Science-diseases

For the disease brochure 1 travelars diharrea [|Wilderness diarrhea] (WD), also called //wilderness-acquired diarrhea// (WAD) or //backcountry diarrhea//, is the name preferred by some backpackers, hikers, campers and other outdoor recreationalists for traveler's diarrhea that appears in wilderness or "backcountry" situations while still in their home country.[|[][|3][|]] It is due to the same agents as all other traveler's diarrhea, which are usually bacterial and viral in short expeditions and may be giardiasis in longer expeditions.[|[][|3][|]] and is largely due to the absence of treated water and poor hygiene.[|[][|3][|]] Some people reserve the name //backpacker's diarrhea// as a synonym for [|giardiasis]. Most cases are self-limited and the pathogen is most often not identified. hide] * [|1] [|Incidence] 
 * Traveler's diarrhea** (in American English) or **traveller's diarrhœa** (in British English), abbreviated to **TD**, is the most common illness affecting travelers. Traveler's [|diarrhea] is defined as three or more unformed [|stools] in 24 hours passed by a traveler, commonly accompanied by abdominal [|cramps], [|nausea], and bloating.[|[][|1][|]] It does not imply a specific organism, but enterotoxigenic //[|Escherichia coli]// is the most common.[|[][|2][|]]
 * ==Contents==
 * [|2] [|Risk factors]
 * [|3] [|Symptoms]
 * [|4] [|Causes]
 * [|5] [|Treatment]
 * [|5.1] [|Antimotility agents]
 * [|6] [|Prophylaxis]
 * [|7] [|Immunity]
 * [|8] [|Colloquial names]
 * [|8.1] [|Montezuma's revenge]
 * [|9] [|See also]
 * [|10] [|References] ||

[[|edit]] Incidence
Each year 20%–50% of international travelers, an estimated 10 million people, develop [|diarrhea].[|[][|4][|]] TD is also known to [|mountaineers], as it can occur in camps due to poor sanitary conditions. 

[[|edit]] Risk factors
The primary source of infection is ingestion of [|fecally] contaminated food or water. The most important determinant of risk is the traveler's destination. High-risk destinations are the [|developing countries] of [|Latin America], [|Africa], the [|Middle East], and [|Asia].[|[][|4][|]] Some first world countries are also deemed risky.[|[][|5][|]] A worldwide rating of drinking water safety is kept at Safe Water for International Travelers website.[|[][|6][|]] Among backpackers, additional risk factors for this class of infections include drinking untreated surface water and failure by the individual and his or her companions to maintain personal hygiene practices and clean cookware.[|[][|7][|]] Campsites often have very primitive sanitation facilities, if any, making them as potentially dangerous as any third-world country. People at particular high-risk include young adults, [|immunosuppressed] persons, persons with inflammatory-bowel disease or [|diabetes], and those taking H-2 blockers or [|antacids]. Attack rates are similar for men and women.[|[][|4][|]] Although traveler's diarrhea usually resolves within three to five days (mean duration: 3.6 days), in about 20 percent of persons the illness is severe enough to cause bed confinement and in 10 percent of cases the illness lasts more than one week.[|[][|1][|]] For those who get serious infections, TD can occasionally be life-threatening. The serious infections include [|bacillary dysentery], [|amoebic dysentery], and [|cholera].[|[][|1][|]] 

[[|edit]] Symptoms
The onset of TD usually occurs within the first week of travel, but may occur at any time while traveling, and even after returning home. When it appears depends in part on the specific infectious agent. The [|incubation period] for giardiasis averages about 14 days and that of cryptosporidiosis about seven days. Certain other bacterial and viral agents have shorter incubation periods, although hepatitis may take weeks to manifest itself. Most TD cases begin abruptly. The illness usually results in increased frequency, volume, and weight of stool. Altered stool consistency also is common. Typically, a traveler experiences four to five loose or watery bowel movements each day. Other commonly associated symptoms are nausea, vomiting, diarrhea, abdominal cramping, bloating, low fever, urgency, and malaise,[|[][|4][|]] and appetite is usually low or non-existent.[|[][|1][|]] It is much more serious if there is blood or [|mucus] in the diarrhea, belly pain, or high fever. With serious cases of [|cholera], there is a rapid onset of [|symptoms], which include weakness, [|malaise] (feeling rotten), and torrents of watery diarrhea with flecks of mucus (called "rice water" stools). [|Dehydration] is a serious consequence, with death occurring in as quickly as 24 hours with cholera.[|[][|1][|]] 

[[|edit]] Causes
[|Infectious agents] are the primary cause of travellers' diarrhea. [|Bacteria] represent approximately 61% of the [|microorganisms] responsible. [//[|citation needed]//] [|Bacterial enteropathogens] cause approximately 80% of cases.[|[][|4][|]] The most common causative agent isolated in countries surveyed has been [|enterotoxigenic //Escherichia coli//] (ETEC).[|[][|4][|]] Enteroaggregative //[|E. coli]// is increasingly recognized and many studies do not look for this important bacterium.[|[][|1][|]] //[|Shigella] spp.// are the other most common bacteria involved. Incidents in which other bacteria, such as //[|Salmonella]//, //[|Campylobacter]//, //[|Yersinia]//, //[|Aeromonas]//, and //[|Plesiomonas] spp.//, have caused diarrhea are isolated and occur less often. [|Protozoan] [|parasites] such as //[|Giardia lamblia]// and //[|Cryptosporidium]// may also cause diarrhea. Some bacteria release [|toxins] which bind to the [|intestines] and cause diarrhea; others damage the intestines themselves by their direct presence. In infants and children, it is estimated that nearly 70% of diarrhea is due to [|viruses]; for adult travelers, this drops to around 30%. Diarrhea caused by viral agents is usually self-limited.[|[][|1][|]] Pathogens implicated in travellers' diarrhea are:[|[][|1][|]] A sub-type of travelers' diarrhea afflicting hikers and campers, sometimes known as [|wilderness diarrhea], may have a somewhat different frequency distribution of pathogens. 
 * //E. coli//, enterotoxigenic || 20-75% ||
 * //E. coli//, enteroaggregative || 0-20% ||
 * //E. coli//, enteroinvasive || 0-6% ||
 * //Shigella// spp || 2-30% ||
 * //Salmonella// spp || 0-33% ||
 * //[|Campylobacter jejuni]// || 3-17% ||
 * //[|Vibrio parahemolyticus]// || 0-31% ||
 * //[|Aeromonas hydrophila]// || 0-30% ||
 * //Giardia lamblia// || 0 to less than 20% ||
 * //[|Entameba histolytica]// || 0-5% ||
 * //Cryptosporidium sp// || 0 to less than 20% ||
 * [|Rotavirus] || 0-36% ||
 * [|Norwalk virus] || 0-10% ||

[[|edit]] Treatment
TD usually is a self-limited [|disorder] and often resolves without specific treatment; however, [|oral rehydration therapy] is often beneficial to replace lost fluids and [|electrolytes]. Clear, disinfected water or other liquids are routinely recommended for adults.[|[][|4][|]] Water that is purified is best, along with oral rehydration salts to replenish lost [|electrolytes]. [|Carbonated water] (soda), which has been left out so that the [|carbonation] fizz is gone, is useful if nothing else is available.[|[][|1][|]] Travelers who develop three or more loose stools in a 24-hour period — especially if associated with [|nausea], [|vomiting], [|abdominal] [|cramps], [|fever], or [|blood in stools] — should be treated by a doctor and may benefit from [|antimicrobial] therapy.[|[][|4][|]] [|Antibiotics] usually are given for 3–5 days,[|[][|4][|]] but single dose [|azithromycin] or [|levofloxacin] have been used.[|[][|8][|]] If diarrhea persists despite therapy, travelers should be evaluated and treated for possible parasitic infection.[|[][|4][|]] There are different medications needed for bacterial [|dysentery], for amoebic dysentery, for giardia and for worms. There is no medication for //[|Cryptosporidium]//, which can devastate people with [|AIDS]. There can be 100% recovery from [|cholera] when properly treated, which usually only means rehydration, usually through an [|intravenous line].[|[][|1][|]] 

[[|edit]] Antimotility agents
Antimotility agents ([|loperamide], diphenoxylate, and paregoric) primarily reduce diarrhea by slowing transit time in the gut, and, thus, allows more time for absorption. Some persons [//[|who?]//] believe diarrhea is the body's defense mechanism to minimize contact time between gut pathogens and intestinal mucosa. In several studies [//[|who?]//], antimotility agents have been useful in treating travelers' diarrhea by decreasing the duration of diarrhea. However, these agents should never be used by persons with fever or bloody diarrhea, because they can increase the severity of disease by delaying clearance of causative organisms. Because antimotility agents are now available [|over the counter], their injudicious use is of concern. Adverse complications ([|toxic megacolon], [|sepsis], and [|disseminated intravascular coagulation]) have been reported [//[|who?]//] as a result of using these medications to treat diarrhea.[|[][|4][|]] 

[[|edit]] Prophylaxis
It is not recommended to take [|antimicrobial] drugs to prevent TD, because they kill off beneficial bacteria and create resistant breeds of [|pathogenic] (disease-causing) bacteria. Among the primary measures to prevent gastrointestinal illness are keeping good hygiene, getting specific [|vaccines] and [|prophylactic] medications. Studies show a decrease in the incidence of TD with use of [|bismuth subsalicylate] and with use of antimicrobial [|chemoprophylaxis].[|[][|1][|]] [|Dukoral] has been shown to prevent TD and cholera - one dose a few weeks before travel, and another about a week before travel. Additionally, [|vaccine] candidates are in various stages of development for [|enterotoxigenic //E. coli//],[|[][|9][|]] the leading cause of traveler's diarrhea, and //[|Shigella]//.[|[][|10][|]] Traveler's diarrhea is fundamentally a [|sanitation] failure, leading to bacterial contamination of [|drinking water] and food. It is best prevented through proper water quality management systems as found in responsible [|hotels] and resorts. In the absence of that, the next best option for travelers is to take precautions to prevent the disease: If handled properly, well-cooked and packaged foods are usually safe.[|[][|4][|]] Eating raw or undercooked meat and seafood should be avoided. [|Unpasteurized] milk, dairy products, [|mayonnaise] and pastry [|icing] are associated with increased risk for TD, as are foods or drinking beverages purchased from street vendors or other establishments where unhygienic conditions are present.[|[][|1][|]] Several [|probiotics] (//[|Saccharomyces boulardii]// and a mixture of //[|Lactobacillus acidophilus]// and //[|Bifidobacterium bifidum]//) have significant efficacy. In a [|meta-analysis] by McFarland (2005), no serious adverse reactions were reported in the 12 trials. Probiotics may offer a safe and effective method to prevent TD.[|[][|11][|]] According to a study published in June, 2008, in the Lancet, researchers found that patients given a travelers’ diarrhea vaccine (made by the Iomai Corporation) were significantly less likely to suffer from clinically significant diarrhea than those who received a placebo. The study, which followed 170 healthy travelers ages 18-64 to Mexico and Guatemala, found that of the 59 individuals who received the new vaccine, only three suffered from moderate or severe diarrhea, while roughly two dozen of the 111 who received a placebo suffered from moderate or severe diarrhea. Only one of the 59 volunteers in the vaccine group reported severe diarrhea, compared with 12 in the placebo group.[|[][|12][|]] 
 * Maintain good hygiene and only use [|safe water] for drinking and teeth brushing.[|[][|1][|]]
 * Use only safe [|bottled water] and avoid ice. Reports of locals filling bottles with [|tap water], then sealing them and then selling the bottled water as purified water have come out of several countries.[|[][|1][|]]
 * Drink safe beverages — these include bottled [|carbonated] beverages, hot [|tea] or [|coffee] and water boiled or appropriately treated by the traveler.[|[][|1][|]]
 * Active intervention involves boiling water for three to five minutes (depending on elevation), filtering water with appropriate filters or using [|chlorine bleach] (2 drops per [|litre]) or tincture of [|iodine] (5 drops per litre) in the water. The wide availability of safe bottled water makes these interventions usually unnecessary for all but the most remote destinations.[|[][|1][|]]
 * Avoid eating raw fruits and vegetables unless the traveler peels them.[|[][|4][|]]
 * Recently an ultraviolet (UV) water purification device entered the market that allows people to quickly and conveniently treat small amounts of water, even in restaurant settings. The method of action is UV light bonding [|thymine] rungs of the DNA molecule, destroying the organisms' ability to live or replicate. The major advantage (besides convenience) is that UV light also kills viruses when filtration does not. Many travelers are opting for this method because it adds no taste to the water, allows the drinking of cold water, and is extremely economical compared with the cost of buying bottled water.

