text:
Anthrax

Anthrax is an infection caused by the bacterium Bacillus anthracis. Infection typically occurs by contact with the skin, inhalation, or intestinal absorption. 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.

According to the U.S. Centers for Disease Control and Prevention, the first clinical descriptions of cutaneous anthrax were given by Maret in 1752 and Fournier in 1769. Before that, anthrax had been described only in historical accounts. The Prussian scientist Robert Koch was the first to identify Bacillus anthracis as the bacterium that causes anthrax.

Anthrax is spread by contact with the bacterium's 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, 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. 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.

Several countries have developed anthrax as a weapon. It has been used in biowarfare and bioterrorism since 1914. In 1975, the Biological Weapons Convention prohibited the "development, production and stockpiling" of biological weapons. It has since been used in bioterrorism. Likely delivery methods of weaponized anthrax include aerial dispersal or dispersal through livestock; notable bioterrorism uses include the 2001 anthrax attacks and an incident in 1993 by the Aum Shinrikyo group.

Etymology
The English name comes from anthrax (ἄνθραξ), the Greek word for coal, possibly having Egyptian etymology, because of the characteristic black skin lesions people with a cutaneous anthrax infection develop. 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's 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 include Siberian plague, Cumberland disease, charbon, splenic fever, malignant edema, woolsorter's disease and la maladie de Bradford.

Skin
Cutaneous anthrax, also known as hide-porter's disease, is when anthrax occurs on the skin. It is the most common (>90% of cases) and 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 two to 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. It was the first documented non-occupational human anthrax outbreak in the UK since 1960. 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, with the exception of black areas, and may also cause infection deep into the muscle and spread faster. This can make it harder to recognise and treat.

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.

Bacteria

Bacillus anthracis is a rod-shaped, Gram-positive, facultative anaerobe 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 gastrointestinal 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 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, but anthrax vegetative bacteria that escape the body via oozing blood or opening the carcass may form hardy spores. These vegetative bacteria are not contagious. One spore forms per vegetative bacterium. The triggers for spore formation are not known, but 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 inhalation 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 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: 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 and transmission
Anthrax can enter the human body through the intestines (gastrointestinal), lungs (pulmonary), or skin (cutaneous), and causes distinct clinical symptoms based on its site of entry. Anthrax does not usually spread from an infected human to an uninfected human. If the disease is fatal to the person's body, its mass of anthrax bacilli becomes a potential source of infection to others and special precautions should be used to prevent further contamination. Pulmonary anthrax, if left untreated, is almost always fatal. Historically, pulmonary 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 industrialized nations. Cutaneous anthrax is the most common form of transmission but also the least dangerous of the three transmissions. Gastrointestinal anthrax is likely fatal if left untreated, but very rare. 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. In one such event, a young boy died from gastrointestinal anthrax due to the thawing of reindeer corpses from 75 years before contact. Anthrax spores traveled though groundwater used for drinking and caused tens of people to be hospitalized, largely children. Occupational exposure to infected animals or their products (such as skin, wool, and meat) is the usual pathway of exposure for humans. Workers 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 U.S. 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 produce infection. A lethal infection is reported to result from inhalation of about 10,000–20,000 spores, though this dose varies among host species.

Mechanism
The lethality of the anthrax disease is due to the bacterium's 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, consisting of 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 serious 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. By addressing Anthrax from a One Health perspective, we can reduce the risks of transmission and better protect both human and animal populations.

The prevention of anthrax from the environmental sources like air, water, & soil is disinfection used by effective microorganisms thru spraying, and bokashi mudballs mixed with effective microorganisms for the contaminated waterways.

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 subunit vaccine (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. This five-dose series is available to military personnel, scientists who work with anthrax and members of the public who do jobs which cause them to be at-risk. 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 person's 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, up to 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.

Gastrointestinal anthrax infections can be treated, but usually result in fatality rates of 25% to 60%, depending upon how soon treatment commences.

Injection anthrax is the rarest form of anthrax, and has only been seen to have occurred in a group of heroin injecting drug users.

Animals
Anthrax, a bacterial disease caused by Bacillus anthracis, can have devastating effects on animals. It primarily affects herbivores such as cattle, sheep, and goats, but a wide range of mammals, birds, and even humans can also be susceptible. Infection typically occurs through the ingestion of spores in contaminated soil or plants. Once inside the host, the spores transform into active bacteria, producing lethal toxins that lead to severe symptoms. Infected animals often exhibit high fever, rapid breathing, and convulsions, and they may succumb to the disease within hours to days. The presence of anthrax can pose significant challenges to livestock management and wildlife conservation efforts, making it a critical concern for both animal health and public health, as it can occasionally be transmitted to humans through contact with infected animals or contaminated products. Infected animals may stagger, have difficulty breathing, tremble, and finally collapse and die within a few hours.

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. The CDC investigated the source 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 don't know why it happened."

In 2007 two cases of cutaneous anthrax were reported in Danbury, Connecticut. The case involved a 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.

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.

Discovery
Robert Koch, a German physician and scientist, first identified the bacterium that caused the anthrax disease in 1875 in Wollstein (now Wolsztyn, 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 "woolsorter's 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 twice injected with an anthrax vaccine prepared by Pasteur, 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.

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.

In 1942, British scientists at Porton Down began research on Operation Vegetarian, an ultimately unused biowarfare military operation plan which called for animal feed pellets containing linseed infected with anthrax spores of the Vollum-14578 strain to be dropped by air over the countryside of Nazi Germany. The pellets would be eaten by cattle, which would in turn be eaten by the human population and as such severally disrupt the German war effort. In the same year, bioweapons tests were carried out on the uninhabited Gruinard Island in the Scottish Highlands, with Porton Down scientists studying the effect of anthrax on the island's population of sheep. Ultimately, five million pellets were created, though plans to drop them over Germany using Royal Air Force bombers in 1944 were scrapped after the success of Operation Overlord and the subsequent Allied liberation of France. All pellets were destroyed using incinerators in 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 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 gastrointestinal 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. Only a few grams of material were used in these attacks and in August 2008, the US Department of Justice announced they believed that Bruce Ivins, a senior biodefense researcher employed by the United States government, was responsible. These events also spawned many anthrax hoaxes.

Due to these events, the US Postal Service installed biohazard detection systems at its major distribution centers to actively scan for anthrax being transported through the mail. As of 2020, no positive alerts by these systems have occurred.

Decontaminating mail
In response to the postal anthrax attacks and hoaxes, the United States Postal Service sterilized some mail using gamma irradiation and treatment with a proprietary enzyme formula supplied by Sipco Industries.

A scientific experiment performed by a high school student, later published in the Journal of Medical Toxicology, suggested a domestic electric iron at its hottest setting (at least 400 °F) used for at least 5 minutes should destroy all anthrax spores in a common postal envelope.

Other animals
Anthrax is especially rare in dogs and cats, as is evidenced by a single reported case in the United States in 2001. Anthrax outbreaks occur in some wild animal populations with some regularity.

