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Isoniazid

Isoniazid

Isoniazid is a first-line antituberculous medication used in the prevention and treatment of tuberculosis. It is often prescribed under the name INH. The chemical name is isonicotinyl hydrazine or isonicotinic acid hydrazide. It is available in tablet, syrup, and injectable forms (given via intramuscular injection), available world-wide, inexpensive to produce, and is generally well tolerated.

Mechanism of action

Isoniazid is a prodrug and must be activated by bacterial catalase. The active form inhibits the synthesis of mycolic acid in the mycobacterial cell wall. Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid (CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via acetylation. There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug quicker than others. Hence, the half-life is bimodal with peaks at 1 hour and 3 hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure. Isoniazid is bactericidal to rapidly-dividing mycobacteria, but is bacteriostatic if the mycobacterium is slow-growing.

Side effects

Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects, and drug interactions resulting in increased phenytoin (Dilantin) or disulfiram (Antabuse) levels. Peripheral neuropathy and CNS effects are associated with the use of isoniazid and is due to pyridoxine (vitamin B6) depletion, but is uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition, HIV-infection), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (vitamin B6) (10-50 mg/day) with isoniazid.

Reference

- [http://www.cdc.gov/nchstp/tb/pubs/corecurr/default.htm Core Curriculum on Tuberculosis (2000)] Division of Tuberculosis Elimination, Centers for Disease Control and Prevention See Chapter 6, Treatment of LTBI Regimens - [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Chapter6/Chapter_6_Regimens.htm Isoniazid]
See Chapter 7 - Treatment of TB Disease Monitoring - [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Chapter7/Chapter_7_Monitoring.htm Adverse Reactions to First-Line TB Drugs - Isoniazid]
See Table 5 [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Tables/table5.htm First-Line Anti-TB Medications]
- [http://www.aafp.org/afp/980215ap/romero.html Isoniazid Overdose: Recognition and Management] American Family Physician 1998 Feb 15 Category:Tuberculosis

Tuberculosis

Tuberculosis is an infection with the bacterium Mycobacterium tuberculosis, which most commonly affects the lungs (pulmonary TB) but can also affect the central nervous system (meningitis), lymphatic system, circulatory system (miliary TB), genitourinary system, bones and joints. Other names for the disease are:
- TB (short for tuberculosis and also for Tubercle Bacillus)
- Consumption (TB seemed to consume people from within with its symptoms of bloody cough, fever, pallor, and long relentless wasting)
- Wasting disease
- White plague (TB sufferers appeared markedly pale)
- Phthisis (Greek for consumption) and phthisis pulmonalis
- Scrofula (swollen neck glands)
- King's evil (so called because it was believed that a king's touch would heal scrofula)
- Pott's disease of the spine
- Miliary TB (x-ray lesions look like millet seeds)
- Tabes mesenterica (TB of the abdomen)
- Lupus vulgaris (the common wolf - TB of the skin)
- Prosector's wart, also a kind of TB of the skin, transmitted by contact with contaminated cadavers to anatomists, pathologists, veterinarians, surgeons, butchers, etc. Tuberculosis is the most common major infectious disease today, infecting two billion people or one-third of the world's population, with nine million new cases of active disease annually, resulting in two million deaths, mostly in developing countries. Most of those infected (90 percent) have asymptomatic latent TB infection (LTBI). There is a 10 percent lifetime chance that LTBI will progress to active TB disease which, if left untreated, will kill more than 50 percent of its victims. TB is one of the top three infectious killing diseases in the world: HIV/AIDS kills 3 million people each year, TB kills 2 million, and malaria kills 1 million. The neglect of TB control programs, HIV/AIDS, and immigration has caused a resurgence of tuberculosis. Multiple drug resistant strains of TB (MDR-TB) are emerging. The World Health Organization declared TB a global health emergency in 1993.

The bacterium

World Health Organization.]] The cause of tuberculosis, Mycobacterium tuberculosis (MTB), is a slow-growing aerobic bacterium that divides every 16 to 20 hours. This is extremely slow compared to other bacteria, which tend to have division times measured in minutes (among the fastest growing bacteria is a strain of E. coli that can divide roughly every 20 minutes). It is not classified as either Gram-positive or Gram-negative because it does not have the chemical characteristics of either, although it contains peptidoglycan in their cell wall. If a Gram stain is performed, it stains very weakly Gram-positive or not at all. It is a small rod-like bacillus which can withstand weak disinfectants and can survive in a dry state for weeks but, spontaneously, can only grow within a host organism (in vitro culture of M. tuberculosis took a long time to be achieved, but is nowadays a normal laboratory procedure). MTB is identified microscopically by its staining characteristics: it retains certain stains after being treated with acidic solution, and is thus classified as an "acid-fast bacillus" or "AFB". In the most common staining technique, the Ziehl-Neelsen stain, AFB are stained a bright red which stands out clearly against a blue background. Acid-fast bacilli can also be visualized by fluorescent microscopy, and by auramine-rhodamine stain. The M. tuberculosis complex includes 3 other mycobacteria which can cause tuberculosis: M. bovis, M. africanum, and M. microti. The first two are very rare causes of disease and the last one does not cause human disease. :Nontuberculous mycobacteria (NTM) are other mycobacteria (besides M. leprae which causes leprosy) which may cause pulmonary disease resembling TB, lymphadenitis, skin disease, or disseminated disease. These include Mycobacterium avium, M. kansasii, and others.

The disease

Transmission

TB is spread through aerosol droplets which are expelled when persons with active TB disease cough, sneeze, speak, or spit. Close contacts (people with prolonged, frequent, or intense contact) are at highest risk of becoming infected (typically 22 percent infection rate but everything is possible, even up to 100%). A person with untreated, active tuberculosis can infect an estimated 20 other people per year. Others at risk include foreign-born from areas where TB is common, immunocompromised patients (eg. HIV/AIDS), residents and employees of high-risk congregate settings, health care workers who serve high-risk clients, medically underserved, low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, and people who inject illicit drugs. Transmission can only occur from people with active TB disease (not latent TB infection). The probability of transmission depends upon infectiousness of the person with TB (quantity expelled), environment of exposure, duration of exposure, and virulence of the organism. The chain of transmission can be stopped by isolating patients with active disease and starting effective anti-tuberculous therapy.

Pathogenesis

While only 10 percent of TB infection progresses to TB disease, if untreated the death rate is 51 percent. TB infection begins when MTB bacilli reach the pulmonary alveoli, infecting alveolar macrophages, where the mycobacteria replicate exponentially. Bacteria are picked up by dendritic cells, which can transport bacilli to local (mediastinal) lymph nodes, and then through the bloodstream to the more distant tissues and organs where TB disease could potentially develop: lung apices, peripheral lymph nodes, kidneys, brain, and bone. Tuberculosis is classed as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes secrete cytokine such as interferon gamma, which activates macrophages and make them better able to fight infection. T lymphocytes can also directly kill infected cells. Importantly, bacteria are not eliminated with the granuloma, but can become dormant, resulting in a latent infection. Latent infection can be diagnosed only by tuberculin skin test, which yields a delayed hypertype sensitivity response to purified protein derivatives of M. tuberculosis in an infected person. Another feature of the granulomas of human tuberculosis is the development of cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis. If TB bacteria gain entry to the blood stream from an area of tissue damage they spread through the body and set up myriad foci of infection, all appearing as tiny white tubercles in the tissues. This is called miliary tuberculosis and has a high case fatality. In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are in continuity with the air passages bronchi. This material may therefore be coughed up. It contains living bacteria and can pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Affected areas are eventually replaced by scar tissue.