[[|edit]] Immunity
Travelers often get diarrhea from eating and drinking products that do not cause any problems to local people. This is due to [|immunity] that is developed after repeated exposure to pathogens. It is not fully clear how much exposure is needed and up to what extent the immune system can deal with pathogens, but a study among expatriates in Nepal suggests that it can take seven years to develop immunity, presumably in the case of adults who mostly avoided exposure to pathogens.[|[][|13][|]] On the other hand, immunity that US-originated students acquired while living in Mexico appeared to disappear within as little as 8 weeks of non-exposure.[|[][|14][|]] 

[[|edit]] Colloquial names
There are a number of [|colloquialisms] for travelers' diarrhea contracted in various localities, such as "Montezuma's revenge", "turistas"[|[][|15][|]], or "Aztec two step" for travelers' diarrhea contracted in [|Mexico], "Pharaoh's Revenge" in [|Egypt],"Delhi belly" in [|India], or "Bali Belly" in [|Bali]. A recent local term in [|Pattaya], [|Thailand], is "Thai-dal wave". 

[[|edit]] Montezuma's revenge
//Montezuma's revenge// (var. //Moctezuma's revenge//) is the colloquial term for any cases of traveler's diarrhea contracted by tourists visiting [|Mexico]. The name humorously refers to [|Moctezuma II] (1466-1520), the [|Tlatoani] (ruler) of the [|Aztec] civilization who was defeated by [|Hernán Cortés] the [|Spanish conquistador]. It is estimated that 40% of foreign traveler [|vacations] in Mexico are disrupted by infection.[|[][|16][|]] Most cases are mild and resolve in a few days with no treatment. Severe or extended cases, however, may result in extensive fluid loss and/or dangerous [|electrolytic imbalance] which pose a severe medical risk and may prove fatal if mismanaged. The oversight of a medical professional is advised. Not all water supplies in Mexico are contaminated and many hotels have water purification systems that eliminate risk. Certain resort destinations also have large-scale water purification systems which provide safe water city-wide. Roadside and popular food stalls specifically should be avoided. [//[|citation needed]//] 

[[|edit]] See also

 * [|Gastroenteritis]
 * [|Travel medicine]
 * [|Wilderness diarrhea]