Russian researchers estimate arctic permafrost contains around 1.5 million anthrax-infected reindeer carcasses, and the spores may survive in the permafrost for 105 years. A risk exists that global warming in the Arctic can thaw the permafrost, releasing anthrax spores in the carcasses. In 2016, an anthrax outbreak in reindeer was linked to a 75-year-old carcass that defrosted during a heat wave.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Anthrax


text:
Anthrax (American band)

Anthrax is an American thrash metal band from New York City, formed in 1981 by rhythm guitarist Scott Ian and bassist Dan Lilker. The group is considered one of the leaders of the thrash metal scene from the 1980s and is part of the "Big Four" of the genre, along with Metallica, Megadeth and Slayer. They were also one of the first thrash metal bands (along with Overkill and Nuclear Assault) to emerge from the East Coast. The band's current lineup consists of Scott Ian, drummer Charlie Benante, bassist Frank Bello, vocalist Joey Belladonna and lead guitarist Jonathan Donais. Anthrax's lineup has changed numerous times over their career, leaving Ian as the only constant member of the band. Ian and Benante (who replaced one-time drummer Greg D'Angelo in 1983) are the only two members to appear on all of Anthrax's albums, while Bello has been a member of Anthrax since 1984, replacing Lilker.

After cycling through a number of members, Anthrax released their debut album, Fistful of Metal (1984), with singer Neil Turbin. Turbin was replaced by Joey Belladonna later that year, stabilizing the band's lineup. Anthrax's third album Among the Living (1987), which brought the band mainstream success for the first time, is recognised as one of the greatest thrash metal albums. The band's next two outings, State of Euphoria (1988) and Persistence of Time (1990), further cemented their reputation as one of the most successful thrash metal bands, with the latter giving Anthrax their first Grammy Award nomination. In 1992, Anthrax signed to Elektra Records for $10 million and Belladonna was replaced by John Bush of Armoured Saint. Bush's first album with Anthrax, Sound of White Noise (1993), reached number seven on the Billboard 200 chart (their greatest chart success) and spawned the radio hit "Only". Anthrax's subsequent albums with Bush would experience less critical and commercial success; the band would part ways with Elektra following the release of Stomp 442 (1995) due to a lack of promotional support, and Volume 8: The Threat is Real (1998) suffered from the bankruptcy of their record label.

Bush left Anthrax in 2005, after which the band reunited with Belladonna and lead guitarist Dan Spitz. After Belladonna and Spitz's departure in 2007, Anthrax recruited singer Dan Nelson and commenced work on a new album, although Nelson would part ways with the band in 2009. Following a short-lived reunion with Bush, Belladonna rejoined the band for a third time in 2010. Anthrax's first album with Belladonna in 21 years, Worship Music (2011) was released to critical and commercial success, reaching number twelve on the Billboard 200. The band's most recent album to date, For All Kings, was released in 2016.

Anthrax has released 11 studio albums, several other albums, and 26 singles, including collaborating on a single with American hip hop group Public Enemy. Four of the band's studio albums (Among the Living, State of Euphoria, Persistence of Time and Sound of White Noise) have also achieved gold certifications by the RIAA. According to Nielsen SoundScan, Anthrax sold 2.5 million records in the United States from 1991 to 2004, with total worldwide sales of ten million.

Formation (1981–1982)
Anthrax was formed in Queens, New York City, on July 18, 1981, by guitarists Scott Ian and Dan Lilker, with Ian's friend Dave Weiss on drums. The band was named after the disease of the same name which Ian saw in a biology textbook, chosen because it sounded "sufficiently evil". Lilker originally intended for Scott Setari to play bass in the band, during their early phases as a cover band. Anthrax's initial lineup was completed by singer John Connelly, and bassist Paul Kahn. Kahn was briefly replaced by bassist Kenny Kushner before Lilker took over on bass. Future Hittman singer Dirk Kennedy replaced Connelly for a few months and the band brought in lead guitarist Greg Walls. Weiss was then replaced early on by drummer Greg D'Angelo, who was recommended to the band by Walls. Ian's younger brother Jason Rosenfeld had been a temporary vocalist until Ian's former schoolmate Neil Turbin joined the band in late August 1982. Turbin joined the band partly because of guitarist Walls, who Turbin later said was "the best guitarist Anthrax ever had". The band recorded its first demo tape during this time.

Neil Turbin era and debut album (1982–1984)

The band's first performance with Neil Turbin was at Great Gildersleeves, a New York club, in September 1982. This lineup played regularly in the New York–New Jersey area over the next several months. Anthrax was also on the same bill as then-up-and-coming Metallica for several shows in the spring of 1983. Guitarist Walls left Anthrax that summer because of friction with Ian, and drummer D'Angelo left a month later. Turbin said he was seriously considering leaving because of the loss of Walls and D'Angelo, but he stuck it out for another year. Walls was replaced by Bob Berry, who was recommended to Turbin by Rhett Forrester of Riot. Berry was in turn soon replaced by Dan Spitz, who was previously a member of the New Jersey thrash band Overkill.

Drummer Charlie Benante replaced D'Angelo in September 1983 after a several-month courtship by Ian. By this time, Ian and Lilker had befriended New Jersey record store owner Jon Zazula, to whom they had given their demo tapes to critique. Zazula's new record label Megaforce Records had recently released Metallica's debut album Kill 'Em All to great success. In late 1983, Zazula agreed to sign Anthrax and the band recorded the "Soldiers of Metal" single, which was produced by Ross the Boss of Manowar. The B-side was the song "Howling Furies" which was taken from a previous demo with Greg D'Angelo on drums (his only Anthrax recording).

Anthrax released their debut album Fistful of Metal in January 1984. Former guitarist Walls said he was shocked that the album was released without giving credit to Walls as the primary songwriter on "Panic" and "Metal Thrashing Mad", as well as smaller songwriting contributions throughout the album. Tensions were building between Lilker and the rest of the band for various reasons, eventually leading to the band firing Lilker. He would soon form the band Nuclear Assault with former Anthrax roadie / vocalist John Connelly. Lilker was replaced by Benante's nephew and roadie Frank Bello. The band then went on a successful US tour opening for Raven and others to support Fistful of Metal.

In August 1984, Turbin and Anthrax went their separate ways after long-standing personal issues. In his book Eddie Trunk's Essential Hard Rock and Heavy Metal, music journalist Eddie Trunk admits pressuring Jon Zazula, Scott Ian and Anthrax into firing Turbin because of his personal taste in vocals. Singer Matt Fallon was briefly hired in late 1984, but he and the band soon parted ways. The remaining members decided to play live shows as a four-piece billed as "The Diseased" with Scott Ian on vocals, performing hardcore punk covers until a permanent singer could be found.

Initial Joey Belladonna era (1984–1992)
In 1984, Joey Belladonna was chosen as the new vocalist. The Armed and Dangerous EP marked Belladonna's recording debut with Anthrax. The 1992 reissue of the EP included the two songs from the "Soldiers of Metal" single that had Neil Turbin performing on them.

Anthrax's second album Spreading the Disease was released in October 1985. It was well-received as both a technical leap forward from Fistful of Metal and as a more original effort, and remains one of the band's most highly regarded albums. With leftover studio time from these sessions, Ian, Benante and former bandmate Dan Lilker collaborated with vocalist Billy Milano to form the side project Stormtroopers of Death, and recorded the album Speak English or Die in three days. It was released in August 1985 and is now considered a pioneering crossover thrash release, featuring one of the earliest examples of a blast beat on record. Afterwards, the project was put on hold as Ian and Benante turned their focus back on Anthrax.

