<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Anthrax and explain in detail? [/INST] Anthrax is an infection caused by the bacterium Bacillus anthracis. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The skin form presents with a small blister with surrounding swelling that often turns into a painless ulcer with a black center. The inhalation form presents with fever, chest pain and shortness of breath. The intestinal form presents with diarrhea (which may contain blood), abdominal pains, nausea and vomiting. The injection form presents with fever and an abscess at the site of drug injection.According to the Centers for Disease Control the first clinical descriptions of cutaneous anthrax were given by Maret in 1752 and Fournier in 1769. Before that anthrax had been described only through historical accounts. The Prussian scientist Robert Koch (1843–1910) was the first to identify Bacillus anthracis as the bacterium that causes anthrax.
Anthrax is spread by contact with the bacteriums spores, which often appear in infectious animal products. Contact is by breathing or eating or through an area of broken skin. It does not typically spread directly between people. Risk factors include people who work with animals or animal products, travelers, and military personnel. Diagnosis can be confirmed by finding antibodies or the toxin in the blood or by culture of a sample from the infected site.Anthrax vaccination is recommended for people at high risk of infection. Immunizing animals against anthrax is recommended in areas where previous infections have occurred. A two-month course of antibiotics such as ciprofloxacin, levofloxacin and doxycycline after exposure can also prevent infection. If infection occurs, treatment is with antibiotics and possibly antitoxin. The type and number of antibiotics used depend on the type of infection. Antitoxin is recommended for those with widespread infection.A rare disease, human anthrax is most common in Africa and central and southern Asia. It also occurs more regularly in Southern Europe than elsewhere on the continent and is uncommon in Northern Europe and North America. Globally, at least 2,000 cases occur a year, with about two cases a year in the United States. Skin infections represent more than 95% of cases. Without treatment the risk of death from skin anthrax is 23.7%. For intestinal infection the risk of death is 25 to 75%, while respiratory anthrax has a mortality of 50 to 80%, even with treatment. Until the 20th century anthrax infections killed hundreds of thousands of people and animals each year. Anthrax has been developed as a weapon by a number of countries. In herbivorous animals infection occurs when they eat or breathe in the spores while grazing. Animals may become infected by killing and/or eating infected animals.

Etymology
The English name comes from anthrax (ἄνθραξ), the Greek word for coal, possibly having Egyptian etymology, because of the characteristic black skin lesions developed by people with a cutaneous anthrax infection. The central black eschar surrounded by vivid red skin has long been recognised as typical of the disease. The first recorded use of the word "anthrax" in English is in a 1398 translation of Bartholomaeus Anglicus work De proprietatibus rerum (On the Properties of Things, 1240).Anthrax was historically known by a wide variety of names indicating its symptoms, location and groups considered most vulnerable to infection. They included Siberian plague, Cumberland disease, charbon, splenic fever, malignant edema, woolsorters disease and la maladie de Bradford.

Signs and symptoms
Skin
Cutaneous anthrax, also known as hide-porters disease, is when anthrax occurs on the skin. It is the most common form (>90% of anthrax cases). It is the least dangerous form (low mortality with treatment, 23.7% mortality without). Cutaneous anthrax presents as a boil-like skin lesion that eventually forms an ulcer with a black center (eschar). The black eschar often shows up as a large, painless, necrotic ulcer (beginning as an irritating and itchy skin lesion or blister that is dark and usually concentrated as a black dot, somewhat resembling bread mold) at the site of infection. In general, cutaneous infections form within the site of spore penetration between two and five days after exposure. Unlike bruises or most other lesions, cutaneous anthrax infections normally do not cause pain. Nearby lymph nodes may become infected, reddened, swollen, and painful. A scab forms over the lesion soon, and falls off in a few weeks. Complete recovery may take longer.
Cutaneous anthrax is typically caused when B. anthracis spores enter through cuts on the skin. This form is found most commonly when humans handle infected animals and/or animal products.

Injection
In December 2009, an outbreak of anthrax occurred among injecting heroin users in the Glasgow and Stirling areas of Scotland, resulting in 14 deaths. The source of the anthrax is believed to have been dilution of the heroin with bone meal in Afghanistan. Injected anthrax may have symptoms similar to cutaneous anthrax, and may also cause infection deep into the muscle and spread faster.

