<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 Aphthous stomatitis and can you explain it in depth? [/INST] Aphthous stomatitis, or recurrent aphthous stomatitis (RAS), is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term canker sore is also used, mainly in North America, although it may also refer to other types of mouth ulcers. The cause is not completely understood but involves a T cell-mediated immune response triggered by a variety of factors which may include nutritional deficiencies, local trauma, stress, hormonal influences, allergies, genetic predisposition, certain foods, dehydration, some food additives, or some hygienic chemical additives like SDS (common in toothpaste).
These ulcers occur periodically and heal completely between attacks. In the majority of cases, the individual ulcers last about 7–10 days, and ulceration episodes occur 3–6 times per year. Most appear on the non-keratinizing epithelial surfaces in the mouth – i.e. anywhere except the attached gingiva, the hard palate and the dorsum of the tongue – although the more severe forms, which are less common, may also involve keratinizing epithelial surfaces. Symptoms range from a minor nuisance to interfering with eating and drinking. The severe forms may be debilitating, even causing weight loss due to malnutrition.
The condition is very common, affecting about 20% of the general population to some degree. The onset is often during childhood or adolescence, and the condition usually lasts for several years before gradually disappearing. There is no cure, and treatments such as corticosteroids aim to manage pain, reduce healing time and reduce the frequency of episodes of ulceration.

Signs and symptoms
Persons with aphthous stomatitis have no detectable systemic symptoms or signs (i.e., outside the mouth). Generally, symptoms may include prodromal sensations such as burning, itching, or stinging, which may precede the appearance of any lesion by some hours; and pain, which is often out of proportion to the extent of the ulceration and is worsened by physical contact, especially with certain foods and drinks (e.g., if they are acidic or abrasive). Pain is worst in the days immediately following the initial formation of the ulcer, and then recedes as healing progresses. If there are lesions on the tongue, speaking and chewing can be uncomfortable, and ulcers on the soft palate, back of the throat, or esophagus can cause painful swallowing. Signs are limited to the lesions themselves.
Ulceration episodes usually occur about 3–6 times per year. However, severe disease is characterized by virtually constant ulceration (new lesions developing before old ones have healed) and may cause debilitating chronic pain and interfere with comfortable eating. In severe cases, this prevents adequate nutrient intake leading to malnutrition and weight loss.Aphthous ulcers typically begin as erythematous macules (reddened, flat area of mucosa) which develop into ulcers that are covered with a yellow-grey fibrinous membrane that can be scraped away. A reddish "halo" surrounds the ulcer. The size, number, location, healing time, and periodicity between episodes of ulcer formation are all dependent upon the subtype of aphthous stomatitis.

Causes
The cause is not entirely clear, but is thought to be multifactorial. It has been suggested that aphthous stomatitis is not a single entity, but rather a group of conditions with different causes. Multiple research studies have attempted to identify a causative organism, but aphthous stomatitis appears to be non-contagious, non-infectious, and not sexually transmissible. The mucosal destruction is thought to be the result of a T cell (T lymphocyte) mediated immune response which involves the generation of interleukins and tumor necrosis factor alpha (TNF-α). Mast cells and macrophages are also involved, secreting TNF-α along with the T cells. When early aphthous ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T cells. Persons with aphthous stomatitis also have circulating lymphocytes which react with peptides 91–105 of heat shock protein 65–60, and the ratio of CD4+ T cells to CD8+ T cells in the peripheral blood of individuals with aphthous stomatitis is decreased.Aphthous stomatitis has been associated with other autoimmune diseases, namely systemic lupus erythematosus, Behçets disease and inflammatory bowel diseases. However, common autoantibodies are not detected in most patients, and the condition tends to resolve spontaneously with advancing age rather than worsen.
Evidence for the T cell-mediated mechanism of mucosal destruction is strong, but the exact triggers for this process are unknown and are thought to be multiple and varied from one person to the next. This suggests that there are a number of possible triggers, each of which is capable of producing the disease in different subgroups. In other words, different subgroups appear to have different causes for the condition. These can be considered in three general groups, namely primary immuno-dysregulation, decrease of the mucosal barrier and states of heightened antigenic sensitivity (see below). Risk factors in aphthous stomatitis are also sometimes considered as either host-related or environmental.

Immunity
At least 40% of people with aphthous stomatitis have a positive family history, suggesting that some people are genetically predisposed to developing oral ulceration. HLA-B12, HLA-B51, HLA-Cw7, HLA-A2, HLA-A11, and HLA-DR2 are examples of human leukocyte antigen types associated with aphthous stomatitis. However, these HLA types are inconsistently associated with the condition, and also vary according to ethnicity. People who have a positive family history of aphthous stomatitis tend to develop a more severe form of the condition, and at an earlier age than is typical.Stress has effects on the immune system, which may explain why some cases directly correlate with stress. It is often stated that in studies of students with the condition, ulceration is exacerbated during examination periods and lessened during periods of vacation. Alternatively, it has been suggested that oral parafunctional activities such as lip or cheek chewing become more pronounced during periods of stress, and hence the mucosa is subjected to more minor trauma.Aphthous-like ulceration also occurs in conditions involving systemic immuno-dysregulation, e.g. cyclic neutropenia and human immunodeficiency virus infection. In cyclic neutropenia, more severe oral ulceration occurs during periods of severe immuno-dysregulation, and resolution of the underlying neutropenia is associated with healing of the ulcers. The relative increase in percentage of CD8+ T cells, caused by a reduction in numbers of CD4+ T cells may be implicated in RAS-type ulceration in HIV infection.

Mucosal barrier
The thickness of the mucosa may be an important factor in aphthous stomatitis. Usually, ulcers form on the thinner, non-keratinizing mucosal surfaces in the mouth. Factors which decrease the thickness of the mucosa increase the frequency of occurrence, and factors which increase the thickness of the mucosa correlate with decreased ulceration.The nutritional deficiencies associated with aphthous stomatitis (vitamin B12, folate, and iron) can all cause a decrease in the thickness of the oral mucosa (atrophy).Local trauma is also associated with aphthous stomatitis, and it is known that trauma can decrease the mucosal barrier. Trauma could occur during injections of local anesthetic in the mouth, or otherwise during dental treatments, frictional trauma from a sharp surface in the mouth such as broken tooth, or from tooth brushing.Hormonal factors are capable of altering the mucosal barrier. In one study, a small group of females with aphthous stomatitis had fewer occurrences of aphthous ulcers during the luteal phase of the menstrual cycle or with use of the contraceptive pill. This phase is associated with a fall in progestogen levels, mucosal proliferation and keratinization. This subgroup often experiences remission during pregnancy. However, other studies report no correlation between aphthous stomatitis and menstrual period, pregnancy or menopause.Aphthous stomatitis is more common in people who smoke, and there is also a correlation between habit duration and severity of the condition. Tobacco use is associated with an increase in keratinization of the oral mucosa. In extreme forms, this may manifest as leukoplakia or stomatitis nicotina (smokers keratosis). This increased keratinization may mechanically reinforce the mucosa and reduce the tendency of ulcers to form after minor trauma, or present a more substantial barrier to microbes and antigens, but this is unclear. Nicotine is also known to stimulate production of adrenal steroids and reduce production of TNF-α, interleukin-1 and interleukin-6. Smokeless tobacco products also seem to protect against aphthous stomatitis. Cessation of smoking is known to sometimes precede the onset of aphthous stomatitis in people previously unaffected, or exacerbate the condition in those who were already experiencing aphthous ulceration. Despite this correlation, starting smoking again does not usually lessen the condition.

Antigenic sensitivity
Various antigenic triggers have been implicated as a trigger, including L forms of streptococci, herpes simplex virus, varicella-zoster virus, adenovirus, and cytomegalovirus. Some people with aphthous stomatitis may show herpes virus within the epithelium of the mucosa, but without any productive infection. In some persons, attacks of ulceration occur at the same time as asymptomatic viral shedding and elevated viral titres.In some instances, recurrent mouth ulcers may be a manifestation of an allergic reaction. Possible allergens include certain foods (e.g., chocolate, coffee, strawberries, eggs, nuts, tomatoes, cheese, citrus fruits, benzoates, cinnamaldehyde, and highly acidic foods), toothpastes, and mouthwashes. Where dietary allergens are responsible, mouth ulcers usually develop within about 12–24 hours of exposure.Sodium lauryl sulphate (SLS), a detergent present in some brands of toothpaste and other oral healthcare products, may produce oral ulceration in some individuals. It has been shown that aphthous stomatitis is more common in people using toothpastes containing SLS, and that some reduction in ulceration occurs when a SLS-free toothpaste is used. Some have argued that since SLS is almost ubiquitously used in oral hygiene products, there is unlikely to be a true predisposition for aphthous stomatitis caused by SLS.