The US tour to support Spreading the Disease opening for Black Sabbath was canceled after four dates due to Sabbath singer Glenn Hughes' voice problems. In April 1986, Anthrax attempted its first tour of Europe beginning in Bochum, Germany, supported by Overkill and Agent Steel. The tour included a show near Chernobyl, Ukraine, immediately after the Chernobyl disaster. Later that year, Anthrax toured Europe with Metallica. The tour began on September 10 at St David's Hall and ended on September 26 in Solnahallen, Sweden. The Swedish show was Anthrax's last performance before the bus accident the following day, which killed Metallica bassist Cliff Burton.

The band's third studio album Among the Living was released in March 1987, and is often considered by both the band and critics to be a major breakthrough for Anthrax. Produced by Eddie Kramer, it showcased the band's humorous, experimental side and began a lyrical trend focusing on movies, politics, comic books and Stephen King novels. The album was dedicated to Cliff Burton's memory. Propelled by the singles "Indians" and "I Am the Law", the success of Among the Living not only turned Anthrax into a household name (along with the remaining "big four" of thrash metal–Metallica, Megadeth and Slayer), but eventually earned them one of their first certified-gold records by the RIAA. "I Am the Law", which was released as the album's second single, was backed with a rap-metal hybrid "I'm the Man" as its B-side. Anthrax further indulged its appreciation for rap by appearing on the title track of U.T.F.O.'s album, Lethal, and their worship for the genre was also attributed to Ian wearing a t-shirt of Public Enemy both on stage and for publicity photo shoots; in response, Public Enemy name-checked Anthrax in the lyrics to their 1988 single "Bring the Noise". Anthrax toured for over a year to promote Among the Living, touring Europe again with Metallica, the United States with Metal Church, Testament, D.R.I., Exodus and Celtic Frost, and supporting Kiss on their Crazy Nights tour.

Anthrax released their fourth album State of Euphoria in September 1988, and it was produced by Mark Dodson, who had previously worked with Judas Priest, U.D.O. and Metal Church. While the album was not quite as well-received as Among the Living, owing to its "rushed" finish, State of Euphoria was certified gold about five months after its release, and one of the singles "Antisocial", originally by French heavy metal band Trust, became an MTV staple as part of the rotation on Headbangers Ball. By 1989, Anthrax was starting to play at arenas as a headlining or opening act, first supporting Ozzy Osbourne on his No Rest for the Wicked tour in North America, and then headlining European tours with Living Colour, Suicidal Tendencies and King's X, and the U.S. Headbangers Ball Tour with Exodus and Helloween. Also in 1989, MTV sponsored a contest in which the winner had her home trashed by the band. This would later inspire Anthrax's 1992 appearance on the television series Married... with Children, in which the Bundys win a similar TV contest.

Anthrax returned to the studio at the end of 1989 to work on their fifth album, again with Dodson as the producer. Released in August 1990, Persistence of Time was written and recorded during a period of turmoil for Anthrax, as Ian had recently been divorced from his first wife, and the middle of the recording session was interrupted by a fire that caused the band to lose more than $100,000 worth of gear and their rehearsal studio. The band members also claimed it was during this period that there were talks of potentially working with a different singer, a situation that Belladonna was unaware of at the time. Considered by fans to be their serious effort, Persistence of Time was darker, more technical and more progressive than the band's previous work, striking a chord with metal fans wary of Anthrax's "silly" side. The most successful single from the album was a cover of Joe Jackson's "Got the Time", which Jackson said he enjoyed. Persistence of Time was certified gold by the RIAA in early 1991, and the band toured for nearly two years to promote the album, opening for Iron Maiden on their No Prayer for the Dying tour in Europe and North America, and appearing on the Clash of the Titans tour with Megadeth, Slayer and opening act Alice in Chains.

In 1991, Anthrax collaborated with Public Enemy on a version of "Bring the Noise". This was a hit, and a successful tour with Public Enemy followed. "Bring the Noise" has been a live staple for Anthrax since they first played it in concert in 1989. The compilation Attack of the Killer B's was released in 1991, and featured three tracks from their 1989 EP Penikufesin, a new version of "I'm the Man" and a cover of "Bring the Noise" on which Ian did some vocals.

Initial John Bush era (1992–2005)

In early 1992, shortly after signing a $10 million record deal with Elektra Records and following their appearance in Married... with Children, Belladonna was fired from Anthrax over creative and stylistic differences. After firing Belladonna, the remaining members of Anthrax auditioned several vocalists including Mark Osegueda of Death Angel and Spike Xavier of Mind Over Four. However, Armored Saint vocalist John Bush was the standout favorite and had in fact been floated as a potential replacement for Belladonna a few years earlier, due to questions about his reliability stemming from drug and alcohol abuse. The band's first album with Bush and for Elektra, Sound of White Noise, was released in 1993. Produced by Dave Jerden (then-known for his work with Jane's Addiction and Alice in Chains), the album marked a change from Anthrax's earlier work, with a dark sound influenced by alternative rock, and it received mostly positive reviews. Critic Dave Connolley of AllMusic wrote that Bush "has a lower-register voice than Belladonna, and the result is menacing, premeditated, and sinister." The song "Only" was released as the album's first single. In the liner notes for Return of the Killer A's, Ian said that James Hetfield told him it was a "perfect song". In keeping with the band's eye for unlikely collaborations, classical composer Angelo Badalamenti provided music for "Black Lodge" (a nod to Twin Peaks). This album demonstrated that Anthrax had fully shed its cartoonish persona in favor of mature, thoughtful songwriting, which began with Persistence of Time. The success of Sound of White Noise dissolved any fan worries that the band would not recover from their split with Belladonna; it was certified gold by the RIAA nearly two months after its release, and gave Anthrax their highest chart position to date at number seven on the Billboard 200. The album also saw Anthrax continuing to headline arenas and theaters or amphitheaters, taking several bands such as Suicidal Tendencies, White Zombie, Quicksand, Fight and Clawfinger out as supporting acts.

After Sound of White Noise longtime guitarist Dan Spitz left the band to become a watchmaker, leaving Anthrax a quartet temporarily. In 1995, Anthrax released their seventh studio album Stomp 442, on which Charlie Benante played most of the lead-guitar parts. Benante was assisted by Paul Crook, who later became the band's touring lead guitarist for several years, and Dimebag Darrell of Pantera. The album's release followed a shake-up at Elektra the year before, which saw the firing of the label's president, Bob Krasnow, who was replaced by Sylvia Rhone. During a meeting with the band, Rhone told Anthrax that she wouldn't have signed their record deal. Elektra did not promote Stomp 442, and it was less commercially successful than its predecessor. Frustrated by this, Anthrax severed its ties with the label.

In late 1997, Anthrax signed with Ignition Records, an independent label distributed by Tommy Boy Records. The label released Volume 8: The Threat Is Real in July 1998. As on Stomp 442, Benante performed lead guitar parts along with Crook and Darrell. The album also features Pantera vocalist Phil Anselmo making a guest vocal appearance. Towards the end of 1998, Tommy Boy ended its distribution deal with Ignition, after which the label went bankrupt, disrupting its distribution. Anthrax then signed with Beyond Records, who released the greatest-hits album Return of the Killer A's (1999), after which Beyond went out of business as well. During this period a two-vocalist tour with Belladonna and Bush was planned, but Belladonna decided not to participate at the last minute; however, on the mentioned Return of the Killer A's compilation, a cover of The Temptations song "Ball of Confusion" was recorded with the then-current lineup of the band (Ian/Benante/Bello/Bush/Crook), in addition to former vocalist Belladonna and former bassist Lilker. This is the only song to feature both Belladonna and Bush on co-vocals.