[[|edit]] References
//This article contains material from the// [|CDC (Center for Disease Control) website] //which, as a U.S. government publication, is in the [|public domain].// ([|Rickettsioses]) ||<  || [|Typhus] ||< //[|Rickettsia typhi]// ([|Murine typhus]) · //[|Rickettsia prowazekii]// ([|Epidemic typhus]) || [|M-] //[|Neisseria gonorrhoeae/gonococcus]// ([|Gonorrhea]) · //[|Moraxella catarrhalis]// || ([|OX-]) ||<  || [|Lac+] ||< //[|Klebsiella]// ([|Rhinoscleroma], [|Donovanosis]) · //[|Escherichia coli]/[|O157:H7]/[|Enterotoxigenic]// · //[|Enterobacter]// || //[|Salmonella enterica]// ([|Typhoid fever], [|Paratyphoid fever], [|Salmonellosis]) · //[|Shigella dysenteriae]/[|sonnei]/[|flexneri]// ([|Shigellosis], [|Bacillary dysentery]) · //[|Proteus]// ||  || //[|Pasteurella multocida]// ([|Pasteurellosis]) · //[|Actinobacillus]// ([|Actinobacillosis]) || [|enteropathy] ||<  || [|Small intestine]/ ([|duodenum]/[|jejunum]/[|ileum]) ||< [|Enteritis] ([|Duodenitis], [|Jejunitis], [|Ileitis]) — [|Peptic (duodenal) ulcer] ([|Curling's ulcer]) — [|Malabsorption]: [|Coeliac] · [|Tropical sprue] · [|Blind loop syndrome] · [|Whipple's] · [|Short bowel syndrome] · [|Steatorrhea] · [|Milroy disease] || ([|appendix]/[|colon]) ||< [|Appendicitis] · [|Colitis] ([|Pseudomembranous], [|Ulcerative], [|Ischemic], [|Microscopic], [|Collagenous], [|Lymphocytic])[|Functional colonic disease] ([|IBS], [|Intestinal pseudoobstruction]/[|Ogilvie syndrome]) — [|Megacolon]/[|Toxic megacolon] · [|Diverticulitis]/[|Diverticulosis] || other [|biliary tree] ||< [|Cholangitis] ([|PSC], [|Ascending]) · [|Cholestasis]/[|Mirizzi's syndrome] · [|Biliary fistula] · [|Haemobilia] · [|Gallstones]/[|Cholelithiasis] //[|common bile duct]// ([|Choledocholithiasis], [|Biliary dyskinesia]) || Retrieved from "http://en.wikipedia.org/wiki/Traveler%27s_diarrhea"[|Categories]: [|Gastroenterology] | [|Foodborne illnesses] | [|Water-borne diseases] | [|Infectious diseases] | [|Symptoms] | [|Digestive disease symptoms] | [|Tourism in Mexico] | [|Conditions diagnosed by stool test]Hidden categories: [|Wikipedia articles needing rewrite] | [|All articles with unsourced statements] | [|Articles with unsourced statements since June 2008] | [|Articles with specifically-marked weasel-worded phrases] | [|Articles with unsourced statements since December 2008] | [|Wikipedia articles incorporating text from public domain works of the United States Government]
 * 1) ^ [|//**a**//] [|//**b**//] [|//**c**//] [|//**d**//] [|//**e**//] [|//**f**//] [|//**g**//] [|//**h**//] [|//**i**//] [|//**j**//] [|//**k**//] [|//**l**//] [|//**m**//] [|//**n**//] [|//**o**//] [|//**p**//] [|"Travelers' diarrhea"]. safewateronline.com . http://www.safewateronline.com/travelers_d.htm.
 * 2) **[|^]** [|"Dorlands Medical Dictionary:traveler's diarrhea"] . http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzthreezSz000029504zPzhtm . Retrieved on 2008-12-19.
 * 3) ^ [|//**a**//] [|//**b**//] [|//**c**//] Zell SC (1992). "[|Epidemiology of Wilderness-acquired Diarrhea: Implications for Prevention and Treatment]" (PDF). //J Wilderness Med// **3** (3): 241-9 . http://www.wemjournal.org/pdfserv/i0953-9859-003-03-0241.pdf.
 * 4) ^ [|//**a**//] [|//**b**//] [|//**c**//] [|//**d**//] [|//**e**//] [|//**f**//] [|//**g**//] [|//**h**//] [|//**i**//] [|//**j**//] [|//**k**//] [|//**l**//] [|//**m**//] [|"Travelers' Diarrhea"]. Centers for Disease Control and Prevention. November 21, 2006 . http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm.
 * 5) **[|^]** [|European Commission] (March 22, 2007). //[|Portugal: Commission continues legal action over environmental and human health infringements]//. [|Press release] . http://europa.eu/rapid/pressReleasesAction.do?reference=IP/07/393&format=HTML&aged=0&language=EN&guiLanguage=en . Retrieved on 2008-02-25.
 * 6) **[|^]** [|"Safe Water for International Travelers"]. safewateronline.com . http://www.aldeaglobal.com.ar/agua/Default.htm.
 * 7) **[|^]** Hargreaves JS (2006). "[|Laboratory evaluation of the 3-bowl system used for washing-up eating utensils in the field]". //Wilderness Environ Med// **17** (2): 94–102. [|PMID 16805145] . http://www.wemjournal.org/wmsonline/?request=get-document&issn=1080-6032&volume=017&issue=02&page=0094.
 * 8) **[|^]** Sanders JW, Frenck RW, Putnam SD, //et al// (August 2007). "[|Azithromycin and loperamide are comparable to levofloxacin and loperamide for the treatment of traveler's diarrhea in United States military personnel in Turkey]". //Clin. Infect. Dis.// **45** (3): 294–301. [|doi]: [|10.1086/519264] . [|PMID 18688944] . http://www.journals.uchicago.edu/CID/journal/issues/v45n3/50169/brief/50169.abstract.html.
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 * 12) **[|^]** [|Newswise: Researchers Discover Significant Efficacy of Travelers’ Diarrhea Vaccine] Retrieved on June 11, 2008.
 * 13) **[|^]** David R. Shlim, [|Understanding Diarrhea in Travelers. A Guide to the Prevention, Diagnosis, and Treatment of the World's Most Common Travel-Related Illness]. CIWEC Clinic Travel Medicine Center, 2004.
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 * 15) **[|^]** http://medical-dictionary.thefreedictionary.com/Turistas
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 * ||||~ show] [|v] • [|d] • [|e] [|Infectious diseases] · [|Bacterial diseases]: [|G-] (primarily [|A00-A79], [|001-041,080-109]) ||
 * [|Spirochaete] ||<  || [|Treponema] ||< //[|Treponema pallidum]// ([|Syphilis]/[|Bejel], [|Yaws]) · //[|Treponema carateum]// ([|Pinta]) ||
 * [|Borrelia] ||< //[|Borrelia recurrentis]// ([|Relapsing fever]) · //[|Borrelia burgdorferi]// ([|Lyme disease], [|Erythema chronicum migrans], [|Neuroborreliosis]) ||
 * [|Spirillum] ||< //[|Spirillum minus]// ([|Rat-bite fever]/[|Sodoku]) ||
 * [|Leptospira] ||< //[|Leptospira interrogans]// ([|Leptospirosis]) ||
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Leptospira] ||< //[|Leptospira interrogans]// ([|Leptospirosis]) ||
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Spotted fever] ||<  || [|Tick-borne disease] ||< //[|Rickettsia rickettsii]// ([|Rocky Mountain spotted fever]) · //[|Rickettsia conorii]// ([|Boutonneuse fever]) ||
 * Other ||< //[|Rickettsia akari]// ([|Rickettsialpox]) · //[|Orientia tsutsugamushi]// ([|Scrub typhus]) ||  ||   ||
 * [|Anaplasmataceae] ||< //[|Ehrlichia]/////[|Anaplasma]:// [|Ehrlichiosis] ([|Human granulocytic ehrlichiosis], [|Human monocytic ehrlichiosis]) ||  ||
 * [|Rhizobiales] ||<  || [|Brucellaceae] ||< //[|Brucella]// ([|Brucellosis]) ||
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Rhizobiales] ||<  || [|Brucellaceae] ||< //[|Brucella]// ([|Brucellosis]) ||
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Burkholderiales] ||< //[|Burkholderia]// ([|Glanders], [|Melioidosis]) · //[|Bordetella pertussis]/[|Bordetella parapertussis]// ([|Pertussis]) ||  ||
 * [|γ] ||<  || [|Enterobacteriales]
 * [|γ] ||<  || [|Enterobacteriales]
 * [|γ] ||<  || [|Enterobacteriales]
 * [|Slow/weak] ||< //[|Serratia marcescens]// ([|Serratia infection]) · //[|Citrobacter]// ||
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Pasteurellales] ||< //[|Haemophilus]:// //[|influenzae]// ([|Brazilian purpuric fever]) · //[|ducreyi]// ([|Chancroid])
 * [|Pasteurellales] ||< //[|Haemophilus]:// //[|influenzae]// ([|Brazilian purpuric fever]) · //[|ducreyi]// ([|Chancroid])
 * [|Legionellales] ||< //[|Legionella pneumophila]/[|Legionella longbeachae]// ([|Legionellosis]) · //[|Coxiella burnetii]// ([|Q fever]) ||
 * Other ||< //[|Thiotrichales]/[|Francisella]// ([|Tularemia]) · //[|Vibrionales]/[|Vibrio]// ([|Cholera]) · //[|Pseudomonadales]/[|Pseudomonas aeruginosa]// ([|Pseudomonas infection]) ||  ||
 * [|ε] ||<  || [|Campylobacterales] ||< //[|Campylobacter jejuni]// ([|Campylobacteriosis]) · //[|Helicobacter pylori]// ([|Peptic ulcer], [|MALT lymphoma]) ||   ||   ||
 * [|Chlamydiae] ||< //[|Chlamydophila psittaci]// ([|Psittacosis]) · //[|Chlamydophila pneumoniae]// · //[|Chlamydia trachomatis]// ([|Chlamydia], [|Lymphogranuloma venereum], [|Trachoma]) ||
 * [|Bacteroidetes] ||< //[|Bacteroides fragilis]// ||
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||
 * ||||~ show] [|v] • [|d] • [|e] [|Digestive system] · [|Digestive disease] · [|Gastroenterology] (primarily [|K20-K93], [|530-579]) ||
 * [|Upper GI tract] ||<  || [|Esophagus] ||< [|Esophagitis] ([|Candidal]) · //rupture// ([|Boerhaave syndrome], [|Mallory-Weiss syndrome]) · [|UES] ([|Zenker's diverticulum]) · [|LES] ([|Barrett's esophagus]) · [|Esophageal motility disorder] ([|Nutcracker esophagus], [|Achalasia], [|Diffuse esophageal spasm], [|GERD]) · [|Esophageal stricture] · [|Megaesophagus] ||
 * [|Stomach] ||< [|Gastritis] ([|Atrophic], [|Ménétrier's disease], [|Gastroenteritis]) · [|Peptic (gastric) ulcer] ([|Cushing ulcer], [|Dieulafoy's lesion]) · [|Dyspepsia] · [|Pyloric stenosis] · [|Achlorhydria] · [|Gastroparesis] · [|Gastroptosis] · [|Portal hypertensive gastropathy] · [|Gastric antral vascular ectasia] · [|Gastric dumping syndrome] · [|Gastric volvulus] ||  ||
 * [|Intestinal]/
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||
 * ||||~ show] [|v] • [|d] • [|e] [|Digestive system] · [|Digestive disease] · [|Gastroenterology] (primarily [|K20-K93], [|530-579]) ||
 * [|Upper GI tract] ||<  || [|Esophagus] ||< [|Esophagitis] ([|Candidal]) · //rupture// ([|Boerhaave syndrome], [|Mallory-Weiss syndrome]) · [|UES] ([|Zenker's diverticulum]) · [|LES] ([|Barrett's esophagus]) · [|Esophageal motility disorder] ([|Nutcracker esophagus], [|Achalasia], [|Diffuse esophageal spasm], [|GERD]) · [|Esophageal stricture] · [|Megaesophagus] ||
 * [|Stomach] ||< [|Gastritis] ([|Atrophic], [|Ménétrier's disease], [|Gastroenteritis]) · [|Peptic (gastric) ulcer] ([|Cushing ulcer], [|Dieulafoy's lesion]) · [|Dyspepsia] · [|Pyloric stenosis] · [|Achlorhydria] · [|Gastroparesis] · [|Gastroptosis] · [|Portal hypertensive gastropathy] · [|Gastric antral vascular ectasia] · [|Gastric dumping syndrome] · [|Gastric volvulus] ||  ||
 * [|Intestinal]/
 * [|Stomach] ||< [|Gastritis] ([|Atrophic], [|Ménétrier's disease], [|Gastroenteritis]) · [|Peptic (gastric) ulcer] ([|Cushing ulcer], [|Dieulafoy's lesion]) · [|Dyspepsia] · [|Pyloric stenosis] · [|Achlorhydria] · [|Gastroparesis] · [|Gastroptosis] · [|Portal hypertensive gastropathy] · [|Gastric antral vascular ectasia] · [|Gastric dumping syndrome] · [|Gastric volvulus] ||  ||
 * [|Intestinal]/
 * [|Intestinal]/
 * [|Intestinal]/
 * [|Large intestine]
 * [|Large intestine]
 * Large and/or small ||< [|Enterocolitis] ([|Necrotizing]) · [|IBD] ([|Crohn's disease]) — //[|vascular]//: [|Abdominal angina] · [|Mesenteric ischemia] · [|Angiodysplasia] — [|Bowel obstruction]: [|Ileus] · [|Intussusception] · [|Volvulus] · [|Fecal impaction] — [|Constipation] · [|Diarrhea] ([|Infectious]) ||
 * [|Rectum]/[|anus] ||< [|Proctitis] ([|Radiation proctitis]) · [|Proctalgia fugax] · [|Rectal prolapse] · [|Anal fissure]/[|Anal fistula] · [|Anal abscess] ||  ||
 * [|Accessory] ||<  || [|Liver] ||< [|Hepatitis] ([|Viral hepatitis], [|Autoimmune hepatitis], [|Alcoholic hepatitis]) · [|Cirrhosis] ([|PBC]) · [|Fatty liver] ([|NASH]) · //[|vascular]// ([|Hepatic veno-occlusive disease], [|Portal hypertension], [|Nutmeg liver]) · [|Alcoholic liver disease] · [|Liver failure] ([|Hepatic encephalopathy], [|Acute liver failure]) · [|Liver abscess] ([|Pyogenic], [|Amoebic]) · [|Hepatorenal syndrome] · [|Peliosis hepatis] ||
 * [|Gallbladder] ||< [|Cholecystitis] · [|Gallstones]/[|Cholecystolithiasis] · [|Cholesterolosis] · [|Rokitansky-Aschoff sinuses] · [|Postcholecystectomy syndrome] ||
 * [|Bile duct]/
 * [|Accessory] ||<  || [|Liver] ||< [|Hepatitis] ([|Viral hepatitis], [|Autoimmune hepatitis], [|Alcoholic hepatitis]) · [|Cirrhosis] ([|PBC]) · [|Fatty liver] ([|NASH]) · //[|vascular]// ([|Hepatic veno-occlusive disease], [|Portal hypertension], [|Nutmeg liver]) · [|Alcoholic liver disease] · [|Liver failure] ([|Hepatic encephalopathy], [|Acute liver failure]) · [|Liver abscess] ([|Pyogenic], [|Amoebic]) · [|Hepatorenal syndrome] · [|Peliosis hepatis] ||
 * [|Gallbladder] ||< [|Cholecystitis] · [|Gallstones]/[|Cholecystolithiasis] · [|Cholesterolosis] · [|Rokitansky-Aschoff sinuses] · [|Postcholecystectomy syndrome] ||
 * [|Bile duct]/
 * [|Bile duct]/
 * [|Bile duct]/
 * [|Pancreatic] ||< [|Pancreatitis] ([|Acute], [|Chronic], [|Hereditary]) · [|Pancreatic pseudocyst] · [|Exocrine pancreatic insufficiency] · [|Pancreatic fistula] ||  ||
 * [|Hernia] ||< [|Diaphragmatic]: [|Congenital diaphragmatic] · [|Hiatus] — [|Abdominal hernia]: [|Inguinal] ([|Indirect], [|Direct]) · [|Umbilical] · [|Incisional] · [|Femoral] — [|Obturator hernia] · [|Spigelian hernia] ||
 * [|Peritoneal] ||< [|Peritonitis] ([|Spontaneous bacterial peritonitis]) · [|Hemoperitoneum] · [|Pneumoperitoneum] ||
 * [|GI bleeding]/[|BIS] ||< [|Upper] ([|Hematemesis], [|Melena]) · [|Lower] ([|Hematochezia]) ||
 * See also [|congenital], [|neoplasia] ||  ||
 * [|Peritoneal] ||< [|Peritonitis] ([|Spontaneous bacterial peritonitis]) · [|Hemoperitoneum] · [|Pneumoperitoneum] ||
 * [|GI bleeding]/[|BIS] ||< [|Upper] ([|Hematemesis], [|Melena]) · [|Lower] ([|Hematochezia]) ||
 * See also [|congenital], [|neoplasia] ||  ||
 * See also [|congenital], [|neoplasia] ||  ||
 * See also [|congenital], [|neoplasia] ||  ||

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[|.wrongdiagnosis.com/] http://www.wrongdiagnosis.com/m/malaria/complic.htm http://www.wrongdiagnosis.com/t/travelers_diarrhea/intro.htm http://www.wrongdiagnosis.com/c/cholera/intro.htm Clorea is tubular bacterium clean water to prevent oral rehydration and vaccine though vaccine not recommended A vaccine is available in some countries (not the US), but this [|prophylactic] is not currently recommended for routine use by the US [|Centers for Disease Control and Prevention] (CDC)[|[][|14][|]]. During recent years, substantial progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are commercially available in several countries: a killed whole-cell //V. cholerae// O1 in combination with purified recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the genetically manipulated //V. cholerae// O1 strain CVD 103-HgR. The appearance of //V. cholerae// O139 has influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently available vaccines is effective against this strain.[|[][|15][|]] The newer vaccine (brand name: //[|Dukoral]//), an orally administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer adverse effects than the previously available vaccine.[|[][|14][|]] This safe and effective vaccine is available for use by individuals and health personnel. Work is under way to investigate the role of mass vaccination.[|[][|16][|]]

water infected with fecal matter diharrea, cholera was more feared than some other deadly diseases because it dehumanized the victim. [|Diarrhea] and dehydration were so severe that the victim could literally shrink into a [|wizened] caricature of his or her former self before death humans and shellfish and plankton

2. Cholera

//Vibrio cholerae// is a [|Gram-negative] bacterium that produces [|cholera toxin], an [|enterotoxin], whose action on the [|mucosal] [|epithelium] lining of the [|small intestine] is responsible for the disease's infamous characteristic, exhaustive [|diarrhea].[|[][|1][|]] In its most severe forms, cholera is one of the most rapidly fatal illnesses known, and a healthy person's [|blood pressure] may drop to [|hypotensive] levels within an hour of the onset of symptoms; infected patients may die within three hours if medical treatment is not provided.[|[][|1][|]] In a common scenario, the disease progresses from the first [|liquid] [|stool] to [|shock] in 4 to 12 hours, with death following in 18 hours to several days, unless [|oral rehydration therapy] is provided.[|[][|3][|]][|[][|4][|]] hide] * [|1] [|Symptoms] 
 * Cholera**, sometimes known as **Asiatic** or **epidemic cholera**, is an infectious [|gastroenteritis] caused by [|enterotoxin]-producing strains of the [|bacterium] //[|Vibrio cholerae]//.[|[][|1][|]][|[][|2][|]] Transmission to humans occurs through eating food or drinking water contaminated with //cholera vibrios//. The major reservoir for cholera was long assumed to be humans themselves, but considerable evidence exists that aquatic environments can serve as reservoirs of the bacteria.
 * ==Contents==
 * [|2] [|Treatment]
 * [|3] [|Epidemiology]
 * [|3.1] [|Prevention]
 * [|3.2] [|Susceptibility]
 * [|3.3] [|Transmission]
 * [|3.3.1] [|Potential human contribution to transmissibility]
 * [|3.4] [|Diagnosis]
 * [|3.4.1] [|Holding or transport media]
 * [|3.4.2] [|Enrichment media]
 * [|3.4.3] [|Plating media]
 * [|3.5] [|Biochemistry]
 * [|4] [|History]
 * [|4.1] [|Origin and spread]
 * [|4.1.1] [|Recent and ongoing outbreaks]
 * [|4.2] [|Pandemic genetic diversity]
 * [|4.3] [|Famous victims]
 * [|4.4] [|Research]
 * [|4.5] [|False historical report]
 * [|4.6] [|Cholera morbus]
 * [|4.7] [|Other historical information]
 * [|5] [|References]
 * [|6] [|See also]
 * [|7] [|Further reading]
 * [|8] [|External links] ||