Systemic disease
Aphthous-like ulceration may occur in association with several systemic disorders (see table). These ulcers are clinically and histopathologically identical to the lesions of aphthous stomatitis, but this type of oral ulceration is not considered to be true aphthous stomatitis by some sources. Some of these conditions may cause ulceration on other mucosal surfaces in addition to the mouth such as the conjunctiva or the genital mucous membranes. Resolution of the systemic condition often leads to decreased frequency and severity of the oral ulceration.Behçets disease is a triad of mouth ulcers, genital ulcers and anterior uveitis. The main feature of Behçets disease is aphthous-like ulceration, but this is usually more severe than seen in aphthous stomatitis without a systemic cause, and typically resembles major or herpetiforme ulceration or both. Aphthous-like ulceration is the first sign of the disease in 25–75% of cases. Behçets is more common in individuals whose ethnic origin is from regions along the Silk Road (between the Mediterranean and the Far East). It tends to be rare in other countries such as the United States and the United Kingdom. MAGIC syndrome is a possible variant of Behçets disease, and is associated with aphthous-like ulceration. The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis).PFAPA syndrome is a rare condition that tends to occur in children. The name stands for "periodic fever, aphthae, pharyngitis (sore throat) and cervical adenitis" (inflammation of the lymph nodes in the neck). The fevers occur periodically about every 3–5 weeks. The condition appears to improve with tonsillectomy or immunosuppression, suggesting an immunologic cause.In cyclic neutropenia, there is a reduction in the level of circulating neutrophils in the blood that occurs about every 21 days. Opportunistic infections commonly occur and aphthous-like ulceration is worst during this time.Hematinic deficiencies (vitamin B12, folic acid and iron), occurring singly or in combination, and with or without any underlying gastrointestinal disease, may be twice as common in people with RAS. However, iron and vitamin supplements only infrequently improve the ulceration. The relationship to vitamin B12 deficiency has been the subject of many studies. Although these studies found that 0–42% of those with recurrent ulcers have a vitamin B12 deficiency, an association with deficiency is rare. Even in the absence of deficiency, vitamin B12 supplementation may be helpful due to unclear mechanisms. Hematinic deficiencies can cause anemia, which is also associated with aphthous-like ulceration.Gastrointestinal disorders are sometimes associated with aphthous-like stomatitis, e.g. most commonly celiac disease, but also inflammatory bowel disease such as Crohns disease or ulcerative colitis. The link between gastrointestinal disorders and aphthous stomatitis is probably related to nutritional deficiencies caused by malabsorption. Less than 5% of people with RAS have celiac disease, which usually presents with severe malnutrition, anemia, abdominal pain, diarrhea and glossitis (inflammation of the tongue). Sometimes aphthous-like ulcerations can be the only sign of celiac disease. Despite this association, a gluten-free diet does not usually improve the oral ulceration.Other examples of systemic conditions associated with aphthous-like ulceration include reactive arthritis, and recurrent erythema multiforme.

Diagnosis
Diagnosis is mostly based on the clinical appearance and the medical history. The most important diagnostic feature is a history of recurrent, self healing ulcers at fairly regular intervals. Although there are many causes of oral ulceration, recurrent oral ulceration has relatively few causes, most commonly aphthous stomatitis, but rarely Behçets disease, erythema multiforme, ulceration associated with gastrointestinal disease, and recurrent intra-oral herpes simplex infection. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history.Special investigations may be indicated to rule out other causes of oral ulceration. These include blood tests to exclude anemia, deficiencies of iron, folate or vitamin B12, or celiac disease. However, the nutritional deficiencies may be latent and the peripheral blood picture may appear relatively normal. Some suggest that screening for celiac disease should form part of the routine work up for individuals complaining of recurrent oral ulceration. Many of the systemic diseases cause other symptoms apart from oral ulceration, which is in contrast to aphthous stomatitis where there is isolated oral ulceration. Patch testing may be indicated if allergies are suspected (e.g. a strong relationship between certain foods and episodes of ulceration). Several drugs can cause oral ulceration (e.g. nicorandil), and a trial substitution to an alternative drug may highlight a causal relationship.Tissue biopsy is not usually required, unless to rule out other suspected conditions such as oral squamous cell carcinoma. The histopathologic appearance is not pathognomonic (the microscopic appearance is not specific to the condition). Early lesions have a central zone of ulceration covered by a fibrinous membrane. In the connective tissue deep to the ulcer there is increased vascularity and a mixed inflammatory infiltrate composed of lymphocytes, histiocytes and polymorphonuclear leukocytes. The epithelium on the margins of the ulcer shows spongiosis and there are many mononuclear cells in the basal third. There are also lymphocytes and histiocytes in the connective tissue surrounding deeper blood vessels near to the ulcer, described histologically as "perivascular cuffing".

Classification
Aphthous stomatitis has been classified as a type of non-infectious stomatitis (inflammation of the mouth). One classification distinguishes "common simple aphthae", accounting for 95% of cases, with 3–6 attacks per year, rapid healing, minimal pain and restriction of ulceration to the mouth; and "complex aphthae", accounting for 5% of cases, where ulcers may be present on the genital mucosa in addition to mouth, healing is slower and pain is more severe. A more common method of classifying aphthous stomatitis is into three variants, distinguished by the size, number and location of the lesions, the healing time of individual ulcers and whether a scar is left after healing (see below).

Minor aphthous ulceration
This is the most common type of aphthous stomatitis, accounting for about 80–85% of all cases. This subtype is termed minor aphthous ulceration (MiAU), or minor recurrent aphthous stomatitis (MiRAS). The lesions themselves may be referred to as minor aphthae or minor aphthous ulcers. These lesions are generally less than 10 mm in diameter (usually about 2–3 mm), and affect non-keratinized mucosal surfaces (i.e. the labial and buccal mucosa, lateral borders of the tongue and the floor of the mouth). Usually several ulcers appear at the same time, but single ulcers are possible. Healing usually takes seven to ten days and leaves no scar. Between episodes of ulceration, there is usually an ulcer-free period of variable length.

Major aphthous ulceration
This subtype makes up about 10% of all cases of aphthous stomatitis. It is termed major aphthous ulceration (MaAU) or major recurrent aphthous stomatitis (MaRAS). Major aphthous ulcers (major aphthae) are similar to minor aphthous ulcers, but are more than 10 mm in diameter and the ulceration is deeper. Because the lesions are larger, healing takes longer (about twenty to thirty days), and may leave scars. Each episode of ulceration usually produces a greater number of ulcers, and the time between attacks is less than seen in minor aphthous stomatitis. Major aphthous ulceration usually affects non-keratinized mucosal surfaces, but less commonly keratinized mucosa may also be involved, such as the dorsum (top surface) of the tongue or the gingiva (gums). The soft palate or the fauces (back of the throat) may also be involved, the latter being part of the oropharynx rather than the oral cavity. Compared to minor aphthous ulceration, major aphthae tend to have an irregular outline.

Herpetiform ulceration
Herpetiform ulcers, (also termed stomatitis herpetiformis, or herpes-like ulcerations) is a subtype of aphthous stomatitis so named because the lesions resemble a primary infection with herpes simplex virus (primary herpetic gingivostomatitis). However, herpetiform ulceration is not caused by herpes viruses. As with all types of aphthous stomatitis, it is not contagious. Unlike true herpetic ulcers, herpetiforme ulcers are not preceded by vesicles (small, fluid-filled blisters). Herpetiforme ulcers are less than 1 mm in diameter and occur in variably sized crops up to one hundred at a time. Adjacent ulcers may merge to form larger, continuous areas of ulceration. Healing occurs within fifteen days without scarring. The ulceration may affect keratinized mucosal surfaces in addition to non keratinized. Herpetiform ulceration is often extremely painful, and the lesions recur more frequently than minor or major aphthous ulcers. Recurrence may be so frequent that ulceration is virtually continuous. It generally occurs in a slightly older age group than the other subtypes, and females are affected slightly more frequently than males.

RAS type ulceration
Recurrent oral ulceration associated with systemic conditions is termed "RAS-type ulceration", "RAS-like ulceration", or "aphthous-like ulcers". Aphthous stomatitis occurs in individuals with no associated systemic disease. Persons with certain systemic diseases may be prone to oral ulceration, but this is secondary to the underlying medical condition (see the systemic disease section). This kind of ulceration is considered by some to be separate from true aphthous stomatitis. However, this definition is not strictly applied. For example, many sources refer to oral ulceration caused by anemia and/or nutritional deficiencies as aphthous stomatitis, and some also consider Behçets disease to be a variant.