Lungs
Inhalation anthrax usually develops within a week after exposure, but may take up to 2 months. During the first few days of illness, most people have fever, chills, and fatigue. These symptoms may be accompanied by cough, shortness of breath, chest pain, and nausea or vomiting, making inhalation anthrax difficult to distinguish from influenza and community-acquired pneumonia. This is often described as the prodromal period.Over the next day or so, shortness of breath, cough, and chest pain become more common, and complaints not involving the chest such as nausea, vomiting, altered mental status, sweats, and headache develop in one-third or more of people. Upper respiratory tract symptoms occur in only a quarter of people, and muscle pains are rare. Altered mental status or shortness of breath generally brings people to healthcare and marks the fulminant phase of illness.It infects the lymph nodes in the chest first, rather than the lungs themselves, a condition called hemorrhagic mediastinitis, causing bloody fluid to accumulate in the chest cavity, thereby causing shortness of breath. The second (pneumonia) stage occurs when the infection spreads from the lymph nodes to the lungs. Symptoms of the second stage develop suddenly within hours or days after the first stage. Symptoms include high fever, extreme shortness of breath, shock, and rapid death within 48 hours in fatal cases.

Gastrointestinal
Gastrointestinal (GI) infection is most often caused by consuming anthrax-infected meat and is characterized by diarrhea, potentially with blood, abdominal pains, acute inflammation of the intestinal tract, and loss of appetite. Occasional vomiting of blood can occur. Lesions have been found in the intestines and in the mouth and throat. After the bacterium invades the gastrointestinal system, it spreads to the bloodstream and throughout the body, while continuing to make toxins.

Cause
Bacteria
Bacillus anthracis is a rod-shaped, Gram-positive, facultative anaerobic bacterium about 1 by 9 μm in size. It was shown to cause disease by Robert Koch in 1876 when he took a blood sample from an infected cow, isolated the bacteria, and put them into a mouse. The bacterium normally rests in spore form in the soil, and can survive for decades in this state. Herbivores are often infected while grazing, especially when eating rough, irritant, or spiky vegetation; the vegetation has been hypothesized to cause wounds within the GI tract, permitting entry of the bacterial spores into the tissues. Once ingested or placed in an open wound, the bacteria begin multiplying inside the animal or human and typically kill the host within a few days or weeks. The spores germinate at the site of entry into the tissues and then spread by the circulation to the lymphatics, where the bacteria multiply.The production of two powerful exotoxins and lethal toxin by the bacteria causes death. Veterinarians can often tell a possible anthrax-induced death by its sudden occurrence, and by the dark, nonclotting blood that oozes from the body orifices. Most anthrax bacteria inside the body after death are outcompeted and destroyed by anaerobic bacteria within minutes to hours post mortem. However, anthrax vegetative bacteria that escape the body via oozing blood or through the opening of the carcass may form hardy spores. These vegetative bacteria are not contagious. One spore forms per one vegetative bacterium. The triggers for spore formation are not yet known, though oxygen tension and lack of nutrients may play roles. Once formed, these spores are very hard to eradicate.The infection of herbivores (and occasionally humans) by the inhalational route normally begins with inhaled spores being transported through the air passages into the tiny air sacs (alveoli) in the lungs. The spores are then picked up by scavenger cells (macrophages) in the lungs and are transported through small vessels (lymphatics) to the lymph nodes in the central chest cavity (mediastinum). Damage caused by the anthrax spores and bacilli to the central chest cavity can cause chest pain and difficulty breathing. Once in the lymph nodes, the spores germinate into active bacilli that multiply and eventually burst the macrophages, releasing many more bacilli into the bloodstream to be transferred to the entire body. Once in the bloodstream, these bacilli release three proteins named lethal factor, edema factor, and protective antigen. The three are not toxic by themselves, but their combination is incredibly lethal to humans. Protective antigen combines with these other two factors to form lethal toxin and edema toxin, respectively. These toxins are the primary agents of tissue destruction, bleeding, and death of the host. If antibiotics are administered too late, even if the antibiotics eradicate the bacteria, some hosts still die of toxemia because the toxins produced by the bacilli remain in their systems at lethal dose levels.

Exposure
The spores of anthrax are able to survive in harsh conditions for decades or even centuries. Such spores can be found on all continents, including Antarctica. Disturbed grave sites of infected animals have been known to cause infection after 70 years.Historically, inhalational anthrax was called woolsorters disease because it was an occupational hazard for people who sorted wool. Today, this form of infection is extremely rare in advanced nations, as almost no infected animals remain.Occupational exposure to infected animals or their products (such as skin, wool, and meat) is the usual pathway of exposure for humans. Workers who are exposed to dead animals and animal products are at the highest risk, especially in countries where anthrax is more common. Anthrax in livestock grazing on open range where they mix with wild animals still occasionally occurs in the United States and elsewhere.Many workers who deal with wool and animal hides are routinely exposed to low levels of anthrax spores, but most exposure levels are not sufficient to develop anthrax infections. A lethal infection is reported to result from inhalation of about 10,000–20,000 spores, though this dose varies among host species. Little documented evidence is available to verify the exact or average number of spores needed for infection.