[[|edit]] Symptoms
The incubation period is the period from infection until symptoms occur. In cholera this is usually 24-72 hours. The severity of symptoms depends on the dose, i.e. the number of bacteria ingested. Some otherwise healthy individuals may not develop any symptoms at all. Of those who do, only a small proportion develop severe disease. The principal symptom of cholera is diarrhea, which is watery and brown at first, but quickly changes to large volumes of pale fluid stools ('rice-water stools'). In the most severe cases dramatic fluid loss from the continuous diarrhea can lead to [|hypovolemic] shock and collapse within 1 to 4 hours. Depending upon the treatment provided, unconsciousness and death can occur anytime from 12 to 18 hours afterwards, although some individual cases may persist for several days. Fever is not a prominent feature of cholera. Writer [|Susan Sontag] wrote that cholera was more feared than some other deadly diseases because it dehumanized the victim. [|Diarrhea] and dehydration were so severe that the victim could literally shrink into a [|wizened] caricature of his or her former self before death.[|[][|5][|]] Other symptoms include [|nosebleed], rapid [|pulse], [|dry skin], [|tiredness], [|abdominal] [|cramps], [|nausea], leg cramps, and [|vomiting]. 

[[|edit]] Treatment
Hand bill from the [|New York City Board of Health], 1832. The outdated public health advice demonstrates the lack of understanding of the disease and its actual causative factors.Cholera patient being treated by medical staff in 1992 In most cases cholera can be successfully treated with oral rehydration therapy. Prompt replacement of water and [|electrolytes] is the principal treatment for cholera, as [|dehydration] and electrolyte depletion occur rapidly. [|Oral rehydration therapy] or ORT is highly effective, safe, and simple to administer. In situations where commercially produced ORT sachets are too expensive or difficult to obtain, alternative home made solutions using various formulas of water, sugar, table salt, baking soda and fruit have proven effective. In severe cases the administration of [|intravenous] rehydration solutions may be necessary. Antibiotics shorten the course of the disease, and reduce the severity of the symptoms. However [|Oral rehydration therapy] remains the principle treatment. [|Tetracycline] is typically used as the primary antibiotic, although some strains of //V. cholerae// exist that have shown resistance. Other antibiotics that have been proven effective against //V. cholerae// include [|cotrimoxazole], [|erythromycin], [|doxycycline], [|chloramphenicol], and [|furazolidone].[|[][|6][|]] [|Fluoroquinolones] such as [|norfloxacin] also may be used, but resistance has been reported.[|[][|7][|]] Recently [|Hemendra Yadav] reported his findings at the [|All India Institute of Medical Sciences], New Delhi, that Ampicillin resistance has again decreased in the //V.cholerae// strains of Delhi. Rapid diagnostic assay methods are available for the identification of multidrug resistant //V. cholerae//.[|[][|8][|]] New generation antimicrobials have been discovered which are effective against //V. cholerae// in //in vitro// studies.[|[][|9][|]] The success of treatment is greatly impacted by the speed and method of treatment. If treated quickly and properly, the mortality rate is less than 1%, however, untreated the mortality rate rises to 50–60%.[|[][|10][|]][|[][|11][|]] 

[[|edit]] Prevention
Although cholera can be life-threatening, prevention of the disease is straightforward if proper sanitation practices are followed. In the [|first world], due to advanced [|water treatment] and sanitation systems, cholera is no longer a major health threat. The last major outbreak of cholera in the United States occurred in 1910-1911 .[|[][|12][|]][|[][|13][|]] Travelers should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation practices, if instituted in time, are usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted: Cholera hospital in [|Dhaka]. A vaccine is available in some countries (not the US), but this [|prophylactic] is not currently recommended for routine use by the US [|Centers for Disease Control and Prevention] (CDC)[|[][|14][|]]. During recent years, substantial progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are commercially available in several countries: a killed whole-cell //V. cholerae// O1 in combination with purified recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the genetically manipulated //V. cholerae// O1 strain CVD 103-HgR. The appearance of //V. cholerae// O139 has influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently available vaccines is effective against this strain.[|[][|15][|]] The newer vaccine (brand name: //[|Dukoral]//), an orally administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer adverse effects than the previously available vaccine.[|[][|14][|]] This safe and effective vaccine is available for use by individuals and health personnel. Work is under way to investigate the role of mass vaccination.[|[][|16][|]] Sensitive surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provide guidance for improving cholera control activities for the most vulnerable. This will also aid in the developing indicators for appropriate use of oral cholera vaccine.[|[][|17][|]] 
 * Sterilization: Proper disposal and treatment of the germ infected fecal waste produced by cholera victims (and all clothing and bedding that come in contact with it) is of primary importance. All materials (such as clothing and bedding) that come in contact with cholera patients should be [|sterilized] in hot water using [|chlorine] [|bleach] if possible. Hands that touch cholera patients or their clothing and bedding should be thoroughly cleaned and sterilized.
 * Sewage: Treatment of general [|sewage] before it enters the waterways or underground water supplies prevents undiagnosed patients from spreading the disease.
 * Sources: Warnings about cholera contamination posted around contaminated water sources with directions on how to [|decontaminate] the water.
 * Water purification: All water used for drinking, washing, or cooking should be sterilized by boiling or [|chlorination] in any area where cholera may be present. Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections from spreading. [|Water filtration], chlorination, and boiling are by far the most effective means of halting transmission. [|Cloth filters], though very basic, have significantly reduced the occurrence of cholera when used in poor villages in [|Bangladesh] that rely on untreated surface water. Public health education and appropriate sanitation practices are important to help prevent and control transmission.

[[|edit]] Susceptibility
Recent [|epidemiologic research] suggests that an individual's susceptibility to cholera (and other [|diarrheal] infections) is affected by their [|blood type]: Those with [|type O blood] are the most susceptible,[|[][|18][|]][|[][|19][|]] while those with [|type AB] are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B. [//[|citation needed]//] About one million //V. cholerae// bacteria must typically be ingested to cause cholera in normally healthy adults, although increased susceptibility may be observed in those with a weakened [|immune system], individuals with decreased gastric acidity (as from the use of [|antacids]), or those who are [|malnourished]. It has also been hypothesized that the [|cystic fibrosis] genetic [|mutation] has been maintained in humans due to a selective advantage: [|heterozygous] carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to //V. cholerae// infections.[|[][|20][|]] In this model, the genetic deficiency in the [|cystic fibrosis transmembrane conductance regulator] channel proteins interferes with bacteria binding to the [|gastrointestinal] epithelium, thus reducing the effects of an infection. 

[[|edit]] Transmission
[|Drawing] of [|Death] bringing the cholera, in //[|Le Petit Journal]// People infected with cholera suffer acute diarrhea. This highly liquid [|diarrhea], referred to as rice-water stool, is loaded with bacteria that can infect water used by other people. Cholera is transmitted from person to person through ingestion of water contaminated with the cholera bacterium, usually from [|faeces] or other [|effluent]. The source of the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get into waterways or into [|groundwater] or drinking water supplies. Any infected water and any foods washed in the water, as well as [|shellfish] living in the affected [|waterway], can cause an infection. Cholera is rarely spread directly from person to person. //V. cholerae// harbors naturally in the [|zooplankton] of [|fresh], [|brackish], and [|salt water], attached primarily to their chitinous [|exoskeleton].[|[][|21][|]] Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a [|lysogenic] [|bacteriophage].[|[][|22][|]] Coastal cholera outbreaks typically follow [|zooplankton blooms], thus making cholera a [|zoonotic] disease. 

[[|edit]] Potential human contribution to transmissibility
Cholera bacteria grown //in vitro// encounter difficulty subsequently growing in humans without additional stomach acid buffering. In a 2002 study at [|Tufts University School of Medicine], it was found that stomach acidity is a principal factor that contributes to epidemic spread.[|[][|23][|]] In their findings, the researchers found that human colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may contribute to epidemic spread of the disease. When these hyperinfectious bacteria underwent transcription profiles, they were found to possess a unique physiological and behavioral state, characterized by high expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes required for bacterial chemotaxis. Thus, the spread of cholera can be expedited by host physiology. 

[[|edit]] Diagnosis
In epidemic situations a clinical diagnosis is made by taking a history of symptoms from the patient and by a brief examination only. Treatment is usually started without or before confirmation by laboratory analysis of specimens. Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is //[|Vibrio cholerae]// O1. If //V. cholerae// [|serogroup] O1 is not isolated, the laboratory should test for //V. cholerae// O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory. Infection with //V. cholerae// O139 should be reported and handled in the same manner as that caused by //V. cholerae// O1. The associated diarrheal illness should be referred to as cholera and must be reported as a case of cholera to the appropriate public health authorities.[|[][|15][|]] A number of special media have been employed for the cultivation for cholera vibrios. They are classified as follows: 

[[|edit]] Holding or transport media

 * 1) //Venkataraman-ramakrishnan (VR) medium//: This medium has 20g Sea Salt Powder and 5g Peptone dissolved in 1L of distilled water.
 * 2) //Cary-Blair medium//: This the most widely-used carrying media. This is a buffered solution of sodium chloride, sodium thioglycollate, disodium phosphate and calcium chloride at pH 8.4.
 * 3) //Autoclaved sea water//

[[|edit]] Enrichment media

 * 1) //Alkaline peptone water// at pH 8.6
 * 2) //Monsur's taurocholate tellurite peptone water// at pH 9.2

[[|edit]] Plating media
Direct [|microscopy] of stool is not recommended as it is unreliable. Microscopy is preferred only after enrichment, as this process reveals the characteristic motility of //Vibrios// and its inhibition by appropriate [|antiserum]. Diagnosis can be confirmed as well as serotyping done by [|agglutination] with specific sera. 
 * 1) //Alkaline bile salt agar (BSA)//: The colonies are very similar to those on [|nutrient agar].
 * 2) //Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium//: Cholera vibrios produce small translucent colonies with a greyish black centre.
 * 3) //TCBS medium//: This the mostly widely used medium. This medium contains thiosulphate, citrate, bile salts and sucrose. Cholera vibrios produce flat 2-3 mm in diameter, yellow nucleated colonies.