Despite hardships and legal entanglements over album rights, Anthrax continued. In 2001, Rob Caggiano joined the band on lead guitar. During the 2001 anthrax attacks in the United States the band changed its website, providing information about the disease after people began searching "anthrax.com" on internet search engines. Amid a potential PR nightmare, Anthrax issued a press release on October 10, 2001, joking that the band's name would be changed to "something more friendly, like 'Basket Full of Puppies'." Anthrax dispelled any name-change rumors derived from the press release at the November 2001 New York Steel 9/11 benefit concert, when they took the stage in boiler suits with a different word on each one which ultimately read "We're not changing our name". Bello has stated they did so after receiving support from members of the NYPD and FDNY, who believed that changing the name of the band would send the wrong message. A picture of the band in the suits is on the inner tray card of We've Come for You All.

In 2003, the band signed to Sanctuary Records and released their ninth studio album We've Come for You All, praised by metal journalists as a return to form. The band then spent the summer of 2003 on tour with Motörhead.

In early 2004, Anthrax released The Greater of Two Evils, a "live in the studio" re-recording of the earlier work with the band's then-current lineup. Bassist Frank Bello announced shortly afterwards that he was leaving the band to join Helmet, and was replaced by Fates Warning and Armored Saint member Joey Vera.

Reunions with Belladonna and Bush (2005–2010)
In April 2005, Anthrax announced that the "classic" lineup of Scott Ian, Charlie Benante, Dan Spitz, Joey Belladonna and Frank Bello would reform. At some shows on the following tour, they played Among the Living in its entirety. Although the lineup was expected to record a new album after the tour, in January 2007 Ian said that Belladonna had not agreed to a reunion. John Bush also said he wasn't ready to re-commit to Anthrax and said he had been asked to return but had declined. Asked if he wanted to rejoin the band when Belladonna left, Bush said that he "just didn't feel right to do that."

In December 2007, it was announced that the band's new vocalist would be Dan Nelson, formerly of Devilsize, and Rob Caggiano would return as lead guitarist. In May 2008, Anthrax played its first show in 19 months at Double Door in Chicago.

In his monthly Food Coma column posted in December 2008, Scott Ian wrote that he had "been in the studio working on the new Anthrax album", promising to be "giving birth to a really pissed off, loud, fast and heavy child." He later wrote that the album was being mixed by Dave Fortman, who had worked with Evanescence and Slipknot.

In early 2009, Anthrax began a brief tour opening for Iron Maiden in South America. In July, band manager Izvor Zivkovic confirmed the departure of Dan Nelson due to illness. Nelson denied this, saying that he was fired. All subsequent performances were canceled except the August UK Sonisphere Festival, which featured John Bush on vocals. Fan response after his performance led to a "Bring Back Bush" campaign, which was endorsed by Ian.

Soon afterwards, Benante said that Bush had rejoined the band. In February 2010, Anthrax performed five shows as part of Soundwave in Australia. After the Australian shows, Bush said the band intended to re-record the vocals of several tracks from the upcoming album.

Worship Music and For All Kings (2010–2017)

In late 2009, Anthrax confirmed their participation in several "Big Four" concerts with Metallica, Megadeth and Slayer as part of the 2010 Sonisphere Festival dates in Europe. John Bush decided that he did not want to commit to the band full-time, and left Anthrax for the second time. Joey Belladonna returned to the band in early 2010 for the Sonisphere dates as well as committing to record a new studio album with the band. In June 2010 Anthrax, Metallica, Megadeth and Slayer performed on the same bill for the first time ever at seven Sonisphere shows. The Sofia, Bulgaria show was broadcast in cinemas and later released on DVD and Blu-ray. The bands would also play a few shows in the U.S. the following year, including a concert at Yankee Stadium in September 2011.

In April 2011, Anthrax headlined in the Philippines for the first time at the annual Pulp Summer Slam with Death Angel and Hellyeah. The band also headlined the Jägermeister side stage at the Mayhem Festival of 2012, co-headlined by Slayer and Slipknot, and toured with Testament and Death Angel. In June Anthrax released the single "Fight 'Em 'Til You Can't" from the then-upcoming new album on their website as a free download to thank fans for their patience in waiting several years for new material. Worship Music was released on September 12, 2011, and debuted at #12 on the Billboard Top 200 album charts, their highest chart position since Sound of White Noise in 1993.

In January 2013, Anthrax announced that lead guitarist Rob Caggiano had left the band to join Volbeat. It was announced shortly afterwards that Jonathan Donais of Shadows Fall had been hired as the band's touring lead guitarist. Donais was confirmed as an official member in August of that year. In March, Anthrax released the Anthems EP featuring cover versions of 1970s rock songs as well as two new versions of the song "Crawl" from Worship Music. According to Ian, the band began working on its next studio album in late 2013. They released a live DVD, Chile on Hell in 2014 which featured the band's 2013 performance at the Teatro Caupolican in Santiago, Chile. In early 2015, the band confirmed that they had recorded new material and embarked on a tour with Volbeat.

Since Belladonna's return to Anthrax the band has been nominated for three Grammys, in 2012, 2013, and 2014.

The band began 2016 with a short US tour with Lamb of God and released their eleventh studio album For All Kings on February 26, 2016. The album debuted on the Billboard 200 charts at number 9, surpassing the number 12 debut of Worship Music. In March, they opened for Iron Maiden on the Latin American leg of their The Book of Souls World Tour. Anthrax spent the summer playing festivals in Europe before embarking on a fall US and Canadian tour with Slayer and Death Angel. The band continued to tour within the next two years, embarking on The Killthrax Tour with Killswitch Engage twice (in 2017 and 2018), and along with Lamb of God, Behemoth, Testament, Napalm Death and Obituary, they supported Slayer on their final world tour from May to December 2018.

On February 1, 2017, the band embarked on the 70,000 Tons of Metal cruise. They played two sets and became the first of the "Big Four" to attend the open seas festival. During the theater set, they played a cover of Stormtroopers of Death's "March of the S.O.D." and debuted the song "Blood Eagle Wings".

Upcoming twelfth studio album (2017–present)
Anthrax released the live album and DVD Kings Among Scotland in 2018 which was recorded during their Glasgow, Scotland show on the For All Kings tour.

In a March 2017 interview, drummer Charlie Benante hinted that Anthrax would begin working on their twelfth studio album that summer. He also revealed that there are a few unreleased tracks from the For All Kings sessions that could serve as a genesis for the follow-up album, stating, "I think there are two or three that we could dust off and use as a starting point." When asked in May 2018 if they were working on the album, guitarist Scott Ian stated, "Very, very, very preliminary stages. There's a couple of really great riffs. Charlie's sent around some really great ideas. But we haven't actually started working on anything. We've just been too busy touring." A month later, bassist Frank Bello claimed that Anthrax had intended to be back in the studio by mid-2018, but because they agreed to open for Slayer on their farewell tour, they were not expected to start writing their new album until at 2019 at the earliest. In a November 2020 interview with Full Metal Jackie, Ian stated that Anthrax would "certainly be ready to make a record next year", but added that its release date could be pushed back to 2022: "In my brain, I don't wanna put a record out until I can play shows." He later stated that "at some point there should be a [new Anthrax] record" in 2023. In April 2023, Benante said the band would begin recording the new album in two weeks for a 2024 release. Frontman Joey Belladonna began recording his vocals on November 5, 2023.