Mode of infection
Anthrax can enter the human body through the intestines (ingestion), lungs (inhalation), or skin (cutaneous) and causes distinct clinical symptoms based on its site of entry. In general, an infected human is quarantined. However, anthrax does not usually spread from an infected human to an uninfected human. If the disease is fatal to the persons body, though, its mass of anthrax bacilli becomes a potential source of infection to others and special precautions should be used to prevent further contamination. Inhalational anthrax, if left untreated until obvious symptoms occur, is usually fatal.Anthrax can be contracted in laboratory accidents or by handling infected animals, their wool, or their hides. It has also been used in biological warfare agents and by terrorists to intentionally infect as exemplified by the 2001 anthrax attacks.

Mechanism
The lethality of the anthrax disease is due to the bacteriums two principal virulence factors: the poly-D-glutamic acid capsule, which protects the bacterium from phagocytosis by host neutrophils, and the tripartite protein toxin, called anthrax toxin. Anthrax components: protective antigen (PA), edema factor (EF), and lethal factor (LF). PA plus LF produces lethal toxin, and PA plus EF produces edema toxin. These toxins cause death and tissue swelling (edema), respectively.
To enter the cells, the edema and lethal factors use another protein produced by B. anthracis called protective antigen, which binds to two surface receptors on the host cell. A cell protease then cleaves PA into two fragments: PA20 and PA63. PA20 dissociates into the extracellular medium, playing no further role in the toxic cycle. PA63 then oligomerizes with six other PA63 fragments forming a heptameric ring-shaped structure named a prepore. Once in this shape, the complex can competitively bind up to three EFs or LFs, forming a resistant complex. Receptor-mediated endocytosis occurs next, providing the newly formed toxic complex access to the interior of the host cell. The acidified environment within the endosome triggers the heptamer to release the LF and/or EF into the cytosol. It is unknown how exactly the complex results in the death of the cell.
Edema factor is a calmodulin-dependent adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP into cyclic AMP (cAMP) and pyrophosphate. The complexation of adenylate cyclase with calmodulin removes calmodulin from stimulating calcium-triggered signaling, thus inhibiting the immune response. To be specific, LF inactivates neutrophils (a type of phagocytic cell) by the process just described so they cannot phagocytose bacteria. Throughout history, lethal factor was presumed to cause macrophages to make TNF-alpha and interleukin 1, beta (IL1B). TNF-alpha is a cytokine whose primary role is to regulate immune cells, as well as to induce inflammation and apoptosis or programmed cell death. Interleukin 1, beta is another cytokine that also regulates inflammation and apoptosis. The overproduction of TNF-alpha and IL1B ultimately leads to septic shock and death. However, recent evidence indicates anthrax also targets endothelial cells that line serous cavities such as the pericardial cavity, pleural cavity, and peritoneal cavity, lymph vessels, and blood vessels, causing vascular leakage of fluid and cells, and ultimately hypovolemic shock and septic shock.

Diagnosis
Various techniques may be used for the direct identification of B. anthracis in clinical material. Firstly, specimens may be Gram stained. Bacillus spp. are quite large in size (3 to 4 μm long), they may grow in long chains, and they stain Gram-positive. To confirm the organism is B. anthracis, rapid diagnostic techniques such as polymerase chain reaction-based assays and immunofluorescence microscopy may be used.All Bacillus species grow well on 5% sheep blood agar and other routine culture media. Polymyxin-lysozyme-EDTA-thallous acetate can be used to isolate B. anthracis from contaminated specimens, and bicarbonate agar is used as an identification method to induce capsule formation. Bacillus spp. usually grow within 24 hours of incubation at 35 °C, in ambient air (room temperature) or in 5% CO2. If bicarbonate agar is used for identification, then the medium must be incubated in 5% CO2. B. anthracis colonies are medium-large, gray, flat, and irregular with swirling projections, often referred to as having a "medusa head" appearance, and are not hemolytic on 5% sheep blood agar. The bacteria are not motile, susceptible to penicillin, and produce a wide zone of lecithinase on egg yolk agar. Confirmatory testing to identify B. anthracis includes gamma bacteriophage testing, indirect hemagglutination, and enzyme-linked immunosorbent assay to detect antibodies. The best confirmatory precipitation test for anthrax is the Ascoli test.