Progression

In those people in whom TB bacilli overcome the immune system defenses and begin to multiply, there is progression from TB infection to TB disease. This may occur soon after infection (primary TB disease – 1 to 5 percent) or many years after infection (post primary TB, secondary TB, reactivation TB disease of dormant bacilli – 5 to 9 percent). The risk of reactivation increases with immune compromise, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10 percent per year, while in immune competent individuals, the risk is between 5 and 10 percent in a lifetime. About five percent of infected persons will develop TB disease in the first two years, and another five percent will develop disease later in life. In all, about 10 percent of infected persons with normal immune systems will develop TB disease in their lifetime. Some medical conditions increase the risk of progression to TB disease. In HIV infected persons with TB infection, the risk increases to 10 percent each year instead of 10 percent over a lifetime. Other such conditions include drug injection (mainly because of the life style of IV Drug users), substance abuse, recent TB infection (within two years) or history of inadequately treated TB, chest X-ray suggestive of previous TB (fibrotic lesions and nodules), diabetes mellitus, silicosis, prolonged corticosteroid therapy and other immunosuppressive therapy, head and neck cancers, hematologic and reticuloendothelial diseases (leukemia and Hodgkin's disease), end-stage renal disease, intestinal bypass or gastrectomy, chronic malabsorption syndromes, or low body weight (10 percent or more below the ideal). Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of causing a latent infection to become active due to the importance of this cytokine in the immune defense against TB. TB disease most commonly affects the lungs (75 percent or more), where it is called pulmonary TB. Symptoms include a productive, prolonged cough of more than three weeks duration, chest pain, and hemoptysis. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, and easy fatigability. The term consumption arose because sufferers appeared as if they were "consumed" from within by the disease. People from Asian and African descent may have more often lymph node TB than Caucasians. Extrapulmonary sites include the pleura, central nervous system (meningitis), lymphatic system (scrofula of the neck), genitourinary system, and bones and joints (Pott's disease of the spine). An especially serious form is "disseminated", or "miliary" TB, so named because the lung lesions so-formed resemble millet seeds on x-ray. These are more common in immunosuppressed persons and in young children. Pulmonary TB may co-exist with extrapulmonary TB.

Drug resistance

Drug-resistant TB is transmitted in the same way as drug-susceptible TB. Primary resistance develops in persons initially infected with resistant organisms. Secondary resistance (acquired resistance) may develop during TB therapy due to inadequate treatment regimen, not taking the prescribed regimen appropriately or using low quality medication.

Diagnosis

A complete medical evaluation for TB includes a medical history, a physical examination, a tuberculin skin test, a serological test, a chest X-ray, and microbiologic smears and cultures. The measurement of a positive skin test depends upon the person's risk factors for progression of TB infection to TB disease. :See: tuberculosis diagnosis, tuberculosis radiology

Treatment

Persons with TB infection (class 2 or class 4 TB), but who do not have TB disease (class 3 or class 5 TB), cannot spread the infection to other people. TB infection in a person who does not have TB disease is not considered a case of TB and is often referred to as latent TB infection (LTBI). This distinction is important because treatment options will be different for a person who has LTBI instead of active TB disease. :See: tuberculosis treatment

Prevention

Prevention and control efforts include three priority strategies:
- identifying and treating all persons who have TB disease
- finding and evaluating persons who have been in contact with TB patients to determine whether they have TB infection or disease, and treating them appropriately, and
- testing high-risk groups for TB infection to identify candidates for treatment of latent infection and to ensure the completion of treatment. In tropical areas where the incidence of atypical mycobacteria is high, exposure to nontuberculous mycobacteria gives some protection against TB.

BCG vaccine

Many countries use BCG vaccine as part of their TB control programs, especially for infants. The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is high (greater than 80 percent). However, the protective efficacy for preventing pulmonary TB in adolescents and adults is variable, from 0 to 80 percent. In the United Kingdom, children aged 10-14 were typically immunized during school until 2005. (Routine BCG vaccination was stopped as it was no longer cost-effective. The incidence of TB in people born in the UK, and with parents and grandparents who were born in the UK, was at an all time low, and falling. Others continue to be offered BCG vaccination.) The effectiveness of BCG is much lower than in areas where mycobacteria are much less prevalent. In the USA, BCG vaccine is not routinely recommended except for selected persons who meet specific criteria:
- Infants or children with negative skin-test result who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
- Healthcare workers considered on individual basis in settings in which high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and not successful.

Tuberculosis vaccine

The first recombinant tuberculosis vaccine entered clinical trials in the United States in 2004 sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). [http://www2.niaid.nih.gov/newsroom/releases/corixatbvac.htm] A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protecting against re-infection in mice; it may take four to five years to be available in humans. PMID 15690060. Because of the limitations of current vaccines, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.

Animals

Tuberculosis can be carried by many mammals. Domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. As a result, many places have regulations restricting the ownership of novelty pets, possibly including such partially domesticated species as pet skunks; for example, the Canadian province of Quebec forbids the owning of hedgehogs as pets, and the American state of California forbids the ownership of pet gerbils. The strictness of such restrictions generally depends on the public health policies adopted for fighting tuberculosis. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders. Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease. In both the Republic of Ireland and Northern Ireland, badgers have been identified as a vector species for the transmission of bovine tuberculosis. As a result, the government in both regions has mounted an active campaign of eradication of the species in an effort to reduce the incidence of the disease. Badgers have been culled primarily by snaring and gassing. It remains a contentious issue, with proponents and opponents of the scheme citing their own studies to support their position. [http://www.agriculture.ie/index.jsp?file=animal_health/TB.xml] [http://news.bbc.co.uk/1/hi/northern_ireland/4044897.stm] [http://www.badger-killers.co.uk/Ireland/Ireland_news.html]