[[|edit]] Biochemistry
[|TEM] image of //Vibrio cholerae// Most of the //V. cholerae// bacteria in the contaminated water that a host drinks do not survive the very acidic conditions of the [|human stomach].[|[][|24][|]] The few bacteria that do survive conserve their [|energy and stored nutrients] during the passage through the stomach by shutting down much protein production. When the surviving bacteria exit the stomach and reach the [|small intestine], they need to propel themselves through the thick [|mucus] that lines the small intestine to get to the intestinal wall where they can thrive. //V. cholerae// bacteria start up production of the hollow cylindrical protein [|flagellin] to make [|flagella], the curly whip-like tails that they rotate to propel themselves through the mucus that lines the small intestine. Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move themselves any longer. The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins that they manufacture in response to the changed chemical surroundings. On reaching the intestinal wall, //V. cholerae// start producing the toxic proteins that give the infected person a watery [|diarrhea]. This carries the multiplying new generations of //V. cholerae// bacteria out into the drinking water of the next host—if proper sanitation measures are not in place. Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc) Microbiologists have studied the [|genetic mechanisms] by which the //V. cholerae// bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.[|[][|25][|]] Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump [|chloride] ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and sodium ions create a salt water environment in the small intestines which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive amounts of diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and sugar is not taken to replace the blood's water and salts lost in the diarrhea. By inserting separate, successive sections of //V. cholerae// DNA into the DNA of other bacteria such as //[|E. coli]// that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which //V. cholerae// responds to the changing chemical environments of the stomach, [|mucous] layers, and intestinal wall. Researchers have discovered that there is a complex cascade of regulatory proteins that control expression of //V. cholerae// [|virulence] determinants. In responding to the chemical environment at the intestinal wall, the //V. cholerae// bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of [|virulence] genes that produce the toxins that cause diarrhea in the infected person and that permit the bacteria to colonize the intestine.[|[][|25][|]] Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."[|[][|25][|]] 

[[|edit]] Origin and spread
Cholera was originally [|endemic] to the Indian subcontinent, with the [|Ganges River] likely serving as a contamination reservoir. The disease spread by trade routes (land and sea) to [|Russia], then to [|Western Europe], and from Europe to [|North America] during the Irish immigration period. Cholera is now no longer considered a pressing health threat in Europe and North America due to [|filtering] and [|chlorination] of water supplies, but still heavily affects populations in [|developing countries]. 1892 cholera outbreak in [|Hamburg, Germany], hospital ward1892 cholera outbreak in Hamburg, disinfection team 
 * 1816-1826 - **[|First cholera pandemic]**: Previously restricted, the [|pandemic] began in [|Bengal], and then spread across [|India] by 1820. 10,000 British troops and countless Indians died during this pandemic.[|[][|26][|]] The cholera outbreak extended as far as [|China], Indonesia (where more than 100,000 people succumbed on the island of [|Java] alone) and the [|Caspian Sea] before receding. Deaths in [|India] between 1817 and 1860 are estimated to have exceeded 15 million persons. Another 23 million died between 1865 and 1917. [|Russian] deaths during a similar time period exceeded 2 million.[|[][|27][|]]
 * 1829-1851 - **[|Second cholera pandemic]** reached Russia (see [|Cholera Riots]), Hungary (about 100,000 deaths) and Germany in 1831, [|London] (more than 55,000 persons died in the [|United Kingdom])[|[][|28][|]] and [|Paris] in 1832. In London, the disease claimed 6,536 victims; in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all of France.[|[][|29][|]] The epidemic reached [|Quebec], [|Ontario] and [|New York] in the same year and the Pacific coast of North America by 1834. [|[][|30][|]] A two-year outbreak began in [|England] and [|Wales] in 1848 and claimed 52,000 lives.[|[][|31][|]]
 * 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming 14,137 lives, over twice as many as the 1832 outbreak. In 1849 cholera claimed 5,308 lives in the port city of Liverpool, England, and 1,834 in Hull, England.[|[][|29][|]] An outbreak in North America took the life of former [|U.S. President] [|James K. Polk]. Cholera spread throughout the Mississippi river system killing over 4,500 in St. Louis[|[][|29][|]] and over 3,000 in New Orleans[|[][|29][|]] as well as thousands in New York.[|[][|29][|]] In 1849 cholera was spread along the California and Oregon trail as hundreds died on their way to the [|California Gold Rush], [|Utah] and [|Oregon].[|[][|29][|]] It is believed that over 150,000 Americans died during the two pandemics between 1832 and 1849.[|[][|32][|]][|[][|33][|]]
 * 1852-1860 - **[|Third cholera pandemic]** mainly affected Russia, with over a million deaths. In 1853-4, London's epidemic claimed 10,738 lives.
 * 1854 - Outbreak of cholera in Chicago took the lives of 5.5% of the population (about 3,500 people).[|[][|29][|]] The [|Soho] outbreak in London ended after removal of the handle of the [|Broad Street pump] by a committee instigated to action by [|John Snow].[|[][|34][|]]
 * 1863-1875 - **[|Fourth cholera pandemic]** spread mostly in Europe and [|Africa]. At least 30,000 of the 90,000 [|Mecca] pilgrims fell victim to the disease. Cholera claimed 90,000 lives in Russia in 1866.[|[][|35][|]] The epidemic of cholera that spread with the [|Austro-Prussian War] (1866) is estimated to have claimed 165,000 lives in the [|Austrian Empire].[|[][|36][|]] Hungary and [|Belgium] both lost 30,000 people and in the [|Netherlands] 20,000 perished. In 1867, [|Italy] lost 113,000 lives.[|[][|37][|]]
 * 1866 - Outbreak in North America. It killed some 50,000 Americans.[|[][|32][|]] In London, a localized epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water treatment systems--the East End was not quite complete. [|William Farr], using the work of [|John Snow] et al. as to contaminated drinking water being the likely source of the disease, was able to relatively quickly identify the East London Water Company as the source of the contaminated water. Quick action prevented further deaths.[|[][|29][|]] Also a minor outbreak at [|Ystalyfera] in South Wales. Caused by the local water works using contaminated canal water, it was mainly its workers and their families who suffered, 119 died. In the same year more than 21,000 people died in [|Amsterdam, The Netherlands].
 * 1881-1896 - **[|Fifth cholera pandemic]** ; According to Dr A. J. Wall, the 1883-1887 epidemic cost 250,000 lives in Europe and at least 50,000 in Americas. Cholera claimed 267,890 lives in [|Russia] (1892);[|[][|38][|]] 120,000 in [|Spain][|[][|39][|]]; 90,000 in [|Japan] and 60,000 in [|Persia]. In [|Egypt] cholera claimed more that 58,000 lives. The 1892 outbreak in [|Hamburg, Germany] killed 8,600 people. Although generally held responsible for the virulence of the epidemic, the city government went largely unchanged. This was the last serious European cholera outbreak.
 * 1899-1923 - **[|Sixth cholera pandemic]** had little effect in Europe because of advances in public health, but major Russian cities (more than 500,000 people dying of cholera during the first quarter of the 20th century)[|[][|40][|]] and the [|Ottoman Empire] were particularly hard hit by cholera deaths. The 1902-1904 cholera epidemic claimed 200,222 lives in the [|Philippines].[|[][|41][|]] The sixth pandemic killed more than 800,000 in [|India]. The last outbreak in the United States was in 1910-1911 when the [|SMS Moltke] brought infected people to New York City. Vigilant health authorities isolated the infected on [|Swinburne Island]. Eleven people died, including a health care worker on [|Swinburne Island].[|[][|42][|]][|[][|12][|]][|[][|13][|]]
 * 1961-1970s - **[|Seventh cholera pandemic]** began in [|Indonesia], called [|El Tor] after the strain, and reached [|Bangladesh] in 1963, India in 1964, and the USSR in 1966. From [|North Africa] it spread into Italy by 1973. In the late 1970s, there were small outbreaks in Japan and in the South Pacific. There were also many reports of a cholera outbreak near [|Baku] in 1972, but information about it was suppressed in the [|USSR].
 * January 1991 to September 1994 - Outbreak in [|South America], apparently initiated when a ship discharged ballast water. Beginning in [|Peru] there were 1.04 million identified cases and almost 10,000 deaths. The causative agent was an O1, El Tor strain, with small differences from the seventh pandemic strain. In 1992 a new strain appeared in Asia, a non-O1, [|nonagglutinable vibrio] (NAG) named O139 Bengal. It was first identified in [|Tamil Nadu], India and for a while displaced El Tor in southern Asia before decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate between El Tor and the classic strain and occurs in a new [|serogroup]. There is evidence of the emergence of wide-spectrum resistance to drugs such as [|trimethoprim], [|sulfamethoxazole] and [|streptomycin].

[[|edit]] Recent and ongoing outbreaks
[|Wikinews] has related news: 
 * July - December 2007 - A lack of clean drinking water in [|Iraq] has led to an [|outbreak] of cholera.[|[][|43][|]] As of 2 December 2007, the UN has reported 22 deaths and 4,569 laboratory-confirmed cases.[|[][|44][|]]
 * August - October 2008 - As of 29 October 2008, a total of 644 laboratory-confirmed cholera cases, including eight deaths, had been verified in [|Iraq].[|[][|45][|]]
 * November 2008 - [|Doctors Without Borders] reported an outbreak in a refugee camp in the [|Democratic Republic of the Congo]'s eastern provincial capital of [|Goma]. Some 45 cases were reportedly treated between November 7th through 9th.
 * //**[|Wikinews Shorts: November 25, 2008#53 die in Zimbabwe after cholera outbreak]**//
 * //**[|Number of Zimbabwe cholera deaths nears 500]**//
 * November - December 2008 - More than an estimated 57000 people in [|Zimbabwe] are believed to be infected with more than 3000 recorded deaths observed during a current and ongoing [|outbreak].[|[][|46][|]] The number of people infected is believed to be significantly higher and the government is accused of underestimating the spread of the epidemic. The outbreak is a result of mismanagement of water purification infrastructure. Subsequent outbreaks are being observed in neighbouring countries as the medical infrastructure in Zimbabwe is severely crippled by [|hyperinflation] leading to several Zimbabwean citizens seeking medical care elsewhere. The continuing closure of several local hospitals and the scarcity of basic medical commodities such as medicines and personnel is believed to be a major contributor to the spread. According to the [|World Health Organisation], Zimbabwe's government has asked for urgent international help to tackle its cholera outbreak.[|[][|47][|]] [|Médecins Sans Frontières] warned that the epidemic could last until March 2009 at the earliest.[|[][|48][|]][|[][|49][|]]
 * January 2009 - The Mpumalanga province of [|South Africa] has confirmed over 381 new cases of Cholera, bringing the total number of cases treated since November 2008 to 2276. 19 people have died in the province since the outbreak. [|[][|50][|]]

[[|edit]] Pandemic genetic diversity
Amplified fragment length polymorphism (AFLP) fingerprinting of the [|pandemic] isolates of //Vibrio cholerae// has revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. Cluster I consists mainly of strains from the 1960s and 1970s, while cluster II contains mainly strains from the 1980s and 1990s, based on a the change in the clone structure. This grouping of strains is best seen in the strains from the African Continent.[|[][|51][|]] 