Treatment
The vast majority of people with aphthous stomatitis have minor symptoms and do not require any specific therapy. The pain is often tolerable with simple dietary modification during an episode of ulceration such as avoiding spicy and acidic foods and beverages. Many different topical and systemic medications have been proposed (see table), sometimes showing little or no evidence of usefulness when formally investigated. Some of the results of interventions for RAS may in truth represent a placebo effect. No therapy is curative, with treatment aiming to relieve pain, promote healing and reduce the frequency of episodes of ulceration.

Medication
The first line of therapy for aphthous stomatitis are topical agents rather than systemic medication, with topical corticosteroids being the mainstay treatment. Systemic treatment is usually reserved for severe disease due to the risk of adverse side effects associated with many of these agents. A systematic review found that no single systemic intervention was found to be effective. Good oral hygiene is important to prevent secondary infection of the ulcers.Occasionally, in females where ulceration is correlated to the menstrual cycle or to birth control pills, progestogen or a change in birth control may be beneficial. Use of nicotine replacement therapy for people who have developed oral ulceration after stopping smoking has also been reported. Starting smoking again does not usually lessen the condition. Trauma can be reduced by avoiding rough or sharp foodstuffs and by brushing teeth with care. If sodium lauryl sulfate is suspected to be the cause, avoidance of products containing this chemical may be useful and prevent recurrence in some individuals. Similarly patch testing may indicate that food allergy is responsible, and the diet modified accordingly. If investigations reveal deficiency states, correction of the deficiency may result in resolution of the ulceration. For example, there is some evidence that vitamin B12 supplementation may prevent recurrence in some individuals.

Other
Surgical excision of aphthous ulcers has been described, but it is an ineffective and inappropriate treatment. Silver nitrate has also been used as a chemical cauterant. Apart from the mainstream approaches detailed above, there are numerous treatments of unproven effectiveness, ranging from herbal remedies to otherwise alternative treatments, including Aloe vera, Myrtus communis, Rosa damascena, potassium alum, zinc sulfate, nicotine, polio virus vaccine and prostaglandin E2.

Prognosis
By definition, there is no serious underlying medical condition, and most importantly, the ulcers do not represent oral cancer nor are they infectious. However, aphthae are capable of causing significant discomfort. There is a spectrum of severity, with symptoms ranging from a minor nuisance to disabling. Due to pain during eating, weight loss may develop as a result of not eating in severe cases of aphthous stomatitis. Usually, the condition lasts for several years before spontaneously disappearing in later life.

Epidemiology
Aphthous stomatitis affects between 5% and 66% of people, with about 20% of individuals in most populations having the condition to some degree. This makes it the most common disease of the oral mucosa. Aphthous stomatitis occurs worldwide, but is more common in developed countries.Within nations, it is more common in higher socioeconomic groups. Males and females are affected in an equal ratio, and the peak age of onset between 10 and 19 years. About 80% of people with aphthous stomatitis first developed the condition before the age of 30. There have been reports of ethnic variation. For example, in the United States, aphthous stomatitis may be three times more common in white-skinned people than black-skinned people.

History, society and culture
"Aphthous affectations" and "aphthous ulcerations" of the mouth are mentioned several times in the treatise "Of the Epidemics" (part of the Hippocratic corpus, in the 4th century BCE), although it seems likely that this was oral ulceration as a manifestation of some infectious disease, since they are described as occurring in epidemic-like patterns, with concurrent symptoms such as fever.
Aphthous stomatitis was once thought to be a form of recurrent herpes simplex virus infection, and some clinicians still refer to the condition as "herpes" despite this cause having been disproven.The informal term "canker sore" is sometimes used, mainly in North America, either to describe this condition generally, or to refer to the individual ulcers of this condition, or mouth ulcers of any cause unrelated to this condition. The origin of the word "canker" is thought to have been influenced by Latin, Old English, Middle English and Old North French. In Latin, cancer translates to "malignant tumor" or literally "crab" (related to the likening of sectioned tumors to the limbs of a crab). The closely related word in Middle English and Old North French, chancre, now more usually applied to syphilis, is also thought to be involved. Despite this etymology, aphthous stomatitis is not a form of cancer but rather entirely benign.
An aphtha (plural aphthae) is a non specific term that refers to an ulcer of the mouth. The word is derived from the Greek word aphtha meaning "eruption" or "ulcer" </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 APL and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Apnea of prematurity and can you explain it in depth? [/INST] Apnea of prematurity is defined as cessation of breathing by a premature infant that lasts for more than 20 seconds and/or is accompanied by hypoxia or bradycardia. Apnea is traditionally classified as either obstructive, central, or mixed. Obstructive apnea may occur when the infants neck is hyperflexed or conversely, hyperextended.  It may also occur due to low pharyngeal muscle tone or to inflammation of the soft tissues, which can block the flow of air though the pharynx and vocal cords. Central apnea occurs when there is a lack of respiratory effort. This may result from central nervous system immaturity, or from the effects of medications or illness. Many episodes of apnea of prematurity may start as either obstructive or central, but then involve elements of both, becoming mixed in nature.

Pathophysiology
Ventilatory drive is primarily dependent on response to increased levels of carbon dioxide (CO2) and acid in the blood. A secondary stimulus is hypoxia. Responses to these stimuli are impaired in premature infants due to immaturity of specialized regions of the brain that sense these changes.  In addition, premature infants have an exaggerated response to laryngeal stimulation (a normal reflex that closes the airway as a protective measure).

Diagnosis
Apnea of prematurity can be readily identified from other forms of infant apnea such as obstructive apnea, hypoventilation syndromes, breathing regulation issues during feeding, and reflux associated apnea with an infant pneumogram or infant apnea/sleep study.
It has been reported that the incidence of neonatal apnea happens in almost all infants with gestational age of less than 29 weeks or the birth weight of less than 1000g.

Treatment
Medications
Methylxanthines (theophylline and caffeine) have been used for almost three decades to treat apnea of prematurity. Despite this prevalent use, there are concerns of long term negative effects from the use of caffeine. Caffeine and theophylline have similar short-term effects on apnea, but theophylline is associated with higher rates of toxicity.

Respiratory support
Simple tactile stimulation by touching the skin or patting the infant may stop an apneic episode by raising the infants level of alertness.  Increasing the environmental oxygen level by placing the infant in a tent or hood with supplemental oxygen can diminish the frequency of AOP, and may also help the infant maintain adequate oxygenation during short episodes of apnea.  Increased oxygen at low levels can also be delivered using a nasal cannula, which additionally may provide some stimulation due to the tactile stimulation of the cannula </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 Arsenic poisoning and can you explain it in depth? [/INST] Arsenic poisoning is a medical condition that occurs due to elevated levels of arsenic in the body. If arsenic poisoning occurs over a brief period of time, symptoms may include vomiting, abdominal pain, encephalopathy, and watery diarrhea that contains blood. Long-term exposure can result in thickening of the skin, darker skin, abdominal pain, diarrhea, heart disease, numbness, and cancer.The most common reason for long-term exposure is contaminated drinking water. Groundwater most often becomes contaminated naturally; however, contamination may also occur from mining or agriculture. It may also be found in the soil and air. Recommended levels in water are less than 10–50 µg/L (10–50 parts per billion). Other routes of exposure include toxic waste sites and traditional medicines. Most cases of poisoning are accidental. Arsenic acts by changing the functioning of around 200 enzymes. Diagnosis is by testing the urine, blood, or hair.Prevention is by using water that does not contain high levels of arsenic. This may be achieved by the use of special filters or using rainwater. There is not good evidence to support specific treatments for long-term poisoning. For acute poisonings treating dehydration is important. Dimercaptosuccinic acid or dimercaptopropane sulfonate may be used while dimercaprol (BAL) is not recommended. Hemodialysis may also be used.Through drinking water, more than 200 million people globally are exposed to higher-than-safe levels of arsenic. The areas most affected are Bangladesh and West Bengal. Exposure is also more common in people of low income and minorities. Acute poisoning is uncommon. The toxicity of arsenic has been described as far back as 1500 BC in the Ebers papyrus.