History

Tuberculosis has been present in humans since antiquity, as the origins of the disease are in the first domestication of cattle (which also gave humanity viral poxes). Skeletal remains show prehistoric humans (4000 BC) had TB and tubercular decay has been found in the spines of Egyptian mummies from 3000-2400 BC. There were references to TB in India around 2000 BC and TB was present in The Americas from about 2000 BC Phthisis is a Greek term for consumption. Around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times which was almost always fatal. Due to the variety of its symptoms, TB was not identified as a unified disease until the 1820s and was not named tuberculosis until 1839 by J. L. Schönlein. During the years 1838-1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in hopes of curing the disease with the constant temperature and purity of the cave air. The first TB sanatorium opened in 1859 in Poland, with another opening in the United States in 1885. The bacillus-causing tuberculosis, Mycobacterium tuberculosis, was described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine for this discovery in 1905. Koch did not believe that bovine (cattle) and human tuberculosis were similar, which held back the recognition of infected milk as a source of infection. Later, this source was eliminated by pasteurization. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it tuberculin. It was not effective, but was later adapted by von Pirquet for a test for pre-symptomatic tuberculosis. The first genuine success in immunizing against tuberculosis developed from attenuated bovine strain tuberculosis by Albert Calmette and Camille Guerin in 1906 was BCG (Bacillus of Calmette and Guerin). It was first used on humans on July 18, 1921 in France, although national arrogance prevented its widespread use in either the USA, Great Britain, or Germany until after World War II. Tuberculosis caused the most widespread public concern in the 19th and early 20th centuries as the endemic disease of the urban poor. In 1815 England one in four deaths were of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that rather resembled prisons. Whatever the purported benefits of the fresh air and labor in the sanatoria, 75% of those who entered were dead within five years (1908). In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons. In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease's significance was still such that when the Medical Research Council was formed in Britain in 1913 its first project was tuberculosis. It was not until 1946 with the development of the antibiotic streptomycin that treatment rather than prevention became a possibility. Prior to then only surgical intervention was possible as supposed treatment (other than sanatoria), including the pneumothorax technique: collapsing an infected lung to "rest" it and allow lesions to heal, which was an accomplished technique but was of little benefit and was discontinued after 1946. Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, TB cases in Britain, numbering around 50,000 in 1955, had fallen to around 5,500 in 1987, but in 2001 there were over 7,000 confirmed cases. Due to the elimination of public health facilities in New York in the 1970s, there was a resurgence in the 1980s. The number of those failing to complete their course of drugs was very high. NY had to cope with more than 20,000 "unnecessary" TB-patients with many multi-drug resistant strains (i.e., resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993. In 2003, by disabling a set of genes, researchers accidentally created a more lethal and rapidly reproducing strain of tuberculosis bacteria. Christmas Seals was started in 1904 in Denmark as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907-08 to help the National Tuberculosis Association, later called the American Lung Association. During the Industrial Revolution, tuberculosis was more commonly thought of as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that the cause of this was the original victim was draining the life from his/her family members. To cure this, people would dig up the body of what they thought was the vampire, open the chest and burn the heart, sometimes with the rest of the body. Furthermore, people who had TB exhibited symptoms similar to what people considered vampire traits (and may be where much of the common mythology of the vampire comes from) . People with TB often had symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin and would cough blood (which people often figured needed to be replenished because of the loss in this manner, i.e. sucking blood).

Tuberculosis in art, literature, history and film

It has been speculated that the real-life ubiquity of illness and death due to tuberculosis affected the portrayal of these issues in European art and literature as well as history. David Brainerd (born: April 20, 1718, died: October 9, 1747) only lived 29 years. His diary has been published and reflects his reliance upon God's faithfulness amidst his battle with consumption. Brainard's diary has proven historically very influential, particularly to the modern Christian missionary movement. He was a close friend of Theologian and Pastor Jonathan Edwards in New England. More information about Brainerd's life can be found detailed by contemporary pastor/theologian John Piper here[http://www.desiringgod.org/library/biographies/90brainerd.html], with Brainerd's diary being found here [http://www.ccel.org/ccel/edwards/works2.ix.html]. The Life and Death of Mr. Badman (1680) by John Bunyan - "Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave." The pale, "haunted" appearance of tuberculosis sufferers has been seen as an influence on the works of Edgar Allan Poe and in vampire tales. In recent years, this aesthetic has been revived by the "Goth" subculture. The heroine, Mimi, of Puccini's opera La bohème suffers from tuberculosis (a theme carried over in the modern film adaptation Moulin Rouge!). Violetta, heroine of Verdi's La Traviata also dies of the disease. In Jane Eyre by Charlotte Bronte, Jane's best friend in school dies of consumption. It is indicative of the horrible conditions of these types of schools in the 1800s. In Sylvia Plath's novel The Bell Jar, the protagonist Esther's boyfriend Buddy Willard suffers from tuberculosis, much to her liking. Celestine, the heroine of Octave Mirbeau's Diary of a Chambermaid, attempts to contract tuberculosis from her dying lover, Monsieur Georges. In Nicholas Nickleby, by Charles Dickens, Nickleby's faithful companion Smike is beset by tuberculosis. Extensively, in The Magic Mountain, by Thomas Mann, where a three week visit to a sanitarium turns into a seven year sabbatical. Tuberculosis patients were frequent characters in 19th century Russian literature, and even inspired a character type; the consumptive nihilist, examples of which include Bazarov from Ivan Turgenev's Fathers and Sons, Katerina Ivanovna from Fyodor Dostoevsky's Crime and Punishment, Kirillov from Dostoevsky's Demons (aka The Possessed), and Ippolit and Marie from Dostoevsky's The Idiot. The hospitalized mother in the movie My Neighbor Totoro is thought to be suffering from tuberculosis (her ailment is not specifically named in the film, but tuberculosis is cited in the film's novelization). This is an autobiographical reference to the fact that writer/director Hayao Miyazaki's own mother spent several years of his childhood hospitalized with TB. The Sick Child (1886) by Edvard Munch, portrait of his deceased sister Sophie who died of TB at 16. [http://www.museumsnett.no/nasjonalgalleriet/munch/eng/innhold/ngm00839.html] In Hocus Pocus by Kurt Vonnegut, the protagonist contracts TB later in his lifetime. In "Long Day's Journey Into Night" by Eugene O'Neill character Edmund Tyrone is sick with consumption. In the film "Moulin Rouge!", Satine (the beautiful courtesan) is dying from the disease. In the film "Heavenly Creatures", directed by Peter Jackson, Juliet Hulme had TB, and her fear of being sent away 'for the good of her health' played a large role in determining the subsequent actions of herself and Pauline Parker. In the Swedish Film "My Life as a Dog" the protagonist Ingemar deals with his mother suffering from TB. In the Australian novel Seven Little Australians, Judy becomes consumptive after walking from the Blue Mountains to her home. In the 2002 film The Twilight Samurai, the leading character Seibei Iguchi's wife dies of consumption at the beginning of the story. At the end, his opponent tells of the death of his own wife and daughter of consumption. Famous gambler and gunslinger John "Doc" Holliday suffered from tuberculosis until his death in 1887. Doc and his bloody cough were masterfully portrayed by Val Kilmer in the 1993 film Tombstone. Alice Neel (1900-1984), T.B. Harlem, 1940, American. Oil on canvas. JAMA [http://jama.ama-assn.org/cgi/content/extract/293/22/2696 cover] June 8, 2005. Legendary father of country music, Jimmie Rodgers (1897 - 1933) sang the woes of having tuberculosis in the song T.B. Blues (co-written with Raymond E. Hall). Rodgers ultimately died of the disease days after a New York city recording session. Van Morrison's song "TB Sheets" (from the eponymous 1974 album) is about the narrator nursing a girl, who is dying of tuberculosis. The song is a reworking of the TB theme in American blues music. The Catholic Church canonized Saint Therese of the Child Jesus (1873-1897) in 1925, who died of tuberculosis. Holden Caulfield is sent to a sanitarium for potentially having TB in J.D. Salinger's Catcher in the Rye. English Romantic poet John Keats (1795-1821) and some of his family were taken by tuberculosis. In A Moveable Feast, Ernest Hemingway (1899-1961) recounts meeting Ernest Walsh, an Irish poet suffering from TB. "... I looked at him and his marked-for-death look and I thought, you con man conning me with your con."