[[|edit]] Famous victims
The pathos in the last movement of [|Tchaikovsky's] (c. 1840-1893) last symphony made people think that Tchaikovsky had a premonition of death. "A week after the premiere of his [|Sixth Symphony], Tchaikovsky was dead--6 November 1893. The cause of this indisposition and stomach ache was suspected to be his intentionally infecting himself with cholera by drinking contaminated water. The day before, while having lunch with [|Modest] (his brother and biographer), he is said to have poured tap water from a pitcher into his glass and drunk a few swallows. Since the water was not boiled and cholera was once again rampaging [|St. Petersburg], such a connection was quite plausible ...."[|[][|52][|]] Other famous people who succumbed to the disease include: 
 * Major General [|Edward Hand], Adjutant General of the Continental Army and congressman
 * [|James K. Polk], eleventh president of the United States
 * [|Mary Abigail Fillmore], daughter of U.S. president [|Millard Fillmore]
 * Elizabeth Jackson, mother of U.S. president [|Andrew Jackson]
 * Elliott Frost, son of American poet [|Robert Frost][|[][|53][|]]
 * [|Nicolas Léonard Sadi Carnot]
 * [|Georg Wilhelm Friedrich Hegel]
 * Samuel Charles Stowe, son of [|Harriet Beecher Stowe]
 * [|Carl von Clausewitz]
 * [|George Bradshaw]
 * [|Adam Mickiewicz]
 * [|August von Gneisenau]
 * [|William Jenkins Worth]
 * [|John Blake Dillon]
 * Daniel Morgan Boone, founder of [|Kansas City, Missouri], son of [|Daniel Boone]
 * [|James Clarence Mangan]
 * Mohammad Ali Mirza [|Dowlatshahi] of [|Persia]
 * [|Ando Hiroshige], Japanese ukiyo-e woodblock print artist.
 * Juan de Veramendi, Mexican Governor of Texas, father-in-law of [|Jim Bowie]
 * [|Grand Duke Constantine Pavlovich of Russia]
 * William Godwin, father of [|Mary Shelley]
 * Judge Daniel Stanton Bacon, father-in-law of [|George Armstrong Custer]
 * [|Inessa Armand], mistress of [|Lenin] and the mother of Andre, his son.
 * [|Honinbo Shusaku], famous go player.
 * [|Henry Louis Vivian Derozio], Eurasian Portuguese Poet and Teacher. Resided in India.
 * [|Alexandre Dumas, père], French author of [|The Three Musketeers] and [|The Count of Monte Cristo], also contracted cholera in the 1832 Paris epidemic and almost died, before he wrote these two novels.
 * Jane Gibs
 * [|Charles X of France]
 * [|Rutka Laskier] (the polish Anne Frank)

[[|edit]] Research
The Russian-born bacteriologist [|Waldemar Haffkine] developed the first cholera vaccine around 1900. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist [|Filippo Pacini], but its exact nature and his results were not widely known around the world. One of the major contributions to fighting cholera was made by physician and self-trained scientist [|John Snow] (1813-1858), who found the link between cholera and contaminated drinking water in 1854.[|[][|29][|]] In addition, [|Henry Whitehead], an Anglican minister, helped Snow track down and verify the source of the disease, which turned out to be an infected well in London. Their conclusions were widely distributed and firmly established for the first time a definite link between germs and disease. Clean water and good sewage treatment, despite their major engineering and financial cost, slowly became a priority throughout the major developed cities in the world from this time onward. [|Robert Koch], 30 years later, identified //V. cholerae// with a microscope as the bacillus causing the disease in 1885. Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in [|British India] was partitioned into [|West Bengal] and [|East Pakistan] in 1947. Prior to partition, both regions had cholera pathogens with similar characteristics. After 1947, India made more progress on public health than East Pakistan (now [|Bangladesh]). As a consequence, the strains of the pathogen that succeeded in India had a greater incentive in the longevity of the host and are less virulent than the strains prevailing in Bangladesh, which uninhibitedly draw upon the resources of the host population, thus rapidly killing many victims. More recently, in 2002, Alam et al. studied stool samples from patients at the International Centre for Diarrhoeal Disease (ICDDR) in Dhaka, Bangladesh. From the various experiments they conducted, the researchers found a correlation between the passage of //V. cholerae// through the human digestive system and an increased infectivity state. Furthermore, the researchers found that the bacterium creates a hyper-infected state where [|genes] that control biosynthesis of [|amino acids], iron uptake systems, and formation of periplasmic nitrate reductase complexes were induced just before defecation. These induced characteristics allow the cholera vibrios to survive in the rice water stools, an environment of limited oxygen and iron, of patients with a cholera infection.[|[][|23][|]] 

[[|edit]] False historical report
A persistent myth states that [|90,000 people died in Chicago] of cholera and [|typhoid fever] in 1885, but this story has no factual basis.[|[][|54][|]] In 1885, there was a torrential rainstorm that flushed the [|Chicago River] and its attendant pollutants into Lake Michigan far enough that the city's water supply was contaminated. However, because cholera was not present in the city, there were no cholera-related deaths, though the incident caused the city to become more serious about its sewage treatment. 

[[|edit]] Cholera morbus
The term //cholera morbus// was used in the 19th and early 20th centuries to describe both non-epidemic cholera and other gastrointestinal diseases (sometimes epidemic) that resembled cholera. The term is not in current use, but is found in many older references.[|[][|55][|]] The other diseases are now known collectively as [|gastroenteritis]. 

[[|edit]] Other historical information
In the past, people traveling in ships would hang a yellow [|quarantine] flag if one or more of the crew members suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an extended period, typically 30 to 40 days.[|[][|56][|]]. In modern [|international maritime signal flags] the quarantine flag is yellow and black. 

[[|edit]] References

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 * 44) **[|^]** [|Cholera crisis hits Baghdad], The Observer, 2 December, 2007
 * 45) **[|^]** [|Situation report on diarrhoea and cholera in Iraq, 29 Oct 2008], ReliefWeb
 * 46) **[|^]** http://edition.cnn.com/2009/WORLD/africa/01/28/Zimbabwe.cholera/index.html
 * 47) **[|^]** [|"Zimbabwe "asks for cholera help""]. BBC. 2008-12-03 . http://news.bbc.co.uk/1/hi/world/africa/7763397.stm . Retrieved on 2008-12-08.
 * 48) **[|^]** [|"MSF responding to worst cholera outbreak in Zimbabwe in years"]. MSF. 2008-12-15 . http://www.msf.org/msfinternational/invoke.cfm?objectid=3A06C714-15C5-F00A-25B61038A975AFAB&component=toolkit.article&method=full_html . Retrieved on 2008-12-21.
 * 49) **[|^]** [|"Charity warns on Zimbabwe cholera"]. BBC. 2008-12-21 . http://news.bbc.co.uk/2/hi/africa/7794425.stm . Retrieved on 200812-21.
 * 50) **[|^]** [|381 new cholera cases in Mpumalanga], News24, 24 January, 2009
 * 51) **[|^]** Lan R, Reeves PR (2002). "Pandemic Spread of Cholera: Genetic Diversity and Relationships within the Seventh Pandemic Clone of Vibrio cholerae Determined by Amplified Fragment Length Polymorphism". //Journal of Clinical Microbiology// **40** (1): 172–181. [|doi]: [|10.1128/JCM.40.1.172-181.2002].
 * 52) **[|^]** Meumayr A (1997). //Music and medicine: Chopin, Smetana, Tchaikovsky, Mahler: Notes on their lives, works, and medical histories//. Med-Ed Press. pp. 282–3.   (summarizing various theories on what killed the composer [|Tchaikovsky], including his brother [|Modest's] idea that Tchaikovksy drank cholera infested water the day before he became ill).
 * 53) **[|^]** Burnshaw S (2000). [|"Robert Frost"]. American National Biography Online. Archived from [|the original] on 2001-03-18 . http://www.english.uiuc.edu/maps/poets/a_f/frost/life.htm.
 * 54) **[|^]** [|"Did 90,000 people die of typhoid fever and cholera in Chicago in 1885?"]. The Straight Dope. 2004-11-12 . http://www.straightdope.com/columns/041112.html . Retrieved on 2008-01-03.
 * 55) **[|^]** [|"Archaic medical terms"]. Antiquus Morbus. 2007 . http://www.antiquusmorbus.com/English/EnglishC.htm . Retrieved on 2008-01-03.
 * 56) **[|^]** Mackowiak PA (2002). "The origin of quarantine". //Clinical Infectious Diseases// **35**: 1071–2. [|doi]: [|10.1086/344062].

[[|edit]] See also

 * [|The Ghost Map: The Story of London's Most Terrifying Epidemic - and How it Changed Science, Cities and the Modern World] - which tells the story of how [|John Snow] found the cause of a cholera epidemic, which was the start of modern epidemiology.
 * [|The Painted Veil (2006 film)], starring Naomi Watts and Edward Norton, in which cholera is a prominent subject, based on the novel of the same name by [|W. Somerset Maugham].
 * [|The Horseman on the Roof] (1995 film), starring Juliette Binoche and Olivier Martinez, in which the 1832 cholera outbreak in southern France is a major influence to the story line.
 * The Dress Lodger by [|Sheri Holman] - A historical novel set in [|Sunderland, England] during the [|cholera epidemic of 1831].
 * In the novel [|Death in Venice] by [|Thomas Mann] (also a 1971 film by Lucino Visconti starring Dirk Bogard), the main character dies of cholera in [|Venice]; the epidemic is a recurring sub-plot of the story.

[[|edit]] Further reading

 * Crump J, Bopp C, Greene KD, Kubota KA, Middendorf RL, Wells JG, Mintz ED (2003). "Emergence of toxigenic Vibrio cholerae O141 causing cholera-like diarrhea and bloodstream infection in the United States". //Journal of Infectious Diseases// **187**: 866–8.
 * Steinberg EB, Green KD, Bopp CA, Cameron DN, Wells JG, Mintz ED (2001). "Cholera in the United States, 1995-2000: trends at the end of the millennium". //J Infect Dis// **184**: 799–802.