Signs and symptoms
Symptoms of arsenic poisoning begin with headaches, confusion, severe diarrhea, and drowsiness. As the poisoning develops, convulsions and changes in fingernail pigmentation called leukonychia striata (Meess lines, or Aldrich-Meess lines) may occur. When the poisoning becomes acute, symptoms may include diarrhea, vomiting, vomiting blood, blood in the urine, cramping muscles, hair loss, stomach pain, and more convulsions. The organs of the body that are usually affected by arsenic poisoning are the lungs, skin, kidneys, and liver. The final result of arsenic poisoning is coma and death.Arsenic is related to heart disease (hypertension-related cardiovascular disease), cancer, stroke (cerebrovascular diseases), chronic lower respiratory diseases, and diabetes. Skin effects can include skin cancer in the long term, but often prior to skin cancer are different skin lesions. Other effects may include darkening of skin and thickening of skin.Chronic exposure to arsenic is related to vitamin A deficiency, which is related to heart disease and night blindness. The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day.

Cancer
Arsenic increases the risk of cancer. Exposure is related to skin, lung, liver, and kidney cancer among others.Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, micronuclei and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.
Both DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of reactive oxygen species can be promoted.
Moreover, arsenic could cause oxidative stress by depleting the cells antioxidants, especially the ones containing thiol groups. The accumulation of reactive oxygen species like that cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death.
In a rat animal model, urine levels of 8-hydroxy-2-deoxyguanosine (as a biomarker of DNA damage byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased. This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. Considering that a high partial pressure of oxygen is present in lungs and DMA(III) is excreted in gaseous state via the lungs, this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and later on stored in the bladder accounts for the other tumor localizations.
Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation; others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed polymerase chain reactions. It turned out that six of the fragments were hyper- and two of them were hypomethylated. Higher levels of DNA methyltransferase mRNA and enzyme activity were found.Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to carcinogenesis. From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity. MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux. The efflux requires glutathione, but no arsenic-glutathione complex formation.Although many mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling.

Causes
Organic arsenic is less harmful than inorganic arsenic. Seafood is a common source of the less toxic organic arsenic in the form of arsenobetaine. The arsenic reported in 2012 in fruit juice and rice by Consumer Reports was primarily inorganic arsenic. Because of its high toxicity, arsenic is seldom used in the Western world, although in Asia it is still a popular pesticide. Arsenic is mainly encountered occupationally in the smelting of zinc and copper ores.

Drinking water
Arsenic is naturally found in groundwater and presents serious health threats when high amounts exist. Chronic arsenic poisoning results from drinking contaminated well water over a long period of time. Many aquifers contain high concentration of arsenic salts.  The World Health Organization (WHO) Guidelines for drinking water quality established in 1993 a provisional guideline value of 0.01 mg/L (10 parts per billion) for maximum contaminant levels of arsenic in drinking water. This recommendation was established based on the limit of detection for most laboratories testing equipment at the time of publication of the WHO water quality guidelines. More recent findings show that consumption of water with levels as low as 0.00017 mg/L (0.17 parts per billion) over long periods of time can lead to arsenicosis.From a 1988 study in China, the US protection agency quantified the lifetime exposure of arsenic in drinking water at concentrations of 0.0017 mg/L (1.7 ppb), 0.00017 mg/L, and 0.000017 mg/L are associated with a lifetime skin cancer risk of 1 in 10,000, 1 in 100,000, and 1 in 1,000,000 respectively. WHO asserts that a water level of 0.01 mg/L (10 ppb) poses a risk of 6 in 10,000 chance of lifetime skin cancer risk and contends that this level of risk is acceptable.One of the worst incidents of arsenic poisoning via well water occurred in Bangladesh, which the World Health Organization called the "largest mass poisoning of a population in history" recognized as a major public health concern. The contamination in the Ganga-Brahmaputra fluvial plains in India and Padma-Meghna fluvial plains in Bangladesh demonstrated adverse impacts on human health.Mining techniques such as hydraulic fracturing may mobilize arsenic in groundwater and aquifers due to enhanced methane transport and resulting changes in redox conditions, and inject fluid containing additional arsenic.

Groundwater
In the US, the U.S. Geological Survey estimates that the median groundwater concentration is 1 μg/L or less, although some groundwater aquifers, particularly in the western United States, can contain much higher levels. For example, median levels in Nevada were about 8 μg/L but levels of naturally occurring arsenic as high as 1000 μg/L have been measured in the United States in drinking water.Geothermally active zones occur at hotspots where mantle-derived plumes ascend, such as in Hawaii and Yellowstone National Park, US. Arsenic is an incompatible element (does not fit easily into the lattices of common rock-forming minerals). Concentrations of arsenic are high mainly in geothermal waters that leach continental rocks. Arsenic in hot geothermal fluids was shown to be derived mainly from leaching of host rocks at Yellowstone National Park, in Wyoming, US, rather than from magmas.In the western US, there are As (arsenic) inputs to groundwater and surface water from geothermal fluids in and near Yellowstone National Park, and in other western mineralized areas. Groundwater associated with volcanics in California contain As at concentrations ranging up to 48,000 μg/L, with As-bearing sulfide minerals as the main source. Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of As >50 μg/L.In general, because arsenic is an incompatible element, it accumulates in differentiated magmas, and in other western mineralized areas. Weathering of pegmatite veins in Connecticut, US, was thought to contribute As to groundwater.In Pennsylvania, As concentrations in water discharging from abandoned anthracite mines ranged from <0.03 to 15 μg/L and from abandoned bituminous mines, from 0.10 to 64 μg/L, with 10% of samples exceeding the United States Environmental Protection Agency MLC of 10 μg/L.In Wisconsin, As concentrations of water in sandstone and dolomite aquifers were as high as 100 μg/L. Oxidation of pyrite hosted by these formations was the likely source of the As.In the Piedmont of Pennsylvania and New Jersey, groundwater in Mesozoic age aquifers contains elevated levels of As—domestic well waters from Pennsylvania contained up to 65 μg/L, whereas in New Jersey the highest concentration measured recently was 215 μg/L.

Food
In the United States, Schoof et al. estimated an average adult intake of 3.2 μg/day, with a range of 1–20 μg/day. Estimates for children were similar. Food also contains many organic arsenic compounds. The key organic arsenic compounds that can be routinely found in food (depending on food type) include monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), arsenobetaine, arsenocholine, arsenosugars, and arsenolipids. DMAsV or MMAsV can be found in various types of fin fish, crabs, and mollusks, but often at very low levels.Arsenobetaine is the major form of arsenic in marine animals, and, by all accounts, it is considered a compound that is nontoxic under conditions of human consumption. Arsenocholine, which is mainly found in shrimp, is chemically similar to arsenobetaine, and is considered to be "essentially nontoxic". Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic.Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks. Studies addressing arsenosugar toxicity, however, have largely been limited to in vitro studies, which show that arsenosugars are significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites.It has been found that rice is particularly susceptible to accumulation of arsenic from soil.  Rice grown in the United States has an average 260 ppb of arsenic, according to a study; but U.S. arsenic intake remains far below World Health Organization-recommended limits.  China has set a standard for arsenic limits in food (150 ppb), as levels in rice exceed those in water.Arsenic is a ubiquitous element present in American drinking water. In the United States, levels of arsenic that are above natural levels, but still well below danger levels set in federal safety standards, have been detected in commercially raised chickens. The source of the arsenic appears to be the feed additives roxarsone and nitarsone, which are used to control the parasitic infection coccidiosis as well as to increase weight and skin coloring of the poultry.High levels of inorganic arsenic were reportedly found in 83 California wines in 2015.

Soil
Exposure to arsenic in soil can occur through multiple pathways. Compared with the intake of naturally occurring arsenic from water and the diet, soil arsenic constitutes only a small fraction of intake.

Air
The European Commission (2000) reports that levels of arsenic in air range 0–1 ng/m3 in remote areas, 0.2–1.5 ng/m3 in rural areas, 0.5–3 ng/m3 in urban areas, and up to about 50 ng/m3 in the vicinity of industrial sites. Based on these data, the European Commission (2000) estimated that in relation to food, cigarette smoking, water, and soil, air contributes less than 1% of total arsenic exposure.

Pesticides
The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, because of the pesticides environmental persistence, it is estimated that millions of acres of land are still contaminated with lead arsenate residues. This presents a potentially significant public health concern in some areas of the United States (e.g., New Jersey, Washington, and Wisconsin), where large areas of land used historically as orchards have been converted into residential developments.Some modern uses of arsenic-based pesticides still exist. Chromated copper arsenate has been registered for use in the United States since the 1940s as a wood preservative, protecting wood from insects and microbial agents. In 2003, manufacturers of chromated copper arsenate instituted a voluntary recall of residential uses of wood treated with the chemical. The Environmental Protection Agency Act2008 final report stated that chromated copper arsenate is still approved for use in nonresidential applications, such as in marine facilities (pilings and structures), utility poles, and sand highway structures.