References

- Core Curriculum on Tuberculosis: What the Clinician Should Know, 4th edition (2000). Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC). ([http://www.cdc.gov/nchstp/tb/pubs/corecurr/default.htm Internet version]updated Aug 2003).
- Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887-901 ([http://thorax.bmjjournals.com/cgi/content/abstract/55/11/887 fulltext]).
- Thomas Dormandy (1999). The White Death: A History of Tuberculosis. ISBN 0814719279 HB - ISBN 1852853328 PB
- Mountains Beyond Mountains: The Quest of Dr. Paul Farmer, a Man Who Would Cure the World. Tracy Kidder, Random House 2000. ISBN 0812973011. A nonfiction account of treating TB in Haiti, Peru, and elsewhere.
- Ha SJ, Jeon BY, Youn JI, Kim SC, Cho SN, Sung YC. Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis. Gene Ther. 2005 Feb 03; [Epub ahead of print] PMID 15690060
- Blumberg HM, Leonard MK Jr, Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA 2005 Jun 8;293(22):2776-84. PMID 15941808
- Nemery B, Yew WW, Albert R, Brun-Buisson C, Macnee W, Martinez FJ, Angus DC, Abraham E. Tuberculosis, nontuberculous lung infection, pleural disorders, pulmonary function, respiratory muscles, occupational lung disease, pulmonary infections, and social issues in AJRCCM in 2004. Am J Respir Crit Care Med. 2005 Mar 15;171(6):554-62. PMID 15753485

External links

Organizations
- [http://www.cdc.gov/nchstp/tb/default.htm Division of Tuberculosis Elimination] Centers for Disease Control and Prevention Fact sheets, data, and other resources
- [http://www.stoptb.org/ The Stop TB Partnership] international organization. World TB Day.
- [http://www.tbcta.org/ The Tuberculosis Coalition for Technical Assistance - TBCTA] The main purpose of TBCTA is to assist the U.S. Agency for International Development (USAID) and its local (public, private, NGO) partners to improve TB control programs and accelerate the implementation of the Directly Observed Treatment Short Course (DOTS) strategy. With other global TB partners, TBCTA contributes to accelerate the pace of DOTS expansion.
- [http://www.who.int/gtb/ World Health Organization Tuberculosis] home page at World Health Organization - Strategy & Operations, Monitoring & Evaluation Other
- [http://www.umdnj.edu/ntbcweb/history.html Brief History of Tuberculosis] from New Jersey Medical School National Tuberculosis Center
- [http://www.cdc.gov/nchstp/tb/faqs/qa.htm Questions and Answers About TB] from the Centers for Disease Control and Prevention, Division of Tuberculosis Elimination
- [http://jama.ama-assn.org/cgi/content/full/284/21/2789 The New White Plague] David Walton; Paul Farmer, MD, PhD msJAMA December 6, 2000
- [http://www.nlm.nih.gov/medlineplus/tuberculosis.html Tuberculosis] from MedlinePlus an excellent resource for the public from US National Library of Medicine
- [http://blogs.cgdev.org/vaccine Vaccines for Development]
- [http://www.healthdiaries.com/news/infectiousdisease/archives/tuberculosis/ Tuberculosis News] Category:Infectious diseases Category:Pulmonology Category:Tuberculosis zh-min-nan:Hì-lô-pēⁿ ko:결핵 ms:Penyakit Batuk Kering ja:結核 simple:Tuberculosis

Prodrug

A prodrug is a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in the body (in vivo) into the active compound.

Rationale

The rationale behind the use of a prodrug is generally for ADME optimization. Prodrugs are usually designed to improve oral bioavailability - poor absorption from the gastrointestinal tract is usually the limiting factor, and is often due to the chemical properties of the drug. In rational drug design, the knowledge of chemical properties likely to improve absorption and the major metabolic pathways in the body allows the modification of the structure of new chemical entities for improved bioavailability. However, sometimes the use of a prodrug is unintentional, especially in the case of serendipitous drug discoveries, and the drug, is only identified as a prodrug after extensive drug metabolism studies. Prodrugs also occur naturally.

Selected examples

- Enalapril is converted by esterase to the active enalaprilat.
- Valaciclovir is converted by esterase to the active aciclovir.
- Levodopa is converted by DOPA decarboxylase to the active dopamine.
- Psilocybin is dephosphorylated to the active psilocin.
- Heroin is deacetylated by esterase to the active morphine. Category:Pharmacology th:โปรดรัก

Acetylation

Acetylation describes a reaction, usually with acetic acid, that introduces an acetyl functional group into an organic compound. Moreover, it is that process of introducing an acetyl group into a compound, specifically, the substitution of an acetyl group for an active hydrogen atom. A reaction involving the replacement of the hydrogen atom of an hydroxyl group with an acetyl group (CH₃ CO) to yield a specific ester, the acetate. Acetic anhydride is commonly used as an acetylating agent reacting with free hydroxyl groups. In biology, i.e. in living cells, acetylation occurs as a post-translational modification of proteins. For example, histones are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with "histone acetyltransferase" (HAt) or "histone deacetylase" (HDAc) activity. The source (target) of the acetyl group in histone (de)acetylation is Acetyl Coenzyme A (AcCoA). Acetylated histones and nucleosomes represent a type of [http://www.epigenome-noe.net/consulting/webconsulting.php?PHPSESSID=efb53c0d1ed8a8805aa02cfa7ef001dc#7 epigenetic tag] within chromatin. Acetylation brings in a negative charge and neutralizes the interaction of the N termini of histones with the phosphate groups of DNA. As a consequence, the condensed chromatin is transformed into a transiently relaxed structure which allows genes to be transcribed. Acetylated chromatin is thought to be more "relaxed" and is called euchromatin. Methylated chromatin is more condensed (tightly packed), and referred to as heterochromatin. Category:Carboxylic acids Category:Organic reactions

Half-life

The half-life of a radioactive substance is the time required for half of a sample to undergo radioactive decay. The term also has pharmaceutical and other uses. More generally, for a quantity subject to exponential decay, the half-life is the time required for the quantity to fall to half of its initial value. (This article is a narrow discussion of half-life. For phenomena where half-life is applied, see "Related topics" below.) The table at right shows the reduction of the quantity in terms of the number of half-lives elapsed. Quantities subject to exponential decay are commonly denoted by the symbol N. (This convention suggests a decaying number of discrete items. This interpretation is valid in many, but not all, cases of exponential decay.) If the quantity is denoted by the symbol N, the value of N at a time t is given by the formula: :

N(t) = N_0 e^ \,

where
-

N_0

is the initial value of N (at t=0)
- λ is a positive constant (the decay constant). When t=0, the exponential is equal to 1, and N(t) is equal to

N_0

. As t approaches infinity, the exponential approaches zero. In particular, there is a time

t_ \,

such that: :

N(t_) = N_0\cdot\frac

Substituting into the formula above, we have: :

N_0\cdot\frac = N_0 e^ \,

e^ = \frac \,

- \lambda t_ = \ln \frac = - \ln \,

t_ = \frac \,

Thus the half-life is 69.3% of the mean lifetime.

Decay by two or more processes

A radioactive element may decay via two or more different processes. These processes may have different probabilities of occurring, and thus there is also a different half-life associated with each process. As an example, for two decay modes, the amount of substance left after time t is given by :

N(t) = N_0 e^ e^ = N_0 e^

In a fashion similar to the previous section, we can calculate the new total half-life

T _ \,

and we'll find it to be :

T_ = \frac \,

or, in terms of the two half-lives :

T_ = \frac \,

where

t _1 \,

is the half-life of the first process, and

t _2 \,

is the half life of the second process. An interesting example of this is that of a capacitor

C

being discharged through two parallel resistors,

R_1

and

R_2

. The discharge process can either be thought of as two decay modes as above, with: :

t _1 = R _1 C \ln 2 \,

t _2 = R _2 C \ln 2 \,

T_ = \frac = \frac

or as decay through a single equivalent resistor, using the expression for parallel resistance: :

R _ = \frac \,

T_ = R _ C \ln 2 \,

Bimodal

Bimodal can mean
- A bimodal distribution in statistics.
- The use of two pitch collections in music, see polytonality.