Prevention
Precautions are taken to avoid contact with the skin and any fluids exuded through natural body openings of a deceased body that is suspected of harboring anthrax. The body should be put in strict quarantine. A blood sample is collected and sealed in a container and analyzed in an approved laboratory to ascertain if anthrax is the cause of death. The body should be sealed in an airtight body bag and incinerated to prevent the transmission of anthrax spores. Microscopic visualization of the encapsulated bacilli, usually in very large numbers, in a blood smear stained with polychrome methylene blue (McFadyean stain) is fully diagnostic, though the culture of the organism is still the gold standard for diagnosis. Full isolation of the body is important to prevent possible contamination of others.Protective, impermeable clothing and equipment such as rubber gloves, rubber apron, and rubber boots with no perforations are used when handling the body. No skin, especially if it has any wounds or scratches, should be exposed. Disposable personal protective equipment is preferable, but if not available, decontamination can be achieved by autoclaving. Used disposable equipment is burned and/or buried after use. All contaminated bedding or clothing is isolated in double plastic bags and treated as biohazard waste. Respiratory equipment capable of filtering small particles, such the US National Institute for Occupational Safety and Health- and Mine Safety and Health Administration-approved high-efficiency respirator, is worn.

Vaccines
Vaccines against anthrax for use in livestock and humans have had a prominent place in the history of medicine. The French scientist Louis Pasteur developed the first effective vaccine in 1881. Human anthrax vaccines were developed by the Soviet Union in the late 1930s and in the US and UK in the 1950s. The current FDA-approved US vaccine was formulated in the 1960s.Currently administered human anthrax vaccines include acellular (United States) and live vaccine (Russia) varieties. All currently used anthrax vaccines show considerable local and general reactogenicity (erythema, induration, soreness, fever) and serious adverse reactions occur in about 1% of recipients. The American product, BioThrax, is licensed by the FDA and was formerly administered in a six-dose primary series at 0, 2, 4 weeks and 6, 12, 18 months, with annual boosters to maintain immunity. In 2008, the FDA approved omitting the week-2 dose, resulting in the currently recommended five-dose series. New second-generation vaccines currently being researched include recombinant live vaccines and recombinant subunit vaccines. In the 20th century the use of a modern product (BioThrax) to protect American troops against the use of anthrax in biological warfare was controversial.

Antibiotics
Preventive antibiotics are recommended in those who have been exposed. Early detection of sources of anthrax infection can allow preventive measures to be taken. In response to the anthrax attacks of October 2001, the United States Postal Service (USPS) installed biodetection systems (BDSs) in their large-scale mail processing facilities. BDS response plans were formulated by the USPS in conjunction with local responders including fire, police, hospitals, and public health. Employees of these facilities have been educated about anthrax, response actions, and prophylactic medication. Because of the time delay inherent in getting final verification that anthrax has been used, prophylactic antibiotic treatment of possibly exposed personnel must be started as soon as possible.

Treatment
Anthrax cannot be spread from person to person, except in the rare case of skin exudates from cutaneous anthrax. However, a persons clothing and body may be contaminated with anthrax spores. Effective decontamination of people can be accomplished by a thorough wash-down with antimicrobial soap and water. Wastewater is treated with bleach or another antimicrobial agent. Effective decontamination of articles can be accomplished by boiling them in water for 30 minutes or longer. Chlorine bleach is ineffective in destroying spores and vegetative cells on surfaces, though formaldehyde is effective. Burning clothing is very effective in destroying spores. After decontamination, there is no need to immunize, treat, or isolate contacts of persons ill with anthrax unless they were also exposed to the same source of infection.

Antibiotics
Early antibiotic treatment of anthrax is essential; delay significantly lessens chances for survival. Treatment for anthrax infection and other bacterial infections includes large doses of intravenous and oral antibiotics, such as fluoroquinolones (ciprofloxacin), doxycycline, erythromycin, vancomycin, or penicillin. FDA-approved agents include ciprofloxacin, doxycycline, and penicillin. In possible cases of pulmonary anthrax, early antibiotic prophylaxis treatment is crucial to prevent possible death. Many attempts have been made to develop new drugs against anthrax, but existing drugs are effective if treatment is started soon enough.

Monoclonal antibodies
In May 2009, Human Genome Sciences submitted a biologic license application (BLA, permission to market) for its new drug, raxibacumab (brand name ABthrax) intended for emergency treatment of inhaled anthrax. On 14 December 2012, the US Food and Drug Administration approved raxibacumab injection to treat inhalational anthrax. Raxibacumab is a monoclonal antibody that neutralizes toxins produced by B. anthracis. In March 2016, FDA approved a second anthrax treatment using a monoclonal antibody which neutralizes the toxins produced by B. anthracis. Obiltoxaximab is approved to treat inhalational anthrax in conjunction with appropriate antibacterial drugs, and for prevention when alternative therapies are not available or appropriate.