The band's recording of "Antisocial" was prominently featured in the 2017 movie It but was not included on its official soundtrack release.

Anthrax – alongside Testament, Corrosion of Conformity, Armored Saint, DevilDriver, John 5, Doro and Metal Church – participated in Megadeth's first-ever cruise called "Megacruise", which took place in October 2019. They resumed live activity during the summer and fall of 2021, with a livestream performance that saw the band celebrate its 40th anniversary, as well as appearances at U.S. festivals such as Aftershock and Welcome to Rockville.

Although 2021 marked the band's 40th anniversary, the planned global anniversary tour was delayed due to travel complications arising from the COVID-19 pandemic; instead, the band performed a livestream concert on July 16 of that year. The tour was delayed to 2022, with a North American leg beginning on July 16 with Black Label Society and Hatebreed as support, followed by a European tour to begin on September 27 with Municipal Waste, and then they toured North America again in January and February 2023 with Black Label Society and Exodus. The band also released the full livestream setlist as a live album under the title XL on July 15, 2022.

On March 28, 2024, it was announced that original Anthrax bassist Dan Lilker would be performing with the band for the first time in 40 years on their spring 2024 tour dates by filling in for Bello, who was unable to perform due to "personal reasons".

In support of their upcoming twelfth studio album, Anthrax will co-headline a European tour with Kreator in November and December 2024, with Testament as the opening act.

Ex-members incidents
In 2012, Anthrax and former vocalist Dan Nelson reached an undisclosed settlement after the vocalist was fired during a 2009 tour.

In October 2014, ex-vocalist Neil Turbin accused guitarist Scott Ian of "fabricating lies" about his split with the band in 1984 to "draw attention" to Ian's autobiography.

In October 2015, former guitarist Dan Spitz took issue with a 2004 Guitar.com article (since offline) which suggested that the band's drummer, Charlie Benante, was responsible for laying down lead guitar on many of the group's classic songs.

In a 2016 interview with Metal Voice, and again in a video that he uploaded to YouTube in December 2020, former guitarist Greg Walls claimed that he had contributed to the writing of the songs on the band's first album, Fistful of Metal, specifically claiming to have written all the music to "Metal Thrashing Mad" and the majority of "Panic" but the band copyrighted the songs without his credit. In the same videos, Walls also claimed that he told Scott to drop the name "Rosenfeld" and simply go by "Scott Ian".

Musical style, influences, and legacy
Anthrax is one of the bands responsible for the emergence of speed metal and thrash metal. It exhibited a typical thrash metal sound on its early albums and was known for humor and comic book references in the lyrics, distinguishing the band from its contemporaries. According to Rolling Stone, Anthrax was one of the few heavy metal bands to receive critical praise and redefine the genre during the 1980s. Original guitarists Scott Ian and Dan Spitz' styles were described as "aggressive and head pounding", with power chords and "chugging" pedal points providing the sonic drive. Author Thomas Harrison wrote that Anthrax played metal at a faster tempo because of its punk influences. It is said that many pioneering thrash musicians, such as Anthrax, were influenced equally by heavy metal and punk rock. In 1989, Brad Tolinski of Guitar World magazine noted that, "If Exodus is a speed metal equivalent of the Rolling Stones, then New York-based Anthrax must surely be the genre's Beatles." The band's sixth album, 1993's Sound of White Noise (its first with singer John Bush), incorporated grunge and alternative metal influences in a darker vein. Critics consider the band's studio releases from the Bush era as having a more alternative metal, grunge and groove metal sound. The album Worship Music marked a return to thrash metal and the return of singer Joey Belladonna. Although the songs are credited to the whole band, since Spreading the Disease the music has been written almost entirely by Charlie Benante and the lyrics by Scott Ian, although John Bush made some lyrical contributions during his tenure in the band.

Anthrax has been influenced by a variety of music, including classic rock and hard rock acts as Rush, Cheap Trick, AC/DC, Kiss, Queen, Thin Lizzy, Boston and Journey, all of whom the band had covered on its EP Anthems. Their other influences include heavy metal bands such as Black Sabbath, Iron Maiden, Judas Priest, Accept, Motörhead, Exodus, UFO,  Saxon, and Raven, as well as hardcore punk bands such as Bad Brains, D.R.I., Suicidal Tendencies, and GBH. Anthrax is a member of the "big four" of thrash metal with Metallica, Megadeth and Slayer, and often credited as one of the first bands of the genre to emerge from the East Coast, along with Overkill and Nuclear Assault. The band has been credited for laying the groundwork for rap metal and nu metal. According to Nielsen SoundScan, Anthrax sold 2.5 million records in the United States from 1991 to 2004, and 10 million worldwide.

Anthrax has influenced multiple bands such as Pantera, Sepultura, Cannibal Corpse, Testament, Death Angel, Korn, Limp Bizkit, 311, Papa Roach, Killswitch Engage, Sevendust, Terror and Insane Clown Posse.

Anthrax has been known to reference or draw influences from numerous sources in popular culture. "I Am the Law" is about the comic book character Judge Dredd. The title track to the album Among the Living is based on the Stephen King novel The Stand, in particular the character of villain Randall Flagg, while "A Skeleton in the Closet" is based on King's novella Apt Pupil and "Efilnikufesin (N.F.L.)" pays tribute to actor and original Saturday Night Live cast member John Belushi. The song "The Constant" is based on an episode of Lost.

The band, for a period of time, used a caricature of a bald man's face as a mascot; he was colloquially christened the "Not Man". The face itself comes from a rubber kids toy called "Magic Monster".

Band members

 * Scott Ian – rhythm guitar, backing vocals (1981–present), lead guitar (1981)
 * Charlie Benante – drums (1983–present)
 * Frank Bello – bass, backing vocals (1984–2004, 2005–present)
 * Joey Belladonna – lead vocals (1984–1992, 2005–2007, 2010–present)
 * Jon Donais – lead guitar, backing vocals (2013–present)

Discography
Studio albums
 * Fistful of Metal (1984)
 * Spreading the Disease (1985)
 * Among the Living (1987)
 * State of Euphoria (1988)
 * Persistence of Time (1990)
 * Sound of White Noise (1993)
 * Stomp 442 (1995)
 * Volume 8: The Threat Is Real (1998)
 * We've Come for You All (2003)
 * Worship Music (2011)
 * For All Kings (2016)

Awards and accolades
California Music Awards

 * rowspan="1" |2004 || We've Come for You All || Outstanding Hard Rock Album ||
 * rowspan="1" |2004 || We've Come for You All || Outstanding Hard Rock Album ||

Classic Rock Roll of Honour Awards

 * rowspan= "1" |2012 || Anthrax || Metal Guru || Won
 * rowspan= "1" |2012 || Anthrax || Metal Guru || Won

Grammy Awards

 * 1991 || Persistence of Time || rowspan=3"| Best Metal Performance ||
 * 1992 || Attack of the Killer B's ||
 * 1995 || "Bring the Noise" ||
 * rowspan="1"| 2013 || "I'm Alive" || Best Hard Rock/Metal Performance ||
 * 2014 || "T.N.T." || rowspan="2"| Best Metal Performance ||
 * 2015 || "Neon Knights" ||
 * rowspan="1"| 2013 || "I'm Alive" || Best Hard Rock/Metal Performance ||
 * 2014 || "T.N.T." || rowspan="2"| Best Metal Performance ||
 * 2015 || "Neon Knights" ||
 * 2014 || "T.N.T." || rowspan="2"| Best Metal Performance ||
 * 2015 || "Neon Knights" ||
 * 2015 || "Neon Knights" ||