Bactericidal

A bacteriocide or bactericide is a substance that kills bacteria and, preferably, nothing else. Bacteriocidal antibiotics kill bacteria: bacteriostatic antibiotics only slow their growth or reproduction.

Mycobacterium

see text Mycobacterium is the a genus of actinobacteria, given its own family, the Mycobacteriaceae. It includes many pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy. Most mycobacteria are classified into two categories, the fast-growing kind and the slow-growing kind, and most mycobacteria share some common characteristics:
- They are widespread organisms, typically living in water (including tap water treated with chlorine) and food sources.
- They can colonize their hosts without the hosts showing any adverse signs. For example, millions of people around the world are infected with M. tuberculosis but will never know it because they will not develop symptoms.
- All mycobacteria are aerobic and acid fast. As a genus, they share a characteristic cell wall, thicker than in many other bacteria, hydrophobic, waxy and rich in mycolic acids/mycolates. The mycobacterial cell wall makes a substantial contribution to the hardiness of this genus.
- Mycobacterial infections are notoriously difficult to treat. The organisms are hardy and due to their cell wall, which is neither truely gram negative or positive and unique to the family, they are naturally resistant to a number of antibiotics which utilize the destruction of cell walls such as penicillin. Also, because of this cell wall, they can survive long exposure to acids, alkalis, detergents, oxidative bursts, lysis by complement and antibiotics which naturally leads to antibiotic resistance. Most mycobacteria are susceptible to the antibiotics clarithromycin and rifamycin, but antibiotic-resistant strains are known to exist.
- Mycobacteria tend to be fastidious (difficult to culture), sometimes taking over two years to develop in culture. As well as being fastidious, some species also have extremely long reproductive cycles (M. leprae, for example, may take more than 20 days to proceed through one division cycle; E. coli, for comparison, takes only half an hour ), making laboratory culture a slow process.

Medical classification

Mycobacteria can be classified into several major groups for purpose of diagnosis and treatment:
- M. tuberculosis complex which can cause tuberculosis: M. tuberculosis, M. bovis, M. africanum, and M. micoti
- M. leprae which causes Hansen's disease or leprosy
- Nontuberculous mycobacteria (NTM) are all the other mycobacteria which can cause pulmonary disease resembling tuberculosis, lymphadenitis, skin disease, or disseminated disease.

Species

- M. abscessus, which is also a common water contaminant and was until recently thought to be a subspecies of M. chelonae.
- M. africanum
- M. asiaticum
- M. avium complex (MAC), which is a significant cause of death in AIDS patients. This complex also includes M. avium paratuberculosis, which has been implicated in Crohn's disease in humans and Johne's disease in sheep.
- M. bovis
- M. chelonae, which is a common water contaminant and can also infect wounds.
- M. fortuitum
- M. gordonae
- M. haemophilum
- M. intracellulare
- M. kansasii, which can cause life-threatening infections in people with compromised immune systems
- M. lentiflavum
- M. leprae, which causes leprosy
- M. malmoense
- M. marinum
- M. microti
- M. phlei
- M. scrofulaceum
- M. smegmatis
- M. triplex
- M. tuberculosis, which causes tuberculosis
- M. ulcerans, which causes the "Buruli", or "Bairnsdale, ulcer"
- M. uvium
- M. xenopi
Staining

- Fite’s stain
- Ziehl-Neelsen stain
- Kinyoun stain
Reference

- Diagnosis and Treatment of Disease Caused by Nontuberculous Mycobacteria. American Thoracic Society. Am J Respiratory and Critical Care Medicine. Aug 1997 156(2) Part 2 Supplement [http://www.thoracic.org/adobe/statements/nontuberc1-27.pdf PDF format]
See also

- Leprosy (Hansen's disease)
- Tuberculosis Category:Actinobacteria

Bacteriostatic

Bacteriostatic antibiotics hamper the growth of bacteria by #interfering with bacteria protein production, #interfering with bacteria DNA production #interfering with bacteria cellular metabolism Bacteriostatic antibiotics inhibit growth and reproduction of the bacteria, though do not kill it, while bactericidal antibiotics kill bacteria. Bacteriostatic agents must work with the immune system to remove the microorganisms from the body. High concentrations of most bacteriostatic agents are also bactericidal, whereas low concentrations of bactericidal agents are only bacteriostatic. This group includes the tetracyclines, sulphonamides, trimethoprim, chloramphenicol, macrolides and lincosamides.

Rash

: : : A rash is a change in the skin which affects its appearance or texture. A rash may be localised to one part of the body, or affect all the skin. Rashes may cause the skin to change colour, itch, become warm, bumpy, dry, cracked or blistered, swell and may be painful. The causes, and therefore treatments for, rashes vary widely. Diagnosis must take into account such things as the appearance of the rash, other symptoms, what the patient may have been exposed to, occupation, and occurrence in family members. The presence of a rash may aid diagnosis of the patient's condition. Not only the appearance and sensation of the rash but also the distribution (which parts of the body are affected and where it arose and spread to) and evolution of the rash may be important as certain patterns of rashes and their associated signs and symptoms are diagnostic of certain diseases. For example, the rash in measles is an erythematous, maculopapular rash that begins a few days after the fever starts; it classically starts at the head and spreads downwards.

Causes

Common causes of rashes include:
- allergies, for example to foods, dyes, medicines, insect stings; such rashes are often called hives
- skin contact with an irritant
- infection or reaction to a vaccine
- skin diseases such as eczema or acne
- autoimmune disorders such as psoriasis
- cancer or other disease
- pregnancy
- exposure to sun or heat
- lead poisoning

External links

- [http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Guide to rashes on Medline Plus Medical Encyclopedia] - includes photographs
- [http://health.discovery.com/diseasesandcond/encyclopedia/3059.html Rashes on DiscoveryHealth.com] Category:Symptoms

Liver function tests

Liver function tests (LFTs or LFs), are groups of clinical biochemistry laboratory blood assays designed to give a doctor or other health professional information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, while it is vital that these diseases are detected early. Hepatic involvement in some diseases can be of crucial importance.

Regular liver panel

Total Protein (TP)

The liver produces most of the plasma proteins in the body. So it makes sense to measure the amount of protein in the blood. Reference range (60-80 g/L).

Albumin (Alb)

Albumin is a protein made specifically by the liver, and can be measured cheaply and easily. It is the main constituent of total protein; the remaining fraction is called globulin (including e.g. the immunoglobulins). Albumin levels are decreased in chronic liver disease, such as cirrhosis. It is also decreased in nephrotic syndrome, where it is lost through the urine. Poor nutrition or states of protein catabolism may also lead to hypoalbuminaemia. The half-life of albumin is approximately 20 days. Albumin is not considered to be an especially useful marker of liver synthetic function, coagulation factors (see below) are much more sensitive. The reference range is 30-50 g/L.