Prognosis
Cutaneous anthrax is rarely fatal if treated, because the infection area is limited to the skin, preventing the lethal factor, edema factor, and protective antigen from entering and destroying a vital organ. Without treatment, about 20% of cutaneous skin infection cases progress to toxemia and death.Before 2001, fatality rates for inhalation anthrax were 90%; since then, they have fallen to 45%. People that progress to the fulminant phase of inhalational anthrax nearly always die, with one case study showing a death rate of 97%. Anthrax meningoencephalitis is also nearly always fatal.GI infections can be treated, but usually result in fatality rates of 25% to 60%, depending upon how soon treatment commences. This form of anthrax is the rarest.

Epidemiology
Globally, at least 2,000 cases occur a year.

United States
The last fatal case of natural inhalational anthrax in the United States occurred in California in 1976, when a home weaver died after working with infected wool imported from Pakistan. To minimize the chance of spreading the disease, the body was transported to UCLA in a sealed plastic body bag within a sealed metal container for autopsy.Gastrointestinal anthrax is exceedingly rare in the United States, with only two cases on record. The first case was reported in 1942, according to the Centers for Disease Control and Prevention. During December 2009, the New Hampshire Department of Health and Human Services confirmed a case of gastrointestinal anthrax in an adult female.
In 2007 two cases of cutaneous anthrax were reported in Danbury, Connecticut. The case involved the maker of traditional African-style drums who was working with a goat hide purchased from a dealer in New York City which had been previously cleared by Customs. While the hide was being scraped, a spider bite led to the spores entering the bloodstream. His son also became infected.The CDC investigated the source of the December 2009 infection and the possibility that it was contracted from an African drum recently used by the woman taking part in a drum circle. The woman apparently inhaled anthrax, in spore form, from the hide of the drum. She became critically ill, but with gastrointestinal anthrax rather than inhaled anthrax, which made her unique in American medical history. The building where the infection took place was cleaned and reopened to the public and the woman recovered. The New Hampshire state epidemiologist, Jodie Dionne-Odom, stated "It is a mystery. We really dont know why it happened."

Croatia
In July 2022, dozens of cattle in a nature park in Lonjsko Polje, a flood plain by the Sava river, died of anthrax and 6 people have been hospitalized with light, skin-related symptoms.

United Kingdom
In November 2008, a drum maker in the United Kingdom who worked with untreated animal skins died from anthrax. In December 2009, an outbreak of anthrax occurred among heroin addicts in the Glasgow and Stirling areas of Scotland, resulting in 14 deaths. The source of the anthrax is believed to have been dilution of the heroin with bone meal in Afghanistan.

History
Discovery
Robert Koch, a German physician and scientist, first identified the bacterium that caused the anthrax disease in 1875 in Wollstein (now Wolsztyn - a town in Poland). His pioneering work in the late 19th century was one of the first demonstrations that diseases could be caused by microbes. In a groundbreaking series of experiments, he uncovered the lifecycle and means of transmission of anthrax. His experiments not only helped create an understanding of anthrax but also helped elucidate the role of microbes in causing illness at a time when debates still took place over spontaneous generation versus cell theory. Koch went on to study the mechanisms of other diseases and won the 1905 Nobel Prize in Physiology or Medicine for his discovery of the bacterium causing tuberculosis.Although Koch arguably made the greatest theoretical contribution to understanding anthrax, other researchers were more concerned with the practical questions of how to prevent the disease. In Britain, where anthrax affected workers in the wool, worsted, hides, and tanning industries, it was viewed with fear. John Henry Bell, a doctor born & based in Bradford, first made the link between the mysterious and deadly "woolsorters disease" and anthrax, showing in 1878 that they were one and the same. In the early 20th century, Friederich Wilhelm Eurich, the German bacteriologist who settled in Bradford with his family as a child, carried out important research for the local Anthrax Investigation Board. Eurich also made valuable contributions to a Home Office Departmental Committee of Inquiry, established in 1913 to address the continuing problem of industrial anthrax. His work in this capacity, much of it collaboration with the factory inspector G. Elmhirst Duckering, led directly to the Anthrax Prevention Act (1919).