'''Kerrang! Awards'''

 * rowspan= "1" |2004 || Anthrax || Spirit of Rock Award || Won
 * rowspan= "1" |2004 || Anthrax || Spirit of Rock Award || Won

Loudwire Music Awards

 * rowspan= "3" |2017 || Anthrax || Best Live Band ||
 * Charlie Benante || Best Drummer ||
 * Frank Bello || Best Bassist ||
 * Charlie Benante || Best Drummer ||
 * Frank Bello || Best Bassist ||
 * Frank Bello || Best Bassist ||

Metal Hammer Golden Gods Awards

 * 2005 || rowspan="3"| Anthrax || Best Metal Band || Won
 * 2012 || Metal As Fuck || Won
 * 2016 || Inspiration Award || Won
 * 2012 || Metal As Fuck || Won
 * 2016 || Inspiration Award || Won
 * 2016 || Inspiration Award || Won

Metal Storm Awards

 * rowspan= "1" |2016 || For All Kings || Best Heavy/Melodic Metal Album || Won
 * rowspan= "1" |2016 || For All Kings || Best Heavy/Melodic Metal Album || Won

Revolver Music Awards (formerly known as Revolver Golden Gods Awards)

 * rowspan= "3" |2016 || Anthrax || Revolver Innovator Award || Won
 * rowspan= "3" |2016 || Anthrax || Revolver Innovator Award || Won

title: Anthrax (American band)


text:
Pythagorean tuning

Pythagorean tuning is a system of musical tuning in which the frequency ratios of all intervals are based on the ratio 3:2. This ratio, also known as the "pure" perfect fifth, is chosen because it is one of the most consonant and easiest to tune by ear and because of importance attributed to the integer 3. As Novalis put it, "The musical proportions seem to me to be particularly correct natural proportions." Alternatively, it can be described as the tuning of the syntonic temperament in which the generator is the ratio 3:2 (i.e., the untempered perfect fifth), which is ≈ 702 cents wide.

The system dates to Ancient Mesopotamia; see. The system is named, and has been widely misattributed, to Ancient Greeks, notably Pythagoras (sixth century BC) by modern authors of music theory, while Ptolemy, and later Boethius, ascribed the division of the tetrachord by only two intervals, called "semitonium", "tonus", "tonus" in Latin (256:243 × 9:8 × 9:8), to Eratosthenes. The so-called "Pythagorean tuning" was used by musicians up to the beginning of the 16th century. "The Pythagorean system would appear to be ideal because of the purity of the fifths, but some consider other intervals, particularly the major third, to be so badly out of tune that major chords [may be considered] a dissonance."

The Pythagorean scale is any scale which can be constructed from only pure perfect fifths (3:2) and octaves (2:1). In Greek music it was used to tune tetrachords, which were composed into scales spanning an octave. A distinction can be made between extended Pythagorean tuning and a 12-tone Pythagorean temperament. Extended Pythagorean tuning corresponds 1-on-1 with western music notation and there is no limit to the number of fifths. In 12-tone Pythagorean temperament however one is limited by 12-tones per octave and one cannot play most music according to the Pythagorean system corresponding to the enharmonic notation, instead one finds that for instance the diminished sixth becomes a "wolf fifth".

Method
12-tone Pythagorean temperament is based on a stack of intervals called perfect fifths, each tuned in the ratio 3:2, the next simplest ratio after 2:1. Starting from D for example (D-based tuning), six other notes are produced by moving six times a ratio 3:2 up, and the remaining ones by moving the same ratio down:

 * E♭–B♭–F–C–G–D–A–E–B–F♯–C♯–G♯

This succession of eleven 3:2 intervals spans across a wide range of frequency (on a piano keyboard, it encompasses 77 keys). Since notes differing in frequency by a factor of 2 are perceived as similar and given the same name (octave equivalence), it is customary to divide or multiply the frequencies of some of these notes by 2 or by a power of 2. The purpose of this adjustment is to move the 12 notes within a smaller range of frequency, namely within the interval between the base note D and the D above it (a note with twice its frequency). This interval is typically called the basic octave (on a piano keyboard, an octave has only 12 keys). This dates to antiquity: in Ancient Mesopotamia, rather than stacking fifths, tuning was based on alternating ascending fifths and descending fourths (equal to an ascending fifth followed by a descending octave), resulting in the notes of a pentatonic or heptatonic scale falling within an octave.

 * {| class="wikitable" style="text-align: center"

! class="unsortable"|Note ! class="unsortable"|Interval from D ! class="unsortable"|Formula != ! class="unsortable"|= ! class="unsortable"|Frequency ratio ! Size (cents) ! 12-TET-dif (cents)
 * D
 * unison
 * $$\frac{1}{1}$$
 * $$3^{0} \times 2^{0}$$
 * $$\frac{3^0}{2^0}$$
 * $$\frac{1}{1}$$
 * style="text-align: right"| 0.00
 * style="text-align: right"| 0.00
 * E♭
 * minor second
 * $$\left( \frac{2}{3} \right)^5 \times 2^3$$
 * $$3^{-5} \times 2^{8}$$
 * $$\frac{2^8}{3^5}$$
 * $$\frac{256}{243}$$
 * style="text-align: right"| 90.22
 * style="text-align: right"| −9.78
 * E
 * major second
 * $$\left( \frac{3}{2} \right)^2 \times \frac{1}{2}$$
 * $$3^{2} \times 2^{-3}$$
 * $$\frac{3^2}{2^3}$$
 * $$\frac{9}{8}$$
 * style="text-align: right"|  203.91
 * style="text-align: right"| 3.91
 * F
 * minor third
 * $$\left( \frac{2}{3} \right)^3 \times 2^2$$
 * $$3^{-3} \times 2^{5}$$
 * $$\frac{2^5}{3^3}$$
 * $$\frac{32}{27}$$
 * style="text-align: right"| 294.13
 * style="text-align: right"| −5.87
 * F♯
 * major third
 * $$\left( \frac{3}{2} \right)^4 \times \left( \frac{1}{2} \right)^2$$
 * $$3^{4} \times 2^{-6}$$
 * $$\frac{3^4}{2^6}$$
 * $$\frac{81}{64}$$
 * style="text-align: right"|  407.82
 * style="text-align: right"| 7.82
 * G
 * perfect fourth
 * $$\frac{2}{3} \times 2$$
 * $$3^{-1} \times 2^{2}$$
 * $$\frac{2^2}{3^1}$$
 * $$\frac{4}{3}$$
 * style="text-align: right"| 498.04
 * style="text-align: right"| −1.96
 * A♭
 * diminished fifth
 * $$\left( \frac{2}{3} \right)^6 \times 2^4$$
 * $$3^{-6} \times 2^{10}$$
 * $$\frac{2^{10}}{3^6}$$
 * $$\frac{1024}{729}$$
 * style="text-align: right"|  588.27
 * style="text-align: right"|  −11.73
 * G♯
 * augmented fourth
 * $$\left( \frac{3}{2} \right)^6 \times \left( \frac{1}{2} \right)^3$$
 * $$3^{6} \times 2^{-9}$$
 * $$\frac{3^6}{2^9}$$
 * $$\frac{729}{512}$$
 * style="text-align: right"|  611.73
 * style="text-align: right"| 11.73
 * A
 * perfect fifth
 * $$\frac{3}{2}$$
 * $$3^{1} \times 2^{-1}$$
 * $$\frac{3^1}{2^1}$$
 * $$\frac{3}{2}$$
 * style="text-align: right"| 701.96
 * style="text-align: right"| 1.96
 * B♭
 * minor sixth
 * $$\left( \frac{2}{3} \right)^4 \times 2^3$$
 * $$3^{-4} \times 2^{7}$$
 * $$\frac{2^7}{3^4}$$
 * $$\frac{128}{81}$$
 * style="text-align: right"| 792.18
 * style="text-align: right"| −7.82
 * B
 * major sixth
 * $$\left( \frac{3}{2} \right)^3 \times \frac{1}{2}$$
 * $$3^{3} \times 2^{-4}$$
 * $$\frac{3^3}{2^4}$$
 * $$\frac{27}{16}$$
 * style="text-align: right"| 905.87
 * style="text-align: right"| 5.87
 * C
 * minor seventh
 * $$\left( \frac{2}{3} \right)^2 \times 2^2$$
 * $$3^{-2} \times 2^{4}$$
 * $$\frac{2^4}{3^2}$$
 * $$\frac{16}{9}$$
 * style="text-align: right"| 996.09
 * style="text-align: right"| −3.91
 * C♯
 * major seventh
 * $$\left( \frac{3}{2} \right)^5 \times \left( \frac{1}{2} \right)^2$$
 * $$3^{5} \times 2^{-7}$$
 * $$\frac{3^5}{2^7}$$
 * $$\frac{243}{128}$$
 * style="text-align: right"| 1109.78
 * style="text-align: right"| 9.78
 * }
 * $$\frac{16}{9}$$
 * style="text-align: right"| 996.09
 * style="text-align: right"| −3.91
 * C♯
 * major seventh
 * $$\left( \frac{3}{2} \right)^5 \times \left( \frac{1}{2} \right)^2$$
 * $$3^{5} \times 2^{-7}$$
 * $$\frac{3^5}{2^7}$$
 * $$\frac{243}{128}$$
 * style="text-align: right"| 1109.78
 * style="text-align: right"| 9.78
 * }
 * }