Alanine transaminase (ALT)

Alanine transaminase (ALT), also called Serum Glutamic Pyruvic Transaminase (SGPT) or Alanine aminotransferrase (ALAT) is an enzyme present in hepatocytes (liver cells). When a cell is damaged, it leaks this enzyme into the blood, where it is measured. ALT rises dramatically in acute liver damage, such as viral hepatitis or paracetamol (acetaminophen) overdose. Elevations are often measured in multiples of the upper limit of normal (ULN). The reference range is 15-45 U/L in most laboratories.

Alkaline phosphatase (ALP)

Alkaline phosphatase (ALP) is an enzyme in the cells lining the biliary ducts of the liver. If there is an obstruction in the bile duct, e.g. gallstones, ALP levels in plasma will rise. ALP is also present in bone and placental tissue, so it is higher in growing children (as their bones are being remodelled). The reference range is usually 30-120 U/L.

Total bilirubin (TBIL)

Bilirubin is a breakdown product of heme (a part of hemoglobin in red blood cells). The liver is responsible for clearing this, excreting it out through bile into the instestine. Problems with the liver or blockage of the drainage of bile will cause increased levels of bilirubin, as will increased haemolysis of red cells. Direct bilirubin, or unconjugated bilirubin is often measured in tandem, especially if the total bilirubin level is elevated. Bilirubin is unconjugated before the liver modifies it for excretion. It is dangerous in babies, as it can pass the blood-brain barrier causing kernicterus.

Other tests commonly requested alongside LFTs:

Aspartate transaminase (AST)

Aspartate transaminase (AST) also called Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransferase (ASAT) is similar to ALT in that it is another enzyme associated with liver parenchymal cells. It is raised in acute liver damage. It is also present in red cells and cardiac muscle.

Gamma glutamyl transpeptidase (GGT)

Although reasonably specific to the liver and a more sensitive marker for cholestatic damage than ALP, Gamma glutamyl transpeptidase (GGT) may be elevated with even minor, sub-clinical levels of liver dysfunction. It can also be helpful in identifying the cause of an isolated elevation in ALP. GGT is raised in alcohol toxicity (acute and chronic).

Coagulation tests (e.g. INR)

The liver is responsible for the production of coagulation factors. The international normalized ratio (INR) measures the speed of a particular pathway of coagulation, comparing it to normal. If the INR is increased, it means it is taking longer than usual for blood to clot. The INR will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired: it is not a sensitive measure of liver function. It is very important to normalize the INR before operating on people with liver problems (usually by transfusion with blood plasma containing the deficient factors) as they could bleed excessively. Category:Chemical pathology

Hepatitis

Hepatitis is a gastroenterological disease, featuring inflammation of the liver. The clinical signs and prognosis, as well as the therapy, depend on the cause.

Signs and symptoms

Hepatitis is characterised by fatigue, malaise, joint aches, abdominal pain, vomiting 2-3 times per day for the first 5 days, loss of appetite, dark urine, fever, hepatomegaly (enlarged liver) and jaundice (icterus). Some chronic forms of hepatitis show very few of these signs and only present when the longstanding inflammation has led to the replacement of liver cells by connective tissue; the result is cirrhosis. Certain liver function tests can also indicate hepatitis.

Types of hepatitis

Viral

Most cases of acute hepatitis are due to viral infections:
- Hepatitis A
- Hepatitis B
- Hepatitis C
- D-agent (requires presence of the hepatitis B virus)
- Hepatitis E
- Hepatitis F (discredited)
- Hepatitis G :Please see the respective articles for more detailed information Hepatitis A is an enterovirus transmitted by the orofecal route, such as contaminated food. It causes an acute form of hepatitis and does not have a chronic stage. The patient's immune system makes antibodies against Hepatitis A that confer immunity against future infection. People with Hepatitis A are usually advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent infection from hepatitis A for life. Hepatitis B causes both acute and chronic hepatitis in some patients who are unable to eliminate the virus. Identified methods of transmission include blood (blood transfusion, now rare), tattoos (both amateur and professionally done), sexually or vertically (from mother to her unborn child). However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention. In the United States, 95% of patients clear their infection and develop antibodies against Hepatitis B virus. 5% of patients do not clear the infection and develop chronic infection; only these people are at risk of long term complications of Hepatitis B. Patients with chronic hepatitis B have antibodies against Hepatitis B, but these antibodies are not enough to clear the infection that establishes itself in the DNA of the affected liver cells. The continued production of virus combined with antibodies is a likely cause of immune complex disease seen in these patients. A vaccine is available that will prevent infection from hepatitis B for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are three, FDA-approved treatment options available for persons with a chronic hepatitis B infection: alpha-interferon, adefovir and lamivudine. In about 45% of persons on treatment achieve a sustained repsonse. Hepatitis C (originally "non-A non-B hepatitis") is probably not transmitted sexually but only by blood contact. It leads to a chronic form of hepatitis, culminating in cirrhosis. It can remain asymptomatic for 10-20 years. No vaccine is available for hepatitis C. Patients with hepatitis C are prone to severe hepatitis if they contract either hepatitis A or B, so all hepatitis C patients should be immunized against Hepatitis A and Hepatitis B if they are not already immune. Two other hepatitis viruses are known, hepatitis D and E. The D agent, an RNA passenger virus, cannot proliferate without the presence of hepatitis B virus, because its genome lacks certain essential genes. Hepatitis E produces symptoms similar to hepatitis A, although it can take a fulminant course in some patients, particularly pregnant women; it is more prevalent in the Indian subcontinent. Another kind of hepatitis, hepatitis G, has been identified. Other viruses can cause infectious hepatitis:
- Mumps virus
- Rubella virus
- Cytomegalovirus
- Epstein-Barr virus
- Other herpes viruses

Alcoholic hepatitis

Ethanol, mostly in alcoholic beverages, is an important cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption. Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset. Roughly one in four people that consume more than three drinks per day during a period of ten to fifteen years will experience some level of alcoholic hepatitis. Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C. The combination of hepatitis C and alcohol consumption accelerates the development cirrhosis in Western countries.

Drug induced hepatitis

A large number of drugs can cause hepatitis. The anti-diabetic drug troglitazone was withdrawn in 2000 for causing hepatitis. Other drugs associated with hepatitis[http://www.healthatoz.com/healthatoz/Atoz/dc/caz/infc/hepa/hepres.html]:
- Halothane (a specific type of anesthetic gas)
- Methyldopa (antihypertensive)
- Isoniazid (INH) and rifampicin (tuberculosis-specific antibiotics)
- Phenytoin and valproic acid (antiepileptics)
- Zidovudine (antiretroviral i.e. against AIDS)
- Ketoconazole (antifungal)
- Nifedipine (antihypertensive)
- Ibuprofen and indomethacin (NSAIDs)
- Amitriptyline (antidepressant)
- Amiodarone (antiarrhythmic)
- Nitrofurantoin (antibiotic)
- Oral contraceptives
- Some herbs and nutritional supplements The clinical course of drug-induced hepatitis is quite variable, depending on the drug and the patient's tendency to react to the drug. For example, halothane hepatitis can range from mild to fatal as can INH-induced hepatitis. Oral contraceptives can cause structural changes in the liver. Amiodarone hepatitis can be untreatable since the long half life of the drug (up to 60 days) means that there is no effective way to stop exposure to the drug. Statins can cause elevations of liver function blood tests normally without indicating an underlying hepatitis. Lastly, human variability is such that any drug can be a cause of hepatitis.

