prone to urban flooding, one solution is the repair and expansion of man-made sewer systems and stormwater infrastructure. Another strategy is to reduce impervious surfaces in streets, parking lots and buildings through natural drainage channels, porous paving, and wetlands (collectively known as green infrastructure or sustainable urban drainage systems (SUDS)). Areas identified as flood-prone can be converted into parks and playgrounds that can tolerate occasional flooding. Ordinances can be adopted to require developers to retain stormwater on site and require buildings to be elevated, protected by floodwalls and levees, or designed to withstand temporary inundation. Property owners can also invest in solutions themselves, such as re-landscaping their property to take the flow of water away from their building and installing rain barrels, sump pumps, and check valves.
In some areas, the presence of certain species (such as beavers) can be beneficial for flood control reasons. Beavers build and maintain beaver dams which will reduce the height of flood waves moving down the river (during periods of heavy rains), and will reduce or eliminate damage to human structures, at the cost of minor flooding near the dams (often on farmland). Besides this, they also boost wildlife populations and filter pollutants (manure, fertilisers, slurry). UK environment minister Rebecca Pow stated that in the future the beavers could be considered a "public good" and landowners would be paid to have them on their land.

Flood risk management
Analysis of flood information
A series of annual maximum flow rates in a stream reach can be analyzed statistically to estimate the 100-year flood and floods of other recurrence intervals there. Similar estimates from many sites in a hydrologically similar region can be related to measurable characteristics of each drainage basin to allow indirect estimation of flood recurrence intervals for stream reaches without sufficient data for direct analysis.
Physical process models of channel reaches are generally well understood and will calculate the depth and area of inundation for given channel conditions and a specified flow rate, such as for use in floodplain mapping and flood insurance. Conversely, given the observed inundation area of a recent flood and the channel conditions, a model can calculate the flow rate. Applied to various potential channel configurations and flow rates, a reach model can contribute to selecting an optimum design for a modified channel. Various reach models are available as of 2015, either 1D models (flood levels measured in the channel) or 2D models (variable flood depths measured across the extent of a floodplain). HEC-RAS, the Hydraulic Engineering Center model, is among the most popular software, if only because it is available free of charge. Other models such as TUFLOW combine 1D and 2D components to derive flood depths across both river channels and the entire floodplain.
Physical process models of complete drainage basins are even more complex. Although many processes are well understood at a point or for a small area, others are poorly understood at all scales, and process interactions under normal or extreme climatic conditions may be unknown. Basin models typically combine land-surface process components (to estimate how much rainfall or snowmelt reaches a channel) with a series of reach models. For example, a basin model can calculate the runoff hydrograph that might result from a 100-year storm, although the recurrence interval of a storm is rarely equal to that of the associated flood. Basin models are commonly used in flood forecasting and warning, as well as in analysis of the effects of land use change and climate change.

Flood forecasting
Anticipating floods before they occur allows for precautions to be taken and people to be warned so that they can be prepared in advance for flooding conditions. For example, farmers can remove animals from low-lying areas and utility services can put in place emergency provisions to re-route services if needed. Emergency services can also make provisions to have enough resources available ahead of time to respond to emergencies as they occur. People can evacuate areas to be flooded.
In order to make the most accurate flood forecasts for waterways, it is best to have a long time-series of historical data that relates stream flows to measured past rainfall events. Coupling this historical information with real-time knowledge about volumetric capacity in catchment areas, such as spare capacity in reservoirs, ground-water levels, and the degree of saturation of area aquifers is also needed in order to make the most accurate flood forecasts.
Radar estimates of rainfall and general weather forecasting techniques are also important components of good flood forecasting. In areas where good quality data is available, the intensity and height of a flood can be predicted with fairly good accuracy and plenty of lead time. The output of a flood forecast is typically a maximum expected water level and the likely time of its arrival at key locations along a waterway, and it also may allow for the computation of the likely statistical return period of a flood. In many developed countries, urban areas at risk of flooding are protected against a 100-year flood – that is a flood that has a probability of around 63% of occurring in any 100-year period of time.
According to the U.S. National Weather Service (NWS) Northeast River Forecast Center (RFC) in Taunton, Massachusetts, a rule of thumb for flood forecasting in urban areas is that it takes at least 1 inch (25 mm) of rainfall in around an hours time in order to start significant ponding of water on impermeable surfaces. Many NWS RFCs routinely issue Flash Flood Guidance and Headwater Guidance, which indicate the general amount of rainfall that would need to fall in a short period of time in order to cause flash flooding or flooding on larger water basins.In the United States, an integrated approach to real-time hydrologic computer modelling uses observed data from the U.S. Geological Survey (USGS), various cooperative observing networks, various automated weather sensors, the NOAA National Operational Hydrologic Remote Sensing Center (NOHRSC), various hydroelectric companies, etc. combined with quantitative precipitation forecasts (QPF) of expected rainfall and/or snow melt to generate daily or as-needed hydrologic forecasts. The NWS also cooperates with Environment Canada on hydrologic forecasts that affect both the US and Canada, like in the area of the Saint Lawrence Seaway.
The Global Flood Monitoring System, "GFMS", a computer tool which maps flood conditions worldwide, is available online. Users anywhere in the world can use GFMS to determine when floods may occur in their area. GFMS uses precipitation data from NASAs Earth observing satellites and the Global Precipitation Measurement satellite, "GPM". Rainfall data from GPM is combined with a land surface model that incorporates vegetation cover, soil type, and terrain to determine how much water is soaking into the ground, and how much water is flowing into streamflow.
Users can view statistics for rainfall, streamflow, water depth, and flooding every 3 hours, at each 12-kilometer gridpoint on a global map. Forecasts for these parameters are 5 days into the future. Users can zoom in to see inundation maps (areas estimated to be covered with water) in 1-kilometer resolution.

Society and culture
Myths and religion
Legends of great, civilization-destroying floods are widespread in many cultures. Flood events in the form of divine retribution have also been described in religious texts. The Genesis flood narrative plays a prominent role in Judaism, Christianity and Islam.

Etymology
The word "flood" comes from the Old English flōd, a word common to Germanic languages (compare German Flut, Dutch vloed from the same root as is seen in flow, float; also compare with Latin fluctus, flumen), meaning "a flowing of water, tide, an overflowing of land by water, a deluge, Noahs Flood; mass of water, river, sea, wave," </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Refsum disease and can you explain it in depth? [/INST] Refsum disease  is an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Refsum disease typically is adolescent onset and is diagnosed by above average levels of phytanic acid. Humans obtain the necessary phytanic acid primarily through diet. It is still unclear what function phytanic acid plays physiologically in humans, but has been found to regulate fatty acid metabolism in the liver of mice.

Presentation
Individuals with Refsum disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation or remission occur. Symptoms also include ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including retinitis pigmentosa, cataracts, and night blindness. In 80% of patients diagnosed with Refsum disease, sensorineural hearing loss has been reported. This is hearing loss as the result of damage to the inner ear or the nerve connectIng ear to the brain.

Cause
Refsum disease is a peroxisomal disorder caused by the impaired alpha-oxidation of branched chain fatty acids resulting in buildup of phytanic acid and its derivatives in the plasma and tissues. This may be due to deficiencies of phytanoyl-CoA hydroxylase or peroxin-7 activity. In general, Refsum disease is caused by PHYH mutations.PEX7 gene mutations can interrupt the peroxisomal transport of proteins as this gene codes for the peroxin 7 protein receptor. These mutations in the PEX7 gene generally lead to rhizomelic chondrodysplasia punctata type 1- which impairs development of many parts of the body </s>