[[|edit]] External links
[|Wiktionary], the free dictionary. || [|1854 Broad Street cholera outbreak] - [|2007 Central Luzon hog cholera outbreak] - [|2007 Iraq cholera outbreak] - [|2008 Congo cholera outbreak] - [|2008–2009 Zimbabwean cholera outbreak] ||  || ([|Rickettsioses]) ||<  || [|Typhus] ||< //[|Rickettsia typhi]// ([|Murine typhus]) · //[|Rickettsia prowazekii]// ([|Epidemic typhus]) || [|M-] //[|Neisseria gonorrhoeae/gonococcus]// ([|Gonorrhea]) · //[|Moraxella catarrhalis]// || ([|OX-]) ||<  || [|Lac+] ||< //[|Klebsiella]// ([|Rhinoscleroma], [|Donovanosis]) · //[|Escherichia coli]/[|O157:H7]/[|Enterotoxigenic]// · //[|Enterobacter]// || //[|Salmonella enterica]// ([|Typhoid fever], [|Paratyphoid fever], [|Salmonellosis]) · //[|Shigella dysenteriae]/[|sonnei]/[|flexneri]// ([|Shigellosis], [|Bacillary dysentery]) · //[|Proteus]// ||  || //[|Pasteurella multocida]// ([|Pasteurellosis]) · //[|Actinobacillus]// ([|Actinobacillosis]) || Retrieved from "http://en.wikipedia.org/wiki/Cholera"[|Categories]: [|Gastroenterology] | [|Infectious diseases] | [|Neurotoxins] | [|Foodborne illnesses] | [|Bacterial diseases] | [|Water-borne diseases] | [|Pandemics] | [|Biological weapons] | [|Neglected diseases] | [|Microbiology] | [|Cholera]Hidden categories: [|Pages with DOIs broken since 2008] | [|All articles with unsourced statements] | [|Articles with unsourced statements since December 2008]
 * [[image:http://upload.wikimedia.org/wikipedia/en/thumb/4/4a/Commons-logo.svg/40px-Commons-logo.svg.png width="40" height="54" caption="Sister project" link="http://commons.wikimedia.org/wiki/Special:Search/Cholera"]] || [|Wikimedia Commons] has media related to: **//[|Cholera]//** ||
 * [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/f/f8/Wiktionary-logo-en.svg/40px-Wiktionary-logo-en.svg.png width="40" height="44" caption="Sister project" link="http://en.wiktionary.org/wiki/Special:Search/Cholera"]] || Look up //**[|cholera]**// in
 * [|Cholera] - [|World Health Organization]
 * [|What is Cholera?] - [|Centers for Disease Control and Prevention]
 * [|Cholera information for travelers] - Centers for Disease Control and Prevention
 * Steven Shapin, [|"Sick City: Maps and mortality in the time of cholera"], [|The New Yorker] May 2006. A review of Steven Johnson, “The Ghost Map: The story of London’s most terrifying epidemic — and how it changed science, cities, and the modern world”
 * [|Cholera Epidemic in NYC in 1832] [|New York Times] 15 April 2008
 * ||||||~ show] [|v] • [|d] • [|e] **Cholera** ||
 * Cholera ||< [|Symptoms] - [|Treatment] - [|Prevention] - [|Susceptibility] - [|Transmission] - [|Diagnosis] - [|History] || [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/f/f6/Vibrio_cholerae.jpg/180px-Vibrio_cholerae.jpg width="180" height="147" caption="Vibrio cholerae" link="http://en.wikipedia.org/wiki/File:Vibrio_cholerae.jpg"]] ||
 * [|Cholera Bacteria] ||< [|Vibrio cholerae] - **[|Strains]**: [|Classic] -[|El Tor]
 * Discovery**:[|1854 Broad Street cholera outbreak] - [|John Snow] - [|Reverend Henry Whitehead] ||
 * [|Treatment] ||< [|Oral rehydration therapy]
 * [|Antibiotics]**:[|Tetracycline] - [|cotrimoxazole] - [|erythromycin] - [|doxycycline] - [|chloramphenicol] - [|furazolidone]
 * [|Fluoroquinolones]**:[|norfloxacin] ||
 * [|Outbreaks] ||< **[|Cholera Pandemics]**: [|First cholera pandemic] - [|Second cholera pandemic] - [|Third cholera pandemic] - [|Fourth cholera pandemic] - [|Fifth cholera pandemic] - [|Sixth cholera pandemic] - [|Seventh cholera pandemic]
 * [|Antibiotics]**:[|Tetracycline] - [|cotrimoxazole] - [|erythromycin] - [|doxycycline] - [|chloramphenicol] - [|furazolidone]
 * [|Fluoroquinolones]**:[|norfloxacin] ||
 * [|Outbreaks] ||< **[|Cholera Pandemics]**: [|First cholera pandemic] - [|Second cholera pandemic] - [|Third cholera pandemic] - [|Fourth cholera pandemic] - [|Fifth cholera pandemic] - [|Sixth cholera pandemic] - [|Seventh cholera pandemic]
 * [|Outbreaks] ||< **[|Cholera Pandemics]**: [|First cholera pandemic] - [|Second cholera pandemic] - [|Third cholera pandemic] - [|Fourth cholera pandemic] - [|Fifth cholera pandemic] - [|Sixth cholera pandemic] - [|Seventh cholera pandemic]
 * ||||~ show] [|v] • [|d] • [|e] [|Infectious diseases] · [|Bacterial diseases]: [|G-] (primarily [|A00-A79], [|001-041,080-109]) ||
 * [|Spirochaete] ||<  || [|Treponema] ||< //[|Treponema pallidum]// ([|Syphilis]/[|Bejel], [|Yaws]) · //[|Treponema carateum]// ([|Pinta]) ||
 * [|Borrelia] ||< //[|Borrelia recurrentis]// ([|Relapsing fever]) · //[|Borrelia burgdorferi]// ([|Lyme disease], [|Erythema chronicum migrans], [|Neuroborreliosis]) ||
 * [|Spirillum] ||< //[|Spirillum minus]// ([|Rat-bite fever]/[|Sodoku]) ||
 * [|Leptospira] ||< //[|Leptospira interrogans]// ([|Leptospirosis]) ||
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Leptospira] ||< //[|Leptospira interrogans]// ([|Leptospirosis]) ||
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * Multiple ||< [|Noma] · [|Trench mouth] ||  ||
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Proteobacteria] ||<  || [|α] ||<   || [|Rickettsiales] ||<   || [|Rickettsiaceae]/
 * [|Spotted fever] ||<  || [|Tick-borne disease] ||< //[|Rickettsia rickettsii]// ([|Rocky Mountain spotted fever]) · //[|Rickettsia conorii]// ([|Boutonneuse fever]) ||
 * Other ||< //[|Rickettsia akari]// ([|Rickettsialpox]) · //[|Orientia tsutsugamushi]// ([|Scrub typhus]) ||  ||   ||
 * [|Anaplasmataceae] ||< //[|Ehrlichia]/////[|Anaplasma]:// [|Ehrlichiosis] ([|Human granulocytic ehrlichiosis], [|Human monocytic ehrlichiosis]) ||  ||
 * [|Rhizobiales] ||<  || [|Brucellaceae] ||< //[|Brucella]// ([|Brucellosis]) ||
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Rhizobiales] ||<  || [|Brucellaceae] ||< //[|Brucella]// ([|Brucellosis]) ||
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Bartonellaceae] ||< [|Bartonellosis]: //[|Bartonella henselae]// ([|Cat scratch fever]) · //[|Bartonella quintana]// ([|Trench fever]) · //either henselae or quintana// ([|Bacillary angiomatosis]) · //[|Bartonella bacilliformis]// ([|Carrion's disease]) ||  ||   ||
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|β] ||<  || [|Neisseriales] ||< [|M+] //[|Neisseria meningitidis/meningococcus]// ([|Meningococcal disease], [|Waterhouse-Friderichsen syndrome])
 * [|Burkholderiales] ||< //[|Burkholderia]// ([|Glanders], [|Melioidosis]) · //[|Bordetella pertussis]/[|Bordetella parapertussis]// ([|Pertussis]) ||  ||
 * [|γ] ||<  || [|Enterobacteriales]
 * [|γ] ||<  || [|Enterobacteriales]
 * [|γ] ||<  || [|Enterobacteriales]
 * [|Slow/weak] ||< //[|Serratia marcescens]// ([|Serratia infection]) · //[|Citrobacter]// ||
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Lac-] ||< //[|Yersinia pestis]// ([|Plague]/[|Bubonic plague]) · //[|Yersinia enterocolitica]//
 * [|Pasteurellales] ||< //[|Haemophilus]:// //[|influenzae]// ([|Brazilian purpuric fever]) · //[|ducreyi]// ([|Chancroid])
 * [|Pasteurellales] ||< //[|Haemophilus]:// //[|influenzae]// ([|Brazilian purpuric fever]) · //[|ducreyi]// ([|Chancroid])
 * [|Legionellales] ||< //[|Legionella pneumophila]/[|Legionella longbeachae]// ([|Legionellosis]) · //[|Coxiella burnetii]// ([|Q fever]) ||
 * Other ||< //[|Thiotrichales]/[|Francisella]// ([|Tularemia]) · //[|Vibrionales]/[|Vibrio]// (**Cholera**) · //[|Pseudomonadales]/[|Pseudomonas aeruginosa]// ([|Pseudomonas infection]) ||  ||
 * [|ε] ||<  || [|Campylobacterales] ||< //[|Campylobacter jejuni]// ([|Campylobacteriosis]) · //[|Helicobacter pylori]// ([|Peptic ulcer], [|MALT lymphoma]) ||   ||   ||
 * [|Chlamydiae] ||< //[|Chlamydophila psittaci]// ([|Psittacosis]) · //[|Chlamydophila pneumoniae]// · //[|Chlamydia trachomatis]// ([|Chlamydia], [|Lymphogranuloma venereum], [|Trachoma]) ||
 * [|Bacteroidetes] ||< //[|Bacteroides fragilis]// ||
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||
 * [|Chlamydiae] ||< //[|Chlamydophila psittaci]// ([|Psittacosis]) · //[|Chlamydophila pneumoniae]// · //[|Chlamydia trachomatis]// ([|Chlamydia], [|Lymphogranuloma venereum], [|Trachoma]) ||
 * [|Bacteroidetes] ||< //[|Bacteroides fragilis]// ||
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||
 * [|Bacteroidetes] ||< //[|Bacteroides fragilis]// ||
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||
 * //Primarily [|rods] except [|Neisseriaceae] and [|Spirochaete]. Primarily [|OX+] except [|Enterobacteriaceae]. Primarily extracellular except [|Rickettsiales]/[|Chlamydia]/[|Treponema] ([|obligate]) and [|Brucella]/[|Listeria]/[|Legionella] ([|facultative]). Primarily [|aerobic] or [|facultative anaerobic] except [|Bacteroides].// ||  ||

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.3 Maleria Malaria is one of the most common infectious diseases and an enormous [|public health] problem. The disease is caused by [|protozoan] [|parasites] of the [|genus] //[|Plasmodium]//. Only four types of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by //[|Plasmodium falciparum]// and //[|Plasmodium vivax]//, but other related species (//[|Plasmodium ovale]//, //[|Plasmodium malariae]//) can also affect humans. This group of human-pathogenic //Plasmodium// species is usually referred to as //malaria parasites//. Usually, people get malaria by being bitten by an infective female [|//Anopheles// mosquito]. Only Anopheles mosquitoes can transmit malaria, and they must have been infected through a previous blood meal taken on an infected person. When a mosquito bites an infected person, a small amount of blood is taken, which contains microscopic malaria parasites. About one week later, when the mosquito takes its next blood meal, these parasites mix with the mosquito's saliva and are injected into the person being bitten. The parasites multiply within [|red blood cells], causing symptoms that include symptoms of [|anemia] (light-headedness, shortness of breath, [|tachycardia], etc.), as well as other general symptoms such as [|fever], [|chills], [|nausea], [|flu-like illness], and, in severe cases, [|coma], and death. Malaria transmission can be reduced by preventing mosquito bites with [|mosquito nets] and [|insect repellents], or by mosquito control measures such as spraying [|insecticides] inside houses and draining standing water where mosquitoes lay their eggs. Although some are under development, no [|vaccine] is currently available for malaria; preventive drugs must be taken continuously to reduce the risk of infection. These [|prophylactic] drug treatments are often too expensive for most people living in [|endemic] areas. Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial [|immunity] (resistance); the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Malaria infections are treated through the use of [|antimalarial drugs], such as [|quinine] or [|artemisinin] derivatives. However, parasites have [|evolved] to be resistant to many of these drugs. Therefore, in some areas of the world, only a few drugs remain as effective treatments for malaria. hide] * [|1] [|History] 
 * Malaria** is a [|vector]-borne [|infectious disease] caused by [|protozoan] [|parasites]. It is widespread in [|tropical] and subtropical regions, including parts of the [|Americas], [|Asia], and [|Africa]. Each year, there are approximately 515 million cases of malaria, killing between one and three million people, the majority of whom are young children in [|Sub-Saharan Africa].[|[][|1][|]] Ninety percent of malaria-related deaths occur in Sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty[|[][|2][|]] and a major hindrance to [|economic development].
 * ==Contents==
 * [|2] [|Distribution and impact]
 * [|2.1] [|Socio-economic effects]
 * [|3] [|Symptoms]
 * [|4] [|Causes]
 * [|4.1] [|Malaria parasites]
 * [|5] [|Mosquito vectors and the Plasmodium life cycle]
 * [|6] [|Pathogenesis]
 * [|7] [|Evolutionary pressure of malaria on human genes]
 * [|7.1] [|Sickle-cell disease]
 * [|7.2] [|Thalassaemias]
 * [|7.3] [|Duffy antigens]
 * [|7.4] [|G6PD]
 * [|7.5] [|HLA and interleukin-4]
 * [|8] [|Diagnosis]
 * [|8.1] [|Symptomatic diagnosis]
 * [|8.2] [|Microscopic examination of blood films]
 * [|8.3] [|Field tests]
 * [|8.4] [|Molecular methods]
 * [|8.5] [|Laboratory tests]
 * [|9] [|Treatment]
 * [|9.1] [|Antimalarial drugs]
 * [|9.2] [|Counterfeit drugs]
 * [|10] [|Prevention and disease control]
 * [|10.1] [|Vector control]
 * [|10.2] [|Prophylactic drugs]
 * [|10.3] [|Indoor residual spraying]
 * [|10.4] [|Mosquito nets and bedclothes]
 * [|10.5] [|Vaccination]
 * [|10.6] [|Other methods]
 * [|11] [|See also]
 * [|12] [|References]
 * [|13] [|External links] ||