Copper smelting
Exposure studies in the copper smelting industry are much more extensive and have established definitive links between arsenic, a by-product of copper smelting, and lung cancer via inhalation. Dermal and neurological effects were also increased in some of these studies. Although as time went on, occupational controls became more stringent and workers were exposed to reduced arsenic concentrations, the arsenic exposures measured from these studies ranged from about 0.05 to 0.3 mg/m3 and are significantly higher than airborne environmental exposures to arsenic (which range from 0 to 0.000003 mg/m3).

Pathophysiology
Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenase complex, which catalyzes the oxidation of pyruvate to acetyl-CoA by NAD+. With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular apoptosis. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic can raise lactate levels and lead to lactic acidosis. Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.
Arsenic in cells clearly stimulates the production of hydrogen peroxide (H2O2). When the H2O2 reacts with certain metals such as iron or manganese it produces a highly reactive hydroxyl radical. Inorganic arsenic trioxide found in ground water particularly affects voltage-gated potassium channels,
disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure,
central nervous system dysfunction, anemia, and death.

Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing fibrinolysis. Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-α, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis.
Arsenic has also been shown to induce cardiac hypertrophy by activating certain transcription factors involved in pathologically remodeling the heart. Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure, probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage.  Although arsenic causes toxicity, it can also play a protective role.

Mechanism
Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde 3-phosphate dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis.) As shown by Gresser (1981), submitochondrial particles synthesize adenosine-5-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.
Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide.
It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.

Kinetics
The two forms of inorganic arsenic, reduced (trivalent As(III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulated in tissues and body fluids. In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation; the most frequently excreted metabolite (≥ 90%) in the urine of mammals is dimethylarsinic acid or cacodylic acid, DMA(V). Dimethylarsenic acid is also known as Agent Blue and was used as herbicide in the American war in Vietnam.
In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell. Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).
Methylation had been regarded as a detoxification process, but reduction from +5 As to +3 As may be considered as a bioactivation instead. Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent arsenics. Gebel (2002) stated that methylation is a detoxification through accelerated excretion. With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacts with a variety of proteins and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase.The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues.

Heat shock response
Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 110 kDa as well as metallothionein, ubiquitin, mitogen-activated [MAP] kinases, extracellular regulated kinase [ERK], c-jun terminal kinases [JNK] and p38.
Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. The effects are largely dependent on the dosing regime and may be as well inversed.
As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. Thus, taking into account p53s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.

Oxidative stress
Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, AP-1, and NF-κB, as well as the pro-inflammatory cytokines IL-8 and TNF-α.  The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity, insulin resistance, inflammation, and diabetes-2. Recent scientific evidence has elucidated the physiological roles of the PPARs in the ω- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-κB and AP-1), pro-inflammatory cytokines (IL-1, -6, -8, -12, and TNF-α), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors.Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of type 2 diabetes. The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.

Diagnosis
Arsenic may be measured in blood or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in the forensic investigation in a case of fatal over dosage. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Organic arsenic compounds tend to be eliminated in the urine in unchanged form, while inorganic forms are largely converted to organic arsenic compounds in the body prior to urinary excretion. The current biological exposure index for U.S. workers of 35 µg/L total urinary arsenic may easily be exceeded by a healthy person eating a seafood meal.Tests are available to diagnose poisoning by measuring arsenic in blood, urine, hair, and fingernails. The urine test is the most reliable test for arsenic exposure within the last few days. Urine testing needs to be done within 24–48 hours for an accurate analysis of an acute exposure. Tests on hair and fingernails can measure exposure to high levels of arsenic over the past 6–12 months. These tests can determine if one has been exposed to above-average levels of arsenic. They cannot predict, however, whether the arsenic levels in the body will affect health. Chronic arsenic exposure can remain in the body systems for a longer period of time than a shorter term or more isolated exposure and can be detected in a longer time frame after the introduction of the arsenic, important in trying to determine the source of the exposure.
Hair is a potential bioindicator for arsenic exposure due to its ability to store trace elements from blood. Incorporated elements maintain their position during growth of hair. Thus for a temporal estimation of exposure, an assay of hair composition needs to be carried out with a single hair which is not possible with older techniques requiring homogenization and dissolution of several strands of hair. This type of biomonitoring has been achieved with newer microanalytical techniques like synchrotron radiation based X-ray fluorescence spectroscopy and microparticle induced X-ray emission. The highly focused and intense beams study small spots on biological samples allowing analysis to micro level along with the chemical speciation. In a study, this method has been used to follow arsenic level before, during and after treatment with arsenious oxide in patients with acute promyelocytic leukemia.

Treatment
Chelation
Dimercaprol and dimercaptosuccinic acid are chelating agents that sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning.  The most important side effect is hypertension.  Dimercaprol is considerably more toxic than succimer. dimercaptosuccinic acid monoesters, e.g. MiADMSA, are promising antidotes for arsenic poisoning.

Nutrition
Supplemental potassium decreases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.

History
Beginning in about 3000 BC arsenic was mined and added to copper in the alloying of bronze, but the adverse health effects of working with arsenic led to it being abandoned when a viable alternative, tin, was discovered.In addition to its presence as a poison, for centuries arsenic was used medicinally. It has been used for over 2,400 years as a part of traditional Chinese medicine. In the western world, arsenic compounds, such as salvarsan, were used extensively to treat syphilis before penicillin was introduced. It was eventually replaced as a therapeutic agent by sulfa drugs and then by other antibiotics. Arsenic was also an ingredient in many tonics (or "patent medicines").
In addition, during the Elizabethan era, some women used a mixture of vinegar, chalk, and arsenic applied topically to whiten their skin. This use of arsenic was intended to prevent aging and creasing of the skin, but some arsenic was inevitably absorbed into the blood stream.During the Victorian era (late 19th century) in the United States, U.S. newspapers advertised "arsenic complexion wafers" that promised to remove facial blemishes such as moles and pimples.Some pigments, most notably the popular Emerald Green (known also under several other names), were based on arsenic compounds. Overexposure to these pigments was a frequent cause of accidental poisoning of artists and craftsmen.
Arsenic became a favored method for murder of the Middle Ages and Renaissance, particularly among ruling classes in Italy allegedly. Because the symptoms are similar to those of cholera, which was common at the time, arsenic poisoning often went undetected.: 63   By the 19th century, it had acquired the nickname "inheritance powder," perhaps because impatient heirs were known or suspected to use it to ensure or accelerate their inheritances.: 21  It was also a common murder technique in the 19th century in domestic violence situations, such as the case of Rebecca Copin, who attempted to poison her husband by "putting arsenic in his coffee".In post-WW1 Hungary, arsenic extracted by boiling fly paper was used in an estimated 300 murders by the Angel Makers of Nagyrév.
In imperial China, arsenic trioxide and sulfides were used in murder, as well as for capital punishment for members of the royal family or aristocracy.  Forensic studies have determined that the Guangxu Emperor (d. 1908) was murdered by arsenic, most likely ordered by the Empress Dowager Cixi or Generalissimo Yuan Shikai.  Likewise, in ancient Korea, and particularly in the Joseon Dynasty, arsenic-sulfur compounds have been used as a major ingredient of sayak (사약; 賜藥), which was a poison cocktail used in capital punishment of high-profile political figures and members of the royal family. Due to social and political prominence of the condemned, many of these events were well-documented, often in the Annals of Joseon Dynasty; they are sometimes portrayed in historical television miniseries because of their dramatic nature.

Legislation
In the U.S. in 1975, under the authority of the Safe Drinking Water Act, the U.S. Environmental Protection Agency determined the National Interim Primary Drinking Water Regulation levels of arsenic (inorganic contaminant – IOCs) to be 0.05 mg/L (50 parts per billion – ppb).Throughout the years, many studies reported dose-dependent effects of arsenic in drinking water and skin cancer. In order to prevent new cases and death from cancerous and non-cancerous diseases, the Safe Drinking Water Act directed the Environmental Protection Agency to revise arsenics levels and specified the maximum contaminant level (MCL). MCLs are set as close to the health goals as possible, considering cost, benefits and the ability of public water systems to detect and remove contaminants using suitable treatment technologies.In 2001, Environmental Protection Agency adopted a lower standard of MCL 0.01 mg/L (10 ppb) for arsenic in drinking water that applies to both community water systems and non-transient non-community water systems.In some other countries, when developing national drinking water standards based on the guideline values, it is necessary to take account of a variety of geographical, socio-economic, dietary and other conditions affecting potential exposure. These factors lead to national standards that differ appreciably from the guideline values. That is the case in countries such as India and Bangladesh, where the permissible limit of arsenic in absence of an alternative source of water is 0.05 mg/L.