First vaccination
Anthrax posed a major economic challenge in France and elsewhere during the 19th century. Horses, cattle, and sheep were particularly vulnerable, and national funds were set aside to investigate the production of a vaccine. French scientist Louis Pasteur was charged with the production of a vaccine, following his successful work in developing methods that helped to protect the important wine and silk industries.In May 1881, Pasteur – in collaboration with his assistants Jean-Joseph Henri Toussaint, Émile Roux and others – performed a public experiment at Pouilly-le-Fort to demonstrate his concept of vaccination. He prepared two groups of 25 sheep, one goat, and several cattle. The animals of one group were injected with an anthrax vaccine prepared by Pasteur twice, at an interval of 15 days; the control group was left unvaccinated. Thirty days after the first injection, both groups were injected with a culture of live anthrax bacteria. All the animals in the unvaccinated group died, while all of the animals in the vaccinated group survived.After this apparent triumph, which was widely reported in the local, national, and international press, Pasteur made strenuous efforts to export the vaccine beyond France. He used his celebrity status to establish Pasteur Institutes across Europe and Asia, and his nephew, Adrien Loir, travelled to Australia in 1888 to try to introduce the vaccine to combat anthrax in New South Wales. Ultimately, the vaccine was unsuccessful in the challenging climate of rural Australia, and it was soon superseded by a more robust version developed by local researchers John Gunn and John McGarvie Smith.The human vaccine for anthrax became available in 1954. This was a cell-free vaccine instead of the live-cell Pasteur-style vaccine used for veterinary purposes. An improved cell-free vaccine became available in 1970.

Engineered strains
The Sterne strain of anthrax, named after the Trieste-born immunologist Max Sterne, is an attenuated strain used as a vaccine, which contains only the anthrax toxin virulence plasmid and not the polyglutamic acid capsule expressing plasmid.
Strain 836, created by the Soviet bioweapons program in the 1980s, was later called by the Los Angeles Times "the most virulent and vicious strain of anthrax known to man".
The virulent Ames strain, which was used in the 2001 anthrax attacks in the United States, has received the most news coverage of any anthrax outbreak. The Ames strain contains two virulence plasmids, which separately encode for a three-protein toxin, called anthrax toxin, and a polyglutamic acid capsule.
Nonetheless, the Vollum strain, developed but never used as a biological weapon during the Second World War, is much more dangerous. The Vollum (also incorrectly referred to as Vellum) strain was isolated in 1935 from a cow in Oxfordshire. This same strain was used during the Gruinard bioweapons trials. A variation of Vollum, known as "Vollum 1B", was used during the 1960s in the US and UK bioweapon programs. Vollum 1B is widely believed to have been isolated from William A. Boyles, a 46-year-old scientist at the US Army Biological Warfare Laboratories at Camp (later Fort) Detrick, Maryland, who died in 1951 after being accidentally infected with the Vollum strain.
US Air Force researchers have developed a vaccine strain to produce an improved anthrax vaccine which requires a minimal number of injections to achieve and maintain long-term immunity. It is designated as the Alls/Gifford (Curlicue) strain.

Society and culture
Site cleanup
Anthrax spores can survive for very long periods of time in the environment after release. Chemical methods for cleaning anthrax-contaminated sites or materials may use oxidizing agents such as peroxides, ethylene oxide, Sandia Foam, chlorine dioxide (used in the Hart Senate Office Building), peracetic acid, ozone gas, hypochlorous acid, sodium persulfate, and liquid bleach products containing sodium hypochlorite. Nonoxidizing agents shown to be effective for anthrax decontamination include methyl bromide, formaldehyde, and metam sodium. These agents destroy bacterial spores. All of the aforementioned anthrax decontamination technologies have been demonstrated to be effective in laboratory tests conducted by the US EPA or others.Decontamination techniques for Bacillus anthracis spores are affected by the material with which the spores are associated, environmental factors such as temperature and humidity, and microbiological factors such as the spore species, anthracis strain, and test methods used.A bleach solution for treating hard surfaces has been approved by the EPA. Chlorine dioxide has emerged as the preferred biocide against anthrax-contaminated sites, having been employed in the treatment of numerous government buildings over the past decade. Its chief drawback is the need for in situ processes to have the reactant on demand.
To speed the process, trace amounts of a nontoxic catalyst composed of iron and tetroamido macrocyclic ligands are combined with sodium carbonate and bicarbonate and converted into a spray. The spray formula is applied to an infested area and is followed by another spray containing tert-butyl hydroperoxide.Using the catalyst method, complete destruction of all anthrax spores can be achieved in under 30 minutes. A standard catalyst-free spray destroys fewer than half the spores in the same amount of time.
Cleanups at a Senate Office Building, several contaminated postal facilities, and other US government and private office buildings, a collaborative effort headed by the Environmental Protection Agency showed decontamination to be possible, but time-consuming and costly. Clearing the Senate Office Building of anthrax spores cost $27 million, according to the Government Accountability Office. Cleaning the Brentwood postal facility in Washington cost $130 million and took 26 months. Since then, newer and less costly methods have been developed.Cleanup of anthrax-contaminated areas on ranches and in the wild is much more problematic. Carcasses may be burned, though often 3 days are needed to burn a large carcass and this is not feasible in areas with little wood. Carcasses may also be buried, though the burying of large animals deeply enough to prevent resurfacing of spores requires much manpower and expensive tools. Carcasses have been soaked in formaldehyde to kill spores, though this has environmental contamination issues. Block burning of vegetation in large areas enclosing an anthrax outbreak has been tried; this, while environmentally destructive, causes healthy animals to move away from an area with carcasses in search of fresh grass. Some wildlife workers have experimented with covering fresh anthrax carcasses with shadecloth and heavy objects. This prevents some scavengers from opening the carcasses, thus allowing the putrefactive bacteria within the carcass to kill the vegetative B. anthracis cells and preventing sporulation. This method also has drawbacks, as scavengers such as hyenas are capable of infiltrating almost any exclosure.The experimental site at Gruinard Island is said to have been decontaminated with a mixture of formaldehyde and seawater by the Ministry of Defence. It is not clear whether similar treatments had been applied to US test sites.