Other toxins that cause hepatitis

Toxins and drugs can cause hepatitis:
- The Death Cap mushroom (Amanita) contains amatoxins such as alpha-amanitin. A single mushroom can be enough to be lethal (10 mg of α-amanitin).
- Yellow phosphorus is an industrial toxin.
- Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage can be limited by prompt administration of acetylcysteine.
- Carbon tetrachloride ("tetra", a dry cleaning agent), chloroform, and trichloroethylene, all chlorinated_hydrocarbons, cause steatohepatitis (hepatitis with fatty liver).

Metabolic disorders

Some metabolic disorders cause different forms of hepatitis. Hemochromatosis (due to iron accumulation) and Wilson's disease (copper accumulation) can cause liver inflammation and necrosis. See below for non-alcoholic steatohepatitis (NASH), effectively a consequence of metabolic syndrome.

Cholestatic

Longstanding obstruction of the bile duct (by gallstones or external obstruction by cancer) leads to destruction and inflammation of liver tissue.

Autoimmune

Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes—possibly due to genetic predisposition or acute liver infection—causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis. Autoimmune hepatitis has a prevalence of 1-2 per 1000. As with most other autoimmune diseases, it affects women much more often than men (8:1). Liver enzymes are elevated, as is bilirubin. Autoimmune Hepatitis can progress to cirrhosis. Treatment is with steroids and disease-modifying antirheumatic drugs (DMARDs). The diagnosis of autoimmune Hepatitis is best achieved with a combination of clinical and laboratory findings. A number of specific antibodies found in the blood (antinuclear antibody (ANA), smooth muscle antibody (SMA), Liver/kidney microsomal antibody (LKM-1) and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased Immunoglobulin G level. However, the diagnosis of autoimmune hepatitis always requires a liver biopsy. In complex cases a scoring system can be used to help determine if a patient has autoimmune hepatitis, which combines clinical and laboratory features of a given case. Four subtypes are recognised, but the clinical utility of distinguishing subtypes is limited. # Positive ANA and SMA, raised immunoglobulin G # Positive LKM-1 (typically children and teenagers; disease can be severe) # All antibodies negative, positive antibodies against soluble liver antigen (SLA) # No autoantibodies detected

Alpha 1-antitrypsin deficiency

In severe cases of alpha 1-antitrypsin deficiency (A1AD), the accumulated protein in the endoplasmic reticulum causes liver cell damage and inflammation.

Nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a type of hepatitis which resembles alcoholic hepatitis on liver biopsy (fat droplets, inflammatory cells, but usually no Mallory's hyalin) but occurs in patients who have no known history of alcohol abuse. NASH is more common in women and the most common cause is obesity or the metabolic syndrome. A related but less serious condition is called "fatty liver" (steatosis hepatis), which occurs in up to 80% of all clinically obese people. A liver biopsy for fatty liver shows fat droplets throughout the liver, but no signs of inflammation or Mallory's hyalin. The diagnosis depends on history, physical exam, blood tests, radiological imaging and sometimes a liver biopsy. The initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging including ultrasound, computed tomographic imaging, or magnetic resonance imaging. However, radiologic imaging cannot readily identify inflammation in the liver. Therefore, the differentiation between steatosis and NASH often requires a liver biopsy. It can also be difficult to distinguish NASH from alcoholic hepatitis when the patient has a history of alcohol consumption. Sometimes in such cases a trial of abstinence from alcohol along with follow -up blood tests and a repeat liver biopsy are required. NASH is becoming recognized as the most important cause of liver disease second only to Hepatitis C in numbers of patients going on to cirrhosis.

References

- Herrmann E, Sarrazin C. [Hepatitis C-virus --virus kinetics and resistance mechanisms]. Z Gastroenterol 1998;36:997-1008. PMID 15136939 [Article in German]
- Hadem J, Wedemeyer H, Manns MP. [Hepatitis as a travel disease]. Internist 2004;45:655-668. PMID 15118829 [Article in German]
- Emerson SU, Purcell RH. Running like water--the omnipresence of hepatitis E. N Engl J Med. 2004;351:2367-8. PMID 15575050
- Prof. Dr. med. Gert Frösner. Moderne Hepatitisdiagnostik ISBN 3-932091-50-7

External links

- [http://www.hepatitisneighborhood.com/ Hepatitis Neighborhood]
- [http://www.liversociety.org/ American Liver Society]
- [http://www.cdc.gov/ncidod/diseases/hepatitis/ Viral Hepatitis at the Centers for Disease Control]
- [http://homepage.mac.com/sholland/contrivances/aihcalc.html Autoimmune Hepatitis Calculator] Category:Gastroenterology Category:Inflammations ms:Penyakit Hepatitis ja:肝炎

Central nervous system

The central nervous system (CNS) represents the largest part of the nervous system. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. Since the strong theoretical influence of cybernetics in the fifties, the CNS is conceived as a system devoted to information processing, where an appropriate motor output is computed as a response to a sensory input. Yet, many threads of research suggest that motor activity exists well before the maturation of the sensory systems and then, that the senses only influence behaviour without dictating it. This has brought the conception of the CNS as an autonomous system. The whole CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon. In the adult, the CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon gives rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles. The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

Parts of the CNS

Spinal Cord
Brain	Brainstem	Rhombencephalon	Pons, Cerebellum, Medulla oblongata
		Mesencephalon	Tectum, Cerebral peduncle, Pretectum, Mesencephalic duct
	Prosencephalon	Diencephalon	Epithalamus, Thalamus, Hypothalamus, Subthalamus, Pituitary Gland, Pineal Gland, Third ventricle
		Telencephalon	Basal ganglia, Rhinencephalon, Amygdala, Hippocampus, Neocortex, Lateral ventricles

External links

- [http://www.sylvius.com Sylvius: 400+ structure neuroanatomical visual glossary; used by over half of U.S. medical schools]
- [http://primate-brain.org High-Resolution Cytoarchitectural Primate Brain Atlases]
- [http://www.marymt.edu/~psychol/brain.html Human Brains: A Learning Tool].
- [http://www.humannervoussystem.info Explaining the human nervous system].
- [http://www.backrack.co.uk/nervous_index.shtml Nervous System - Back Pain - Anatomy (info on nerve pairs)].
- Category:Nervous system

Interaction

:Interaction is also a Science fiction convention Interaction is a kind of action which occurs as two or more objects have an effect upon one another. The idea of a two-way effect is essential in the concept of interaction instead of a one-way causal effect. Combinations of many simple interactions can lead to surprising emergent phenomena. It has different tailored meanings in various sciences. Casual examples of interaction outside of science include:
- communication of any sort, for example two or more people talking to each other, or communication among groups, organisations, nations or states: trade, migration, foreign relations, transportation; etc.
- the feedback during operation of a machines such as a computer or a tool, for example the interaction between a driver and the position of his or her car on the road: by steering the driver influences this position, by looking this information returns to the driver;

Chemistry and medicine

In medicine, most medications can be safely used with other medicines but particular combinations of medicines need to be monitored for interactions, often by the pharmacist. Interactions between drugs fall generally into one of two main categories; pharmacodynamic (involving the actions of the two interacting drugs), and pharmacokinetic (involving the absorption, distribution, metabolism, and excretion of one or both of the interacting drugs upon the other). Sometimes two or medications are used together to create an extra effect - e.g. two different pain killers to provide more complete pain control. These interactions are usually intentional but need to be monitored by the doctor because patients can end up with more effect than is actually required. Sometimes two or more medications work against each other. These interactions are usually well-known and avoided unless both medicines are essential. Careful monitoring is used to prevent problems from the results of the interaction. Other interactions may cause one medicine to have less or more effect than expected and these are usually managed by a dosage adjustment.