In the formulas, the ratios 3:2 or 2:3 represent an ascending or descending perfect fifth (i.e. an increase or decrease in frequency by a perfect fifth, while 2:1 or 1:2 represent a rising or lowering octave). The formulas can also be expressed in terms of powers of the third and the second harmonics.

The major scale based on C, obtained from this tuning is:

 * {| class="wikitable" style="text-align:center"

!Note !colspan="2" | C !colspan="2" | D !colspan="2" | E !colspan="2" | F !colspan="2" | G !colspan="2" | A !colspan="2" | B !colspan="2" | C !Ratio !Step
 * colspan="2" |$1/1$
 * colspan="2" |$9/8$
 * colspan="2" |$81/64$
 * colspan="2" |$4/3$
 * colspan="2" |$3/2$
 * colspan="2" |$27/16$
 * colspan="2" |$243/128$
 * colspan="2" |$2/1$
 * colspan="1" | —
 * colspan="2" |$9/8$
 * colspan="2" |$9/8$
 * colspan="2" |$256/243$
 * colspan="2" |$9/8$
 * colspan="2" |$9/8$
 * colspan="2" |$9/8$
 * colspan="2" |$256/243$
 * colspan="1" | —
 * }

In equal temperament, pairs of enharmonic notes such as A♭ and G♯ are thought of as being exactly the same note—however, as the above table indicates, in Pythagorean tuning they have different ratios with respect to D, which means they are at a different frequency. This discrepancy, of about 23.46 cents, or nearly one quarter of a semitone, is known as a Pythagorean comma.

To get around this problem, Pythagorean tuning constructs only twelve notes as above, with eleven fifths between them. For example, one may use only the 12 notes from E♭ to G♯. This, as shown above, implies that only eleven just fifths are used to build the entire chromatic scale. The remaining interval (the diminished sixth from G♯ to E♭) is left badly out-of-tune, meaning that any music which combines those two notes is unplayable in this tuning. A very out-of-tune interval such as this one is known as a wolf interval. In the case of Pythagorean tuning, all the fifths are 701.96 cents wide, in the exact ratio 3:2, except the wolf fifth, which is only 678.49 cents wide, nearly a quarter of a semitone flatter.

If the notes G♯ and E♭ need to be sounded together, the position of the wolf fifth can be changed. For example, a C-based Pythagorean tuning would produce a stack of fifths running from D♭ to F♯, making F♯-D♭ the wolf interval. However, there will always be one wolf fifth in Pythagorean tuning, making it impossible to play in all keys in tune.

Sizes of intervals
The table above shows only intervals from D. However, intervals can be formed by starting from each of the above listed 12 notes. Thus, twelve intervals can be defined for each interval type (twelve unisons, twelve semitones, twelve intervals composed of 2 semitones, twelve intervals composed of 3 semitones, etc.).

As explained above, one of the twelve fifths (the wolf fifth) has a different size with respect to the other eleven. For a similar reason, each of the other interval types, except for the unisons and the octaves, has two different sizes in Pythagorean tuning. This is the price paid for seeking just intonation. The tables on the right and below show their frequency ratios and their approximate sizes in cents. Interval names are given in their standard shortened form. For instance, the size of the interval from D to A, which is a perfect fifth (P5), can be found in the seventh column of the row labeled D. Strictly just (or pure) intervals are shown in bold font. Wolf intervals are highlighted in red.

The reason why the interval sizes vary throughout the scale is that the pitches forming the scale are unevenly spaced. Namely, the frequencies defined by construction for the twelve notes determine two different semitones (i.e. intervals between adjacent notes):

 * 1) The minor second (m2), also called diatonic semitone, with size $$ S_1 = {256 \over 243} \approx 90.225 \text{ cents} $$ (e.g. between D and E♭)
 * 2) The augmented unison (A1), also called chromatic semitone, with size $$ S_2 =  {3^7 \over 2^{11}} = {2187 \over 2048} \approx 113.685 \text{ cents} $$ (e.g. between E♭ and E)

Conversely, in an equally tempered chromatic scale, by definition the twelve pitches are equally spaced, all semitones having a size of exactly
 * $$ S_E = \sqrt[12]{2} = 100.000 \text{ cents}. $$

As a consequence all intervals of any given type have the same size (e.g., all major thirds have the same size, all fifths have the same size, etc.). The price paid, in this case, is that none of them is justly tuned and perfectly consonant, except, of course, for the unison and the octave.

By definition, in Pythagorean tuning 11 perfect fifths (P5 in the table) have a size of approximately 701.955 cents (700+ε cents, where ε ≈ 1.955 cents). Since the average size of the 12 fifths must equal exactly 700 cents (as in equal temperament), the other one must have a size of 700 − 11ε cents, which is about 678.495 cents (the wolf fifth). As shown in the table, the latter interval, although enharmonically equivalent to a fifth, is more properly called a diminished sixth (d6). Similarly,
 * 9 minor thirds (m3) are ≈ 294.135 cents (300 − 3ε), 3 augmented seconds (A2) are ≈ 317.595 cents (300 + 9ε), and their average is 300 cents;
 * 8 major thirds (M3) are ≈ 407.820 cents (400 + 4ε), 4 diminished fourths (d4) are ≈ 384.360 cents (400 − 8ε), and their average is 400 cents;
 * 7 diatonic semitones (m2) are ≈ 90.225 cents (100 − 5ε), 5 chromatic semitones (A1) are ≈ 113.685 cents (100 + 7ε), and their average is 100 cents.