Biological warfare
Anthrax spores have been used as a biological warfare weapon. Its first modern incidence occurred when Nordic rebels, supplied by the German General Staff, used anthrax with unknown results against the Imperial Russian Army in Finland in 1916. Anthrax was first tested as a biological warfare agent by Unit 731 of the Japanese Kwantung Army in Manchuria during the 1930s; some of this testing involved intentional infection of prisoners of war, thousands of whom died. Anthrax, designated at the time as Agent N, was also investigated by the Allies in the 1940s.A long history of practical bioweapons research exists in this area. For example, in 1942, British bioweapons trials severely contaminated Gruinard Island in Scotland with anthrax spores of the Vollum-14578 strain, making it a no-go area until it was decontaminated in 1990. The Gruinard trials involved testing the effectiveness of a submunition of an "N-bomb" –  a biological weapon containing dried anthrax spores. Additionally, five million "cattle cakes" (animal feed pellets impregnated with anthrax spores) were prepared and stored at Porton Down for "Operation Vegetarian" –  anti livestock attacks against Germany to be made by the Royal Air Force. The plan was for anthrax-based biological weapons to be dropped on Germany in 1944. However, the edible cattle cakes and the bomb were not used; the cattle cakes were incinerated in late 1945.
Weaponized anthrax was part of the US stockpile prior to 1972, when the United States signed the Biological Weapons Convention. President Nixon ordered the dismantling of US biowarfare programs in 1969 and the destruction of all existing stockpiles of bioweapons. In 1978–79, the Rhodesian government used anthrax against cattle and humans during its campaign against rebels. The Soviet Union created and stored 100 to 200 tons of anthrax spores at Kantubek on Vozrozhdeniya Island; they were abandoned in 1992 and destroyed in 2002.American military and British Army personnel are no longer routinely vaccinated against anthrax prior to active service in places where biological attacks are considered a threat.

Sverdlovsk incident (2 April 1979)
Despite signing the 1972 agreement to end bioweapon production, the government of the Soviet Union had an active bioweapons program that included the production of hundreds of tons of anthrax after this period. On 2 April 1979, some of the over one million people living in Sverdlovsk (now called Ekaterinburg, Russia), about 1,370 kilometres (850 mi) east of Moscow, were exposed to an accidental release of anthrax from a biological weapons complex located near there. At least 94 people were infected, of whom at least 68 died. One victim died four days after the release, 10 over an eight-day period at the peak of the deaths, and the last six weeks later. Extensive cleanup, vaccinations, and medical interventions managed to save about 30 of the victims. Extensive cover-ups and destruction of records by the KGB continued from 1979 until Russian President Boris Yeltsin admitted this anthrax accident in 1992. Jeanne Guillemin reported in 1999 that a combined Russian and United States team investigated the accident in 1992.Nearly all of the night-shift workers of a ceramics plant directly across the street from the biological facility (compound 19) became infected, and most died. Since most were men, some NATO governments suspected the Soviet Union had developed a sex-specific weapon. The government blamed the outbreak on the consumption of anthrax-tainted meat, and ordered the confiscation of all uninspected meat that entered the city. They also ordered all stray dogs to be shot and people not have contact with sick animals. Also, a voluntary evacuation and anthrax vaccination program was established for people from 18 to 55.To support the cover-up story, Soviet medical and legal journals published articles about an outbreak in livestock that caused GI anthrax in people having consumed infected meat, and cutaneous anthrax in people having come into contact with the animals. All medical and public health records were confiscated by the KGB. In addition to the medical problems the outbreak caused, it also prompted Western countries to be more suspicious of a covert Soviet bioweapons program and to increase their surveillance of suspected sites. In 1986, the US government was allowed to investigate the incident, and concluded the exposure was from aerosol anthrax from a military weapons facility. In 1992, President Yeltsin admitted he was "absolutely certain" that "rumors" about the Soviet Union violating the 1972 Bioweapons Treaty were true. The Soviet Union, like the US and UK, had agreed to submit information to the UN about their bioweapons programs, but omitted known facilities and never acknowledged their weapons program.