Challenges to implementation
Arsenic removal technologies are traditional treatment processes which have been tailored to improve removal of arsenic from drinking water. Although some of the removal processes, such as precipitative processes, adsorption processes, ion exchange processes, and separation (membrane) processes, may be technically feasible, their cost may be prohibitive.For underdeveloped countries, the challenge is finding the means to fund such technologies. The Environmental Protection Agency, for example, has estimated the total national annualized cost of treatment, monitoring, reporting, record keeping, and administration to enforce the MCL rule to be approximately $181 million </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 Ascariasis and can you explain it in depth? [/INST] Ascariasis is a disease caused by the parasitic roundworm Ascaris lumbricoides. Infections have no symptoms in more than 85% of cases, especially if the number of worms is small. Symptoms increase with the number of worms present and may include shortness of breath and fever in the beginning of the disease. These may be followed by symptoms of abdominal swelling, abdominal pain, and diarrhea. Children are most commonly affected, and in this age group the infection may also cause poor weight gain, malnutrition, and learning problems.Infection occurs by ingestion of food or drink contaminated with Ascaris eggs from feces. The eggs hatch in the intestines, the larvae burrow through the gut wall, and migrate to the lungs via the blood. There they break into the alveoli and pass up the trachea, where they are coughed up and may be swallowed. The larvae then pass through the stomach for a second time into the intestine, where they become adult worms. It is a type of soil-transmitted helminthiasis and part of a group of diseases called helminthiases.Prevention is by improved sanitation, which includes improving access to toilets and proper disposal of feces. Handwashing with soap appears protective. In areas where more than 20% of the population is affected, treating everyone at regular intervals is recommended. Reoccurring infections are common. There is no vaccine. Treatments recommended by the World Health Organization are the medications albendazole, mebendazole, levamisole, or pyrantel pamoate. Other effective agents include tribendimidine and nitazoxanide.About 0.8 to 1.2 billion people globally have ascariasis, with the most heavily affected populations being in sub-Saharan Africa, Latin America, and Asia. This makes ascariasis the most common form of soil-transmitted helminthiasis. As of 2010 it caused about 2,700 deaths a year, down from 3,400 in 1990. Another type of Ascaris infects pigs. Ascariasis is classified as a neglected tropical disease.

Signs and symptoms
In populations where worm infections are widespread, it is common to find that most people are infected by a small number of worms, while a small number of people are heavily infected. This is characteristic of many types of worm infections. Those people who are infected with only a small number of worms usually have no symptoms.

Migrating larvae
As larval stages travel through the body, they may cause visceral damage, peritonitis and inflammation, enlargement of the liver or spleen, and an inflammation of the lungs. Pulmonary manifestations take place during larval migration and may present as Loefflers syndrome, a transient respiratory illness associated with blood eosinophilia and pulmonary infiltrates with radiographic shadowing.

Intestinal blockage
The worms can occasionally cause intestinal blockage when large numbers get tangled into a bolus or they may migrate from the small intestine, which may require surgery. More than 796 A. lumbricoides worms weighing up to 550 g (19 oz) were recovered at autopsy from a two-year-old South African girl. The worms had caused torsion and gangrene of the ileum, which was interpreted as the cause of death.The worms lack teeth. However, they can rarely cause bowel perforations by inducing volvulus and closed-loop obstruction.

Bowel obstruction
Bowel obstruction may occur in up to 0.2 per 1000 per year. A worm may block the ampulla of Vater, or go into the main pancreatic duct, resulting in acute pancreatitis with raised serum levels of amylase and lipase. Occasionally, a worm can travel through the biliary tree and even into the gallbladder, causing acute cholangitis or acute cholecystitis.

Allergies
Ascariasis may result in allergies to shrimp and dustmites due to the shared antigen, tropomyosin; this has not been confirmed in the laboratory.

Malnutrition
The worms in the intestine may cause malabsorption and anorexia, which contribute to malnutrition. The malabsorption may be due to a loss of brush border enzymes, erosion and flattening of the villi, and inflammation of the lamina propria.

Others
Ascaris have an aversion to some general anesthetics and may exit the body, sometimes through the mouth, when an infected individual is put under general anesthesia.

Cause
Transmission
The source of infection is from objects which have been contaminated with fecal matter containing eggs. Ingestion of infective eggs from soil contaminated with human feces or contaminated vegetables and water is the primary route of infection. Infectious eggs may occur on other objects such as hands, money and furniture. Transmission from human to human by direct contact is impossible.Transmission comes through municipal recycling of wastewater into crop fields. This is quite common in emerging industrial economies and poses serious risks for local crop sales and exports of contaminated vegetables. A 1986 outbreak of ascariasis in Italy was traced to irresponsible wastewater recycling used to grow Balkan vegetable exports.The number of ova (eggs) in sewage or in crops that were irrigated with raw or partially treated sewage, is a measure of the degree of ascariasis incidence. For example:

In a study published in 1992, municipal wastewater in Riyadh, Saudi Arabia, detected over 100 eggs per litre of wastewater and in Czechoslovakia was as high as 240–1050 eggs per litre.
In one field study in Marrakech, Morocco, where raw sewage is used to fertilize crop fields, Ascaris eggs were detected at the rate of 0.18 eggs/kg in potatoes, 0.27 eggs/kg in turnip, 4.63 eggs/kg in mint, 0.7 eggs/kg in carrots, and 1.64 eggs/kg in radish. A similar study in the same area showed that 73% of children working on these farms were infected with helminths, particularly Ascaris, probably as a result of exposure to the raw sewage.

Lifecycle
The first appearance of eggs in stools is 60–70 days. In larval ascariasis, symptoms occur 4–16 days after infection. The final symptoms are gastrointestinal discomfort, colic and vomiting, fever, and observation of live worms in stools. Some patients may have pulmonary symptoms or neurological disorders during migration of the larvae. There are generally few or no symptoms. A bolus of worms may obstruct the intestine; migrating larvae may cause pneumonitis and eosinophilia. Adult worms have a lifespan of 1–2 years which means that individuals may be infected all their lives as worms die and new worms are acquired.Eggs can survive potentially for 15 years and a single worm may produce 200,000 eggs a day. They maintain their position by swimming against the intestinal flow.

Mechanism
Ascaris takes most of its nutrients from the partially digested host food in the intestine. There is some evidence that it can secrete enzyme inhibitors, presumably to protect itself from digestion by the hosts enzymes. Children are often more severely affected.

Diagnosis
Most diagnoses are made by identifying the appearance of the worm or eggs in feces. Due to the large quantity of eggs laid, diagnosis can generally be made using only one or two fecal smears.
The diagnosis is usually incidental when the host passes a worm in the stool or vomit. The eggs can be seen in a smear of fresh feces examined on a glass slide under a microscope and there are various techniques to concentrate them first or increase their visibility, such as the ether sedimentation method or the Kato technique. The eggs have a characteristic shape: they are oval with a thick, mamillated shell (covered with rounded mounds or lumps), measuring  35–50 micrometer in diameter and 40–70 in length. During pulmonary disease, larvae may be found in fluids aspirated from the lungs. White blood cell counts may demonstrate peripheral eosinophilia; this is common in many parasitic infections and is not specific to ascariasis. On X-ray, 15–35 cm long filling defects, sometimes with whirled appearance (bolus of worms).

Prevention
Prevention is by improved access to sanitation which includes the use of properly functioning and clean toilets by all community members as one important aspect. Handwashing with soap may be protective; however, there is no evidence it affects the severity of the disease. Eliminating the use of untreated human faeces as fertilizer is also important.In areas where more than 20% of the population is affected treating everyone is recommended. This has a cost of about 2 to 3 cents per person per treatment. This is known as mass drug administration and is often carried out among school-age children. For this purpose, broad-spectrum benzimidazoles such as mebendazole and albendazole are the drugs of choice recommended by WHO.

Treatment
Medications
Medications that are used to kill roundworms are called ascaricides. Those recommended by the World Health Organization for ascariasis are: albendazole, mebendazole, levamisole and pyrantel pamoate. Single‐dose of albendazole, mebendazole, and ivermectin are effective against ascariasis. They are effective at removing parasites and eggs from the intestines. Other effective agents include tribendimidine and nitazoxanide. Pyrantel pamoate may induce intestinal obstruction in a heavy worm load. Albendazole is contraindicated during pregnancy and children under two years of age. Thiabendazole may cause migration of the worm into the esophagus, so it is usually combined with piperazine.Piperazine is a flaccid paralyzing agent that blocks the response of Ascaris muscle to acetylcholine, which immobilizes the worm </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 Assisted reproductive technology and can you explain it in depth? [/INST] Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes or embryos, and/or the use of fertility medication. When used to address infertility, ART may also be referred to as fertility treatment. ART mainly belongs to the field of reproductive endocrinology and infertility. Some forms of ART may be used with regard to fertile couples for genetic purpose (see preimplantation genetic diagnosis). ART may also be used in surrogacy arrangements, although not all surrogacy arrangements involve ART.
The existence of sterility will not always require ART to be the first option to consider, as there are occasions when its cause is a mild disorder that can be solved with more conventional treatments or with behaviors based on promoting health and reproductive habits.