History
//Further information: [|History of malaria]// Charles Louis Alphonse Laveran Malaria has infected humans for over 50,000 years, and may have been a human [|pathogen] for the entire history of the species.[|[][|3][|]] Close relatives of the human malaria parasites remain common in chimpanzees.[|[][|4][|]] References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.[|[][|5][|]] The term malaria originates from [|Medieval] [|Italian]: //mala aria// — "[|bad air]"; and the disease was formerly called **ague** or **marsh fever** due to its association with swamps and marshland. Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of [|Constantine] in [|Algeria] named [|Charles Louis Alphonse Laveran] observed parasites for the first time, inside the [|red blood cells] of people suffering from malaria. He, therefore, proposed that malaria is caused by this [|protozoan], the first time protozoa were identified as causing disease.[|[][|6][|]] For this and later discoveries, he was awarded the 1907 [|Nobel Prize for Physiology or Medicine]. The protozoan was called //Plasmodium// by the Italian scientists [|Ettore Marchiafava] and [|Angelo Celli].[|[][|7][|]] A year later, [|Carlos Finlay], a Cuban doctor treating patients with [|yellow fever] in [|Havana], provided strong evidence that mosquitoes were transmitting disease to and from humans.[|[][|8][|]] This work followed earlier suggestions by [|Josiah C. Nott],[|[][|9][|]] and work by [|Patrick Manson] on the transmission of [|filariasis].[|[][|10][|]] However, it was Britain's [|Sir Ronald Ross] working in the [|Presidency General Hospital] in [|Calcutta] who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.[|[][|11][|]] For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established [|Liverpool School of Tropical Medicine] and directed malaria-control efforts in [|Egypt], [|Panama], [|Greece] and [|Mauritius].[|[][|12][|]] The findings of Finlay and Ross were later confirmed by a medical board headed by [|Walter Reed] in 1900, and its recommendations implemented by [|William C. Gorgas] in [|the health measures undertaken] during construction of the [|Panama Canal]. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease. The first effective treatment for malaria came from the bark of [|cinchona tree], which contains [|quinine]. This tree grows on the slopes of the [|Andes], mainly in [|Peru]. A tincture made of this natural product was used by the inhabitants of [|Peru] to control malaria, and the [|Jesuits] introduced this practice to Europe during the 1640s, where it was rapidly accepted.[|[][|13][|]] However, it was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists [|Pierre Joseph Pelletier] and [|Joseph Bienaimé Caventou].[|[][|14][|]] In the early twentieth century, before [|antibiotics], patients with [|syphilis] were intentionally [|infected] with malaria to create a [|fever], following the work of [|Julius Wagner-Jauregg]. By accurately controlling the fever with [|quinine], the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable to the almost-certain death from syphilis.[|[][|15][|]] Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed.[|[][|16][|]][|[][|17][|]] The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams. 

Distribution and impact
//Further information: [|Diseases of poverty], [|Tropical disease]// Countries which have regions where malaria is [|endemic] as of 2003 (coloured yellow).[|[][|18][|]] Green areas are free of indigenous cases of malaria. Malaria causes about 250 million cases of fever and approximately one million deaths annually.[|[][|19][|]] The vast majority of cases occur in children under 5 years old;[|[][|20][|]] pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992.[|[][|21][|]] Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years.[|[][|22][|]] Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented.[|[][|22][|]] Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/[|tuberculosis] co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old.[|[][|23][|]] Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing [|viral load] and HIV infection increasing a person's susceptibility to malaria infection.[|[][|24][|]] Malaria is presently endemic in a broad band around the equator, in areas of the [|Americas], many parts of [|Asia], and much of [|Africa]; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.[|[][|25][|]] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.[|[][|26][|]] In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.[|[][|27][|]] Malaria is more common in rural areas than in cities; this is in contrast to [|dengue fever] where urban areas present the greater risk.[|[][|28][|]] For example, the cities of [|Vietnam], [|Laos] and [|Cambodia] are essentially malaria-free, but the disease is present in many rural regions.[|[][|29][|]] By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.[|[][|30][|]] The global [|endemic] levels of malaria have not been mapped since the 1960s. However, the [|Wellcome Trust], UK, has funded the [|Malaria Atlas Project][|[][|31][|]] to rectify this, providing a more contemporary and robust means with which to assess current and future malaria [|disease burden]. 

Socio-economic effects
Malaria is not just a disease commonly associated with poverty but also a cause of poverty and a major hindrance to [|economic development]. Tropical regions are affected most, however malaria’s furthest extent reaches into some temperate zones with extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.[|[][|32][|]]. A comparison of average per capita GDP in 1995, adjusted for [|parity of purchasing power], between countries with malaria and countries without malaria gives a fivefold difference ($1,526 USD versus $8,268 USD). In countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.[|[][|33][|]] Poverty is both cause and effect, however, since the poor do not have the financial capacities to prevent or treat the disease. The lowest income group in Malawi carries the burden of having 32% of their annual income used on this disease compared with the 4% of household incomes from low-to-high groups. [//[|citation needed]//] In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.[|[][|20][|]] In some countries with a heavy malaria burden, the disease may account for as much as 40% of public health expenditure, 30-50% of inpatient admissions, and up to 50% of outpatient visits. The extensive use of anti-malaria campaigns in recent decades seek to address the correlation between the disease and poverty. Government subsidies and public healthcare providers made available in closer proximity to all of the people in a town are efficient methods to reduce the cost of treatment for the poor and the rest of the social classes as that would allow equal accessibility and utilization of treatment. [|[][|34][|]] 

Symptoms
Symptoms of malaria include [|fever], [|shivering], [|arthralgia] (joint pain), [|vomiting], [|anemia] (caused by [|hemolysis]), [|hemoglobinuria], [|retinal damage],[|[][|35][|]] and [|convulsions]. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by [|rigor] and then fever and sweating lasting four to six hours, occurring every two days in //P. vivax// and //P. ovale// infections, while every three for //P. malariae//.[|[][|36][|]] //P. falciparum// can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but that may be related to high [|intracranial pressure], children with malaria frequently exhibit [|abnormal posturing], a sign indicating severe brain damage.[|[][|37][|]] Malaria has been found to cause cognitive impairments, especially in children. It causes widespread [|anemia] during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable.[|[][|38][|]][|[][|39][|]] Severe malaria is almost exclusively caused by //P. falciparum// infection and usually arises 6–14 days after infection.[|[][|40][|]] Consequences of severe malaria include [|coma] and death if untreated—young children and pregnant women are especially vulnerable. [|Splenomegaly] (enlarged spleen), severe [|headache], cerebral [|ischemia], [|hepatomegaly] (enlarged liver), [|hypoglycemia], and hemoglobinuria with [|renal failure] may occur. Renal failure may cause [|blackwater fever], where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days.[|[][|40][|]] In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment.[|[][|41][|]] In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten.[|[][|42][|]] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[|[][|43][|]] Chronic malaria is seen in both //P. vivax// and //P. ovale//, but not in //P. falciparum//. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a //P. vivax// infection is 30 years.[|[][|40][|]] Approximately one in five of //P. vivax// malaria cases in [|temperate] areas involve [|overwintering] by hypnozoites (i.e., relapses begin the year after the mosquito bite).[|[][|44][|]] 
 * ~ Species ||~ Appearance ||~ Periodicity ||~ Persistent in liver? ||
 * //[|Plasmodium vivax]// || [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/7/70/Plasmodium_vivax_01.png/200px-Plasmodium_vivax_01.png width="200" height="135" link="http://en.wikipedia.org/wiki/File:Plasmodium_vivax_01.png"]] || tertian || yes ||
 * //[|Plasmodium ovale]// || [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/1/15/Plasmodium_ovale_01.png/200px-Plasmodium_ovale_01.png width="200" height="131" link="http://en.wikipedia.org/wiki/File:Plasmodium_ovale_01.png"]] || tertian || yes ||
 * //[|Plasmodium falciparum]// || [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/f/fc/Plasmodium_falciparum_01.png/200px-Plasmodium_falciparum_01.png width="200" height="134" link="http://en.wikipedia.org/wiki/File:Plasmodium_falciparum_01.png"]] || tertian || no ||
 * //[|Plasmodium malariae]// || [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/0/02/Mature_Plasmodium_malariae_schizont_PHIL_2715_lores.jpg/200px-Mature_Plasmodium_malariae_schizont_PHIL_2715_lores.jpg width="200" height="135" link="http://en.wikipedia.org/wiki/File:Mature_Plasmodium_malariae_schizont_PHIL_2715_lores.jpg"]] || quartan || no ||

Causes
A //Plasmodium// sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color [|electron micrograph].

Malaria parasites
Malaria is caused by [|protozoan] [|parasites] of the genus //[|Plasmodium]// (phylum [|Apicomplexa]). In humans malaria is caused by //[|P. falciparum]//, //[|P. malariae]//, //[|P. ovale]//, //[|P. vivax]// and //[|P. knowlesi]//.[|[][|45][|]][|[][|46][|]] //P. falciparum// is the most common cause of infection and is responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria.[|[][|47][|]] Parasitic //Plasmodium// species also infect birds, reptiles, monkeys, chimpanzees and rodents.[|[][|48][|]] There have been documented human infections with several [|simian] species of malaria, namely //P. knowlesi//, //[|P. inui]//, //[|P. cynomolgi]//,[|[][|49][|]] //[|P. simiovale]//, //[|P. brazilianum]//, //[|P. schwetzi]// and //[|P. simium]//; however, with the exception of //P. knowlesi//, these are mostly of limited public health importance. Although [|avian malaria] can kill chickens and turkeys, this disease does not cause serious economic losses to poultry farmers.[|[][|50][|]] However, since being accidentally introduced by humans it has decimated the [|endemic birds of Hawaii], which evolved in its absence and lack any resistance to it.[|[][|51][|]] 

Mosquito vectors and the //Plasmodium// life cycle
The parasite's primary (definitive) hosts and transmission [|vectors] are female [|mosquitoes] of the //[|Anopheles]// genus. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected //Anopheles// mosquitoes carry //Plasmodium// [|sporozoites] in their [|salivary glands]. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite [|gametocytes] taken up in the blood will further differentiate into male or female [|gametes] and then fuse in the mosquito gut. This produces an [|ookinete] that penetrates the gut lining and produces an [|oocyst] in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer.[|[][|52][|]] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal. Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the //Anopheles// genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by [|blood transfusions], although this is rare.[|[][|53][|]] 

Pathogenesis
The life cycle of malaria parasites in the human body. A mosquito infects a person,by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, then trophozoites (a feeding stage), then schizonts (a reproduction stage), then back into merozoites. Sexual forms called gametocytes are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle. Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, [|sporozoites] in the mosquito's saliva enter the bloodstream and migrate to the [|liver]. Within 30 minutes of being introduced into the human host, the sporozoites infect [|hepatocytes], multiplying asexually and asymptomatically for a period of 6–15 days. Once in the liver, these organisms differentiate to yield thousands of [|merozoites], which, following rupture of their host cells, escape into the blood and infect [|red blood cells], thus beginning the erythrocytic stage of the life cycle.[|[][|54][|]] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[|[][|55][|]] Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells. Some //P. vivax// and //P. ovale// sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.[|[][|56][|]] The parasite is relatively protected from attack by the body's [|immune system] because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the [|spleen]. To avoid this fate, the //P. falciparum// parasite displays adhesive [|proteins] on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen.[|[][|57][|]] This "stickiness" is the main factor giving rise to [|hemorrhagic] complications of malaria. [|High endothelial venules] (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the [|blood brain barrier] possibly leading to coma.[|[][|58][|]] Although the red blood cell surface adhesive proteins (called PfEMP1, for //Plasmodium falciparum// erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and perhaps limitless versions within