In short, similar differences in width are observed for all interval types, except for unisons and octaves, and they are all multiples of ε, the difference between the Pythagorean fifth and the average fifth.

As an obvious consequence, each augmented or diminished interval is exactly 12ε (≈ 23.460) cents narrower or wider than its enharmonic equivalent. For instance, the d6 (or wolf fifth) is 12ε cents narrower than each P5, and each A2 is 12ε cents wider than each m3. This interval of size 12ε is known as a Pythagorean comma, exactly equal to the opposite of a diminished second (≈ −23.460 cents). This implies that ε can be also defined as one twelfth of a Pythagorean comma.

Pythagorean intervals
Four of the above-mentioned intervals take a specific name in Pythagorean tuning. In the following table, these specific names are provided, together with alternative names used generically for some other intervals. The Pythagorean comma does not coincide with the diminished second, as its size (524288:531441) is the reciprocal of the Pythagorean diminished second (531441:524288). Also ditone and semiditone are specific for Pythagorean tuning, while tone and tritone are used generically for all tuning systems. Despite its name, a semiditone (3 semitones, or about 300 cents) can hardly be viewed as half of a ditone (4 semitones, or about 400 cents). All the intervals with prefix sesqui- are justly tuned, and their frequency ratio, shown in the table, is a superparticular number (or epimoric ratio). The same is true for the octave.

 * {| class="wikitable"

! rowspan="3"| Number of semitones!! colspan="4"|Generic names !! colspan="3"|Specific names ! colspan="2"| Quality and number !! colspan="2" rowspan="2"|Other naming conventions !! rowspan="2"|Pythagorean tuning (pitch ratio names)!! rowspan="2"|5-limit tuning !! rowspan="2"|1/4-comma meantone ! Full !! Short
 * 0 || || || colspan="2"| comma || Pythagorean comma (524288:531441) || rowspan="2"| ||rowspan="2"| diesis (128:125)
 * 0 || diminished second || d2 || colspan="2"| || (531441:524288)
 * 1 || minor second || m2 || rowspan="2"| semitone, half tone, half step || diatonic semitone, minor semitone || limma (λείμμα) (256:243) || ||
 * 1 || augmented unison || A1 || chromatic semitone, major semitone || apotome (αποτομή) (2187:2048) || ||
 * 2 || major second || M2
 * colspan="2" | tone, whole tone, whole step
 * colspan="2" style="text-align: center" | epogdoön (επόγδοον), sesquioctavum (9:8) ||
 * 3 || minor third || m3 || colspan="2"| || semiditone (32:27) || sesquiquintum (6:5) ||
 * 4 || major third || M3 || colspan="2"| || ditone (δίτονον) (81:64) || colspan="2" style="text-align: center"| sesquiquartum (5:4)
 * 5 || perfect fourth || P4 || colspan="2" | diatessaron (διατεσσάρων)
 * colspan="2" style="text-align: center" | epitrite (επίτριτος), sesquitertium (4:3) ||
 * 6 || diminished fifth || d5
 * colspan="2" rowspan="2"|
 * 6 || augmented fourth|| A4
 * tritone (τρίτονον) (729:512) || ||
 * 7 || perfect fifth|| P5
 * colspan="2" | diapente (διαπέντε)
 * colspan="2" style="text-align: center" | hemiolion (ημιόλιον), sesquialterum (3:2) ||
 * 12 || (perfect) octave || P8
 * colspan="2" | diapason (διαπασών)
 * colspan="3" style="text-align: center" | duplex (2:1)
 * }
 * 6 || augmented fourth|| A4
 * tritone (τρίτονον) (729:512) || ||
 * 7 || perfect fifth|| P5
 * colspan="2" | diapente (διαπέντε)
 * colspan="2" style="text-align: center" | hemiolion (ημιόλιον), sesquialterum (3:2) ||
 * 12 || (perfect) octave || P8
 * colspan="2" | diapason (διαπασών)
 * colspan="3" style="text-align: center" | duplex (2:1)
 * }
 * 12 || (perfect) octave || P8
 * colspan="2" | diapason (διαπασών)
 * colspan="3" style="text-align: center" | duplex (2:1)
 * }

History and usage
The system dates to Ancient Mesopotamia, and consisted of alternating ascending fifths and descending fourths; see. Within Ancient Greek music, the system had been mainly attributed to Pythagoras (who lived around 500 BCE) by modern authors of music theory; Ancient Greeks borrowed much of their music theory from Mesopotamia, including the diatonic scale, Pythagorean tuning, and modes. The Chinese Shí-èr-lǜ scale uses the same intervals as the Pythagorean scale and was invented between 600 BCE and 240 CE.

Because of the wolf interval when using a 12-tone Pythagorean temperament, this tuning is rarely used today, although it is thought to have been widespread. In music which does not change key very often, or which is not very harmonically adventurous, the wolf interval is unlikely to be a problem, as not all the possible fifths will be heard in such pieces. In extended Pythagorean tuning there is no wolf interval, all perfect fifths are exactly 3:2.

Because most fifths in 12-tone Pythagorean temperament are in the simple ratio of 3:2, they sound very "smooth" and consonant. The thirds, by contrast, most of which are in the relatively complex ratios of 81:64 (for major thirds) and 32:27 (for minor thirds), sound less smooth depending on the instrument.

From about 1510 onward, as thirds came to be treated as consonances, meantone temperament, and particularly quarter-comma meantone, which tunes thirds to the relatively simple ratio of 5:4, became the most popular system for tuning keyboards. At the same time, syntonic-diatonic just intonation was posited first by Ramos and then by Zarlino as the normal tuning for singers.

However, meantone presented its own harmonic challenges. Its wolf intervals proved to be even worse than those of the Pythagorean tuning (so much so that it often required 19 keys to the octave as opposed to the 12 in Pythagorean tuning). As a consequence, meantone was not suitable for all music. From around the 18th century, as the desire grew for instruments to change key, and therefore to avoid a wolf interval, this led to the widespread use of well temperaments and eventually equal temperament.

Pythagorean temperament can still be heard in some parts of modern classical music from singers and from instruments with no fixed tuning such as the violin family. Where a performer has an unaccompanied passage based on scales, they will tend towards using Pythagorean intonation as that will make the scale sound best in tune, then reverting to other temperaments for other passages (just intonation for chordal or arpeggiated figures, and equal temperament when accompanied with piano or orchestra). Such changes are never explicitly notated and are scarcely noticeable to the audience, just sounding 'in tune'.

Discography

 * Bragod is a duo giving historically informed performances of mediaeval Welsh music using the crwth and six-stringed lyre using Pythagorean tuning
 * Gothic Voices – Music for the Lion-Hearted King (Hyperion, CDA66336, 1989), directed by Christopher Page (Leech-Wilkinson)
 * Lou Harrison performed by John Schneider and the Cal Arts Percussion Ensemble conducted by John Bergamo - Guitar & Percussion (Etceter Records, KTC1071, 1990): Suite No. 1 for guitar and percussion and Plaint & Variations on "Song of Palestine"

title: Pythagorean tuning