Procedures
General
With ART, the process of sexual intercourse is bypassed and fertilization of the oocytes occurs in the laboratory environment (i.e., in vitro fertilization).In the US, the Centers for Disease Control and Prevention (CDC) defines ART to include "all fertility treatments in which both eggs and sperm are handled. In general, ART procedures involve surgically removing eggs from a womans ovaries, combining them with sperm in the laboratory, and returning them to the womans body or donating them to another woman." According to CDC, "they do not include treatments in which only sperm are handled (i.e., intrauterine—or artificial—insemination) or procedures in which a woman takes medicine only to stimulate egg production without the intention of having eggs retrieved."In Europe, ART also excludes artificial insemination and includes only procedures where oocytes are handled.The WHO, or World Health Organization, also defines ART this way.

Ovulation induction
Ovulation induction is usually used in the sense of stimulation of the development of ovarian follicles by fertility medication to reverse anovulation or oligoovulation. These medications are given by injection for 8 to 14 days. A health care provider closely monitors the development of the eggs using transvaginal ultrasound and blood tests to assess follicle growth and estrogen production by the ovaries. When follicles have reached an adequate size and the eggs are mature enough, an injection of the hormone hCG initiates the ovulation process. Egg retrieval should occur from 34 to 36 hours after the hCG injection.

In vitro fertilization
In vitro fertilization is the technique of letting fertilization of the male and female gametes (sperm and egg) occur outside the female body.
Techniques usually used in in vitro fertilization include:

Transvaginal ovum retrieval (OVR) is the process whereby a small needle is inserted through the back of the vagina and guided via ultrasound into the ovarian follicles to collect the fluid that contains the eggs.
Embryo transfer is the step in the process whereby one or several embryos are placed into the uterus of the female with the intent to establish a pregnancy.Less commonly used techniques in in vitro fertilization are:

Assisted zona hatching (AZH) is performed shortly before the embryo is transferred to the uterus. A small opening is made in the outer layer surrounding the egg in order to help the embryo hatch out and aid in the implantation process of the growing embryo.
 Intracytoplasmic sperm injection (ICSI) is beneficial in the case of male factor infertility where sperm counts are very low or failed fertilization occurred with previous IVF attempt(s). The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. With ICSI, only one sperm per egg is needed. Without ICSI, you need between 50,000 and 100,000. This method is also sometimes employed when donor sperm is used.
Autologous endometrial coculture is a possible treatment for patients who have failed previous IVF attempts or who have poor embryo quality. The patients fertilized eggs are placed on top of a layer of cells from the patients own uterine lining, creating a more natural environment for embryo development.
In zygote intrafallopian transfer (ZIFT), egg cells are removed from the womans ovaries and fertilized in the laboratory; the resulting zygote is then placed into the fallopian tube.
Cytoplasmic transfer is the technique in which the contents of a fertile egg from a donor are injected into the infertile egg of the patient along with the sperm.
Egg donors are resources for women with no eggs due to surgery, chemotherapy, or genetic causes; or with poor egg quality, previously unsuccessful IVF cycles or advanced maternal age. In the egg donor process, eggs are retrieved from a donors ovaries, fertilized in the laboratory with the sperm from the recipients partner, and the resulting healthy embryos are returned to the recipients uterus.
Sperm donation may provide the source for the sperm used in IVF procedures where the male partner produces no sperm or has an inheritable disease, or where the woman being treated has no male partner.
Preimplantation genetic diagnosis (PGD) involves the use of genetic screening mechanisms such as fluorescent in-situ hybridization (FISH) or comparative genomic hybridization (CGH) to help identify genetically abnormal embryos and improve healthy outcomes.
Embryo splitting can be used for twinning to increase the number of available embryos.

Pre-implantation genetic diagnosis
A pre-implantation genetic diagnosis procedure may be conducted on embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. PGD is an adjunct to ART procedures, and requires in vitro fertilization to obtain oocytes or embryos for evaluation. Embryos are generally obtained through blastomere or blastocyst biopsy. The latter technique has proved to be less deleterious for the embryo, therefore it is advisable to perform the biopsy around day 5 or 6 of development. Sex selection is the attempt to control the sex of offspring to achieve a desired sex in case of X chromosome linked diseases. It can be accomplished in several ways, both pre- and post-implantation of an embryo, as well as at birth. Pre-implantation techniques include PGD, but also sperm sorting.

Others
Other assisted reproduction techniques include:

Mitochondrial replacement therapy (MRT, sometimes called mitochondrial donation) is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of IVF in which some or all of the future babys mitochondrial DNA comes from a third party. This technique is used in cases when mothers carry genes for mitochondrial diseases. The therapy is approved for use in the United Kingdom.
In gamete intrafallopian transfer (GIFT) a mixture of sperm and eggs is placed directly into a womans fallopian tubes using laparoscopy following a transvaginal ovum retrieval.
Reproductive surgery, treating e.g. fallopian tube obstruction and vas deferens obstruction, or reversing a vasectomy by a reverse vasectomy. In surgical sperm retrieval (SSR) the reproductive urologist obtains sperm from the vas deferens, epididymis or directly from the testis in a short outpatient procedure.
By cryopreservation, eggs, sperm and reproductive tissue can be preserved for later IVF.

Risks
The majority of IVF-conceived infants do not have birth defects.
However, some studies have suggested that assisted reproductive technology is associated with an increased risk of birth defects.
Artificial reproductive technology is becoming more available. Early studies suggest that there could be an increased risk for medical complications with both the mother and baby. Some of these include low birth weight, placental insufficiency, chromosomal disorders, preterm deliveries, gestational diabetes, and pre-eclampsia (Aiken and Brockelsby).In the largest U.S. study, which used data from a statewide registry of birth defects,
6.2% of IVF-conceived children had major defects, as compared with 4.4% of naturally conceived children matched for maternal age and other factors (odds ratio, 1.3; 95% confidence interval, 1.00 to 1.67). ART carries with it a risk for heterotopic pregnancy (simultaneous intrauterine and extrauterine pregnancy).
The main risks are:

Genetic disorders
Low birth weight. In IVF and ICSI, a risk factor is the decreased expression of proteins in energy metabolism; Ferritin light chain and ATP5A1.
Preterm birth. Low birth weight and preterm birth are strongly associated with many health problems, such as visual impairment and cerebral palsy. Children born after IVF are roughly twice as likely to have cerebral palsy.Sperm donation is an exception, with a birth defect rate of almost a fifth compared to the general population. It may be explained by that sperm banks accept only people with high sperm count.
Germ cells of the mouse normally have a frequency of spontaneous point mutations that is 5 to 10-fold lower than that in somatic cells from the same individual.  This low frequency in the germline leads to embryos that have a low frequency of point mutations in the next generation.  No significant differences were observed in the frequency or spectrum of mutations between naturally conceived fetuses and assisted-conception fetuses.  This suggests that with respect to the maintenance of genetic integrity assisted conception is safe.Current data indicate little or no increased risk for postpartum depression among women who use ART.Usage of assisted reproductive technology including ovarian stimulation and in vitro fertilization have been associated with an increased overall risk of childhood cancer in the offspring, which may be caused by the same original disease or condition that caused the infertility or subfertility in the mother or father.That said, In a landmark paper by Jacques Balayla et al. it was determined that infants born after ART have similar neurodevelopment than infants born after natural conception.In theory, ART can solve almost all reproductive problems, except for severe pathology or the absence of a uterus (or womb), using specific gamete or embryo donation techniques. However, this does not mean that all women can be treated with assisted reproductive techniques, or that all women who are treated will achieve pregnancy.

Usage
As a result of the 1992 Fertility Clinic Success Rate and Certification Act, the CDC is required to publish the annual ART success rates at U.S. fertility clinics. Assisted reproductive technology procedures performed in the U.S. has over than doubled over the last 10 years, with 140,000 procedures in 2006, resulting in 55,000 births.In Australia, 3.1% of births are a result of ART.The most common reasons for discontinuation of fertility treatment have been estimated to be: postponement of treatment (39%), physical and psychological burden (19%), psychological burden (14%), physical burden (6.32%), relational and personal problems (17%), personal reasons (9%), relational problems (9%), treatment rejection (13%) and organizational (12%) and clinic (8%) problems.