Anthrax bioterrorism
In theory, anthrax spores can be cultivated with minimal special equipment and a first-year collegiate microbiological education.
To make large amounts of an aerosol form of anthrax suitable for biological warfare requires extensive practical knowledge, training, and highly advanced equipment.Concentrated anthrax spores were used for bioterrorism in the 2001 anthrax attacks in the United States, delivered by mailing postal letters containing the spores. The letters were sent to several news media offices and two Democratic senators: Tom Daschle of South Dakota and Patrick Leahy of Vermont. As a result, 22 were infected and five died </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Anticholinergic and explain in detail? [/INST] Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.These agents inhibit the parasympathetic nervous system by selectively blocking the binding of ACh to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, sweat glands, and many other parts of the body.In broad terms, anticholinergics are divided into two categories in accordance with their specific targets in the central and peripheral nervous system and at the neuromuscular junction: antimuscarinic agents, and antinicotinic agents (ganglionic blockers, neuromuscular blockers).The term "anticholinergic" is typically used to refer to antimuscarinics which competitively inhibit the binding of ACh to muscarinic acetylcholine receptors; such agents do not antagonize the binding at nicotinic acetylcholine receptors at the neuromuscular junction, although the term is sometimes used to refer to agents which do so.

Medical uses
Anticholinergic drugs are used to treat a variety of conditions:

Dizziness (including vertigo and motion sickness-related symptoms)
Extrapyramidal symptoms, a potential side-effect of antipsychotic medications
Gastrointestinal disorders (e.g., peptic ulcers, diarrhea, pylorospasm, diverticulitis, ulcerative colitis, nausea, and vomiting)
Genitourinary disorders (e.g., cystitis, urethritis, and prostatitis)
Insomnia, although usually only on a short-term basis
Respiratory disorders (e.g., asthma, chronic bronchitis, and chronic obstructive pulmonary disease [COPD])
Sinus bradycardia due to a hypersensitive vagus nerve
Organophosphate based nerve agent poisoning, such as VX, sarin, tabun, and soman (atropine is favoured in conjunction with an oxime, usually pralidoxime)Anticholinergics generally have antisialagogue effects (decreasing saliva production), and most produce some level of sedation, both being advantageous in surgical procedures.Until the beginning of the 20th century anticholinergic drugs were widely used to treat psychiatric disorders.

Physiological effects
Delirium (often with hallucinations and delusions indistinguishable from reality)
Ocular symptoms (from eye drops): mydriasis, pupil dilation, and acute angle-closure glaucoma in those with shallow anterior chamber
Anhidrosis, dry mouth, dry skin
Fever
Constipation
Tachycardia
Urinary retention
Cutaneous vasodilationClinically the most significant feature is delirium, particularly in the elderly, who are most likely to be affected by the toxidrome.

Side effects
Long-term use may increase the risk of both cognitive and physical decline. It is unclear whether they affect the risk of death generally. However, in older adults they do appear to increase the risk of death.Possible effects of anticholinergics include:

Possible effects in the central nervous system resemble those associated with delirium, and may include:

Older patients are at a higher risk of experiencing CNS side effects.

Toxicity
An acute anticholinergic syndrome is reversible and subsides once all of the causative agents have been excreted. Reversible acetylcholinesterase inhibitor agents such as physostigmine can be used as an antidote in life-threatening cases. Wider use is discouraged due to the significant side effects related to cholinergic excess including seizures, muscle weakness, bradycardia, bronchoconstriction, lacrimation, salivation, bronchorrhea, vomiting, and diarrhea. Even in documented cases of anticholinergic toxicity, seizures have been reported after the rapid administration of physostigmine </s>


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


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


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