Communications

In communications, interactive communication occurs when sources take turns transmitting messages between one another. This should be distinguished from transactive communication, in which sources transmit messages simultaneously.

Media

In media, interactivity is a feature of the media in question. As a result of digitalization and convergence the consumption of media is becoming more interactive. In media the strive for interaction is also a cultural trend.

Physics

In physics, an interaction specifically refers to the action of one physical object upon another and results in an interaction energy - the physical objects under consideration may range from point particles to quantum fields. For example, the interaction of charged particles takes place through the mediation of electromagnetic fields, whereas beta decay occurs by means of the weak interaction. There are believed to be four fundamental interactions in Nature.

Sociology

In sociology, social interaction is a dynamic, changing sequence of social actions between individuals (or groups) who modify their actions and reactions due to the actions by their interaction partner(s). Social interactions can be differentiated into:
- accidental - not planned and likely not repeated. For example, asking a stranger for directions or shopkeeper for product availabity.
- repeated - not planned, bound to happen from time to time. For example, accidentaly meeting a neighbour from time to time when walking on your street;
- regular - not planned, but very common, likely to raise questions when missed. Meeting a doorman or a security guard every workday in your workplace, dining every day in the same restaurant, etc.
- regulated - planned and regulated by customs or law, will definitely raise questions when missed. Interaction in a workplace (coming to work, staff meetings, etc.), family, etc. Social interactions form the basis for social relations.

Disulfiram

Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse® and Antabus®. Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to the harmless acetic acid. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a "hangover" this produces immediate and severe negative reaction to alcohol intake. Some 5-10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body the effects may last for up to 2 weeks after the initial intake. Clearly, patients must be fully informed about the disulfiram-alcohol reaction. The drug's action was discovered by accident in the 1940s in the Danish drug company Medicinalco: workers testing the substance, which was intended to treat parasitic diseases, on themselves reported severe symptoms after alcohol consumption. One weakness with Disulfiram and similar treatments is that if not taken under supervision an alcoholic will often not stick to the treatment, since it is easier to give up the drug than alcohol. Even when strictly taken the negative effects will rarely break the drinking patterns of a chronic alcoholic. In some extreme cases, patients with subcutaneous disulfiram tablet implants have been known to cut or dig out the tablet to avoid its effects. For these reasons disulfiram is not in itself a cure for alcoholism and is usually only indicated for select patients who wish to remain in an enforced state of sobriety during other forms of treatment, such as support groups and psychotherapy.

Similarly acting substances

Coprine, a closely related chemical having the same metabolic effects, occurs naturally in several edible mushroom species, such as the inky cap. Temposil, or citrated calcium carbamide, has the same function as Antabuse but is weaker and safer. Category:Alcohol_abuse Category:Pharmacologic agents ja:ジスルフィラム

Peripheral neuropathy

Peripheral neuropathy is the medical term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of the nerve or from the side-effects of systemic illness. Peripheral neuropathies vary in their presentation and origin, and may affect the nerve or the neuromuscular junction. Major causes of peripheral neuropathy include seizures, nutritional deficiencies, alcoholism and HIV, though diabetes is the most likely cause. Mechanical pressure from staying in one position for too long, a tumor, intraneural hemorrhage, exposing the body to extreme conditions such as radiation, cold temperatures, or toxic substances can also cause peripheral neuropathy. Many of the diseases of the peripheral nervous system may present similarly to muscle problems (myopathies), and so it is important to develop approaches for assessing sensory and motor disturbances in patients so that a physician may make an accurate diagnosis.

Types

Peripheral neuropathies may either be symmetrical and generalized or focal and multifocal, which is usually a good indicator of the cause of the peripheral nerve disease.

Generalized peripheral neuropathy

Generalized peripheral neuropathies are symmetrical, and usually due to various systematic illnesses and disease processes that affect the peripheral nervous system in its entirety. They are further subdivided into several categories:
- Distal axonopathies are the result of some metabolic or toxic derangement of neurons. They may be caused by metabolic diseases such as diabetes, renal failure, deficiency syndromes such as malnutrition and alcoholism, or the effects of toxins or drugs.
- Myelinopathies are due to a primary attack on myelin causing an acute failure of impulse conduction. The most common cause is acute inflammatory demyelinating polyneuropathy (AIDP; aka Guillain-Barré syndrome), though other causes include chronic inflammatory demyelinating syndrome (CIDP), genetic metabolic disorders (e.g., leukodystrophy), or toxins.
- Neuronopathies are the result of destruction of peripheral nervous system (PNS) neurons. They may be caused by motor neurone diseases, sensory neuronopathies (e.g., Herpes zoster), toxins or autonomic dysfunction. Neurotoxins may cause neuronopathies, such as the chemotherapy agent vincristine.

Signs and symptoms

Those with diseases or dysfunctions of their peripheral nerves can present with problems in any of the normal peripheral nerve functions. In terms of sensory function, there are commonly loss of function (negative) symptoms, which include numbness, tremor, and gait imbalance. Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins and needles. Motor symptoms include loss of function (negative) symptoms of weakness, tiredness, heaviness, and gait abnormalities; and gain of function (positive) symptoms of cramps, tremor, and fasciculations. There is also pain in the muscles (myalgia), cramps, etc., and there may also be autonomic dysfunction. During physical examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, though those with a pathology (problem) of the peripheral nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies like Guillain-Barré syndrome); or may show focal sensory disturbance or weakness, such as in mononeuropathies, radiculopathies and plexopathies. Common disorders of the peripheral nerves include focal entrapment neuropathies (e.g., carpal tunnel syndrome), generalized peripheral neuropathies (e.g., diabetic neuropathy), plexopathies (e.g., brachial neuritis) and radiculopathies (e.g., of cranial nerve VII; Facial nerve).

References

# [http://www.med.uwo.ca/UME/Diane/Year2Postings2004-2005/Trimester%202/CNS/DiseasesOfThePeripheralNervousSystemDrHahn.pdf Diseases of the peripheral system] - These lecture notes were presented to a second year medical school class at the [http://www.uwo.ca University of Western Ontario] on 2 December 2004 by [http://communications.uwo.ca/contact_western/search_results.html?department=CLINICAL%20NEUROLOGICAL%20SCIENCES Dr. Angelika F. Hahn]. # [http://www.med.uwo.ca/UME/Diane/Year2Postings2004-2005/Trimester%202/CNS/NerveMuscleDiseasePowerpointDrMNicolle.ppt Approach to Muscle and nerve problems] - Powerpoint slides from a lecture presented to a second year medical school class at the [http://www.uwo.ca University of Western Ontario] on 2 December 2004 by [http://communications.uwo.ca/contact_western/search_results.html?department=CLINICAL%20NEUROLOGICAL%20SCIENCES Dr. Michael W. Nicolle]. # [http://www.med.uwo.ca/UME/Diane/Year2Postings2004-2005/Trimester%202/CNS/ApproachToMuscleOrNerveDiseaseDrMNicolle.pdf Approach to Muscle and nerve problems] - Lecture notes from a lecture presented to a second year medical school class at the [http://www.uwo.ca University o