By country
United States
Many Americans do not have insurance coverage for fertility investigations and treatments. Many states are starting to mandate coverage, and the rate of use is 278% higher in states with complete coverage.There are some health insurance companies that cover diagnosis of infertility, but frequently once diagnosed will not cover any treatment costs.Approximate treatment/diagnosis costs in the United States, with inflation, as of 2021 (US$):

Initial workup: hysteroscopy, hysterosalpingogram, blood tests ~$2,800
Sonohysterogram (SHG) ~ $830–$1,400
Clomiphene citrate cycle ~ $280–$690
IVF cycle ~ $13,900–$41,600
Use of a surrogate mother to carry the child – dependent on arrangementsAnother way to look at costs is to determine the expected cost of establishing a pregnancy. Thus, if a clomiphene treatment has a chance to establish a pregnancy in 8% of cycles and costs $690, the expected cost is $8,300 to establish a pregnancy, compared to an IVF cycle (cycle fecundity 40%) with a corresponding expected cost of $41,600 ($16,600 × 40%).
For the community as a whole, the cost of IVF on average pays back by 700% by tax from future employment by the conceived human being.

European Union
In Europe, 157,500 children were born using assisted reproductive technology in 2015, according to the European Society of Human Reproduction and Embryology (ESHRE). But there are major differences in legislation across the Old Continent.
A European directive fixes standards concerning the use of human tissue and cells, but all ethical and legal questions on ART remain the prerogative of EU member states.

Across Europe, the legal criteria per availability vary somewhat. In 11 countries all women may benefit; in 8 others only heterosexual couples are concerned; in 7 only single women; and in 2 (Austria and Germany) only lesbian couples.
Spain was the first European country to open ART to all women, in 1977, the year the first sperm bank was opened there. In France, the right to ART is accorded to all women since 2019. In the last 15 years, legislation has evolved quickly. For example, Portugal made ART available in 2006 with conditions very similar to those in France, before amending the law in 2016 to allow lesbian couples and single women to benefit. Italy clarified its uncertain legal situation in 2004 by adopting Europes strictest laws: ART is only available to heterosexual couples, married or otherwise, and sperm donation is prohibited.
Today, 21 countries provide partial public funding for ART treatment. The seven others, which do not, are Ireland, Cyprus, Estonia, Latvia, Luxembourg, Malta, and Romania.
Such subsidies are subject to conditions, however. In Belgium, a fixed payment of €1,073 is made for each full cycle of the IVF process. The woman must be aged under 43 and may not carry out more than six cycles of ART. There is also a limit on the number of transferable embryos, which varies according to age and the number of cycles completed.
In France, ART is subsidized in full by national health insurance for women up to age 43, with limits of 4 attempts at IVF and 6 at artificial insemination.
Germany tightened its conditions for public funding in 2004, which caused a sharp drop in the number of ART cycles carried out, from more than 102,000 in 2003 to fewer than 57,000 the following year. Since then the figure has remained stable.
17 countries limit access to ART according to the age of the woman. 10 countries have established an upper age limit, varying from 40 (Finland, Netherlands) to 50 (including Spain, Greece and Estonia).
Since 1994, France is one of a number of countries (including Germany, Spain, and the UK) which use the somewhat vague notion of "natural age of procreation". In 2017, the steering council of Frances Agency of Biomedicine established an age limit of 43 for women using ART.
10 countries have no age limit for ART. These include Austria, Hungary, Italy and Poland.
Most European countries allow donations of gametes by third parties. But the situations vary depending on whether sperm or eggs are concerned. Sperm donations are authorized in 20 EU member states; in 11 of them anonymity is allowed. Egg donations are possible in 17 states, including 8 under anonymous conditions.
On 12 April, the Council of Europe adopted a recommendation which encourages an end to anonymity. In the UK, anonymous sperm donations ended in 2005 and children have access to the identity of the donor when they reach adulthood.
In France, the principle of anonymous donations of sperm or embryos is maintained in the law of bioethics of 2011, but a new bill under discussion may change the situation.

United Kingdom
In the United Kingdom, all patients have the right to preliminary testing, provided free of charge by the National Health Service (NHS). However, treatment is not widely available on the NHS and there can be long waiting lists. Many patients therefore pay for immediate treatment within the NHS or seek help from private clinics.
In 2013, the National Institute for Health and Care Excellence (NICE) published new guidelines about who should have access to IVF treatment on the NHS in England and Wales.The guidelines say women aged between 40 and 42 should be offered one cycle of IVF on the NHS if they have never had IVF treatment before, have no evidence of low ovarian reserve (this is when eggs in the ovary are low in number, or low in quality), and have been informed of the additional implications of IVF and pregnancy at this age. However, if tests show IVF is the only treatment likely to help them get pregnant, women should be referred for IVF straight away.
This policy is often modified by local Clinical Commissioning Groups, in a fairly blatant breach of the NHS Constitution for England which provides that patients have the right to drugs and treatments that have been recommended by NICE for use in the NHS. For example, the Cheshire, Merseyside and West Lancashire Clinical Commissioning Group insists on additional conditions:
The person undergoing treatment must have commenced treatment before her 40th birthday;
The person undergoing treatment must have a BMI of between 19 and 29;
Neither partner must have any living children, from either the current or previous relationships. This includes adopted as well as biological children; and,
Sub-fertility must not be the direct result of a sterilisation procedure in either partner (this does not include conditions where sterilisation occurs as a result of another medical problem). Couples who have undertaken a reversal of their sterilisation procedure are not eligible for treatment.

Canada
Some treatments are covered by OHIP (public health insurance) in Ontario and others are not. Women with bilaterally blocked fallopian tubes and are under the age of 40 have treatment covered but are still required to pay test fees (around CA$3,000–4,000). Coverage varies in other provinces. Most other patients are required to pay for treatments themselves.

Israel
Israels national health insurance, which is mandatory for all Israeli citizens, covers nearly all fertility treatments. IVF costs are fully subsidized up to the birth of two children for all Israeli women, including single women and lesbian couples. Embryo transfers for purposes of gestational surrogacy are also covered.

Germany
On 27 January 2009, the Federal Constitutional Court ruled that it is unconstitutional, that the health insurance companies have to bear only 50% of the cost for IVF. On 2 March 2012, the Federal Council has approved a draft law of some federal states, which provides that the federal government provides a subsidy of 25% to the cost. Thus, the share of costs borne for the pair would drop to just 25%. Since July 2017, assisted reproductive technology is also allowed for married lesbian couples, as German parliament allowed same-sex marriages in Germany.

France
In July 2020, the French Parliament allowed assisted reproductive technology also for lesbian couples and single women.

Cuba
Cuban sources mention that assisted reproduction is completely legal and free in the country.

India
The Government of India has notified the Surrogacy (Regulation) Act 2021 and the Assisted Reproductive Technology (Regulation) Act 2021 to regulate the practice of ART. Prior to that, the National Guidelines for Accreditation, Supervision and Regulation of ART Clinics in India published by the Ministry for Health and Family Welfare, Government of India in the year 2005 was governing the field. Indian law recognises the right of a single woman, who is a major, to have children through ART.

Society and culture
Ethics
Some couples may find it difficult to stop treatment despite very bad prognosis, resulting in futile therapies. This has the potential to give ART providers a difficult decision of whether to continue or refuse treatment.Some assisted reproductive technologies have the potential to be harmful to both the mother and child, posing a psychological and/or physical health risk, which may impact the ongoing use of these treatments.
In Israel, there is research supporting using art, including recycled lab materials from the IVF process, to help women work through some of these mixed emotions.

Fictional representation
Films and other fiction depicting emotional struggles of assisted reproductive technology have had an upswing in the latter part of the 2000s decade, although the techniques have been available for decades. As ART becomes more utilized, the number of people that can relate to it by personal experience in one way or another is growing.For specific examples, refer to the fiction sections in individual subarticles, e.g. surrogacy, sperm donation and fertility clinic.
In addition, reproduction and pregnancy in speculative fiction has been present for many decades.

Historical facts
25 July 1978, Louise Brown was born; this was the first successful birth of a child after IVF treatment. The procedure took place at Dr Kershaws Cottage Hospital (now Dr Kershaws Hospice) in Royton, Oldham, England. Patrick Steptoe (gynaecologist) and Robert Edwards (physiologist) worked together to develop the IVF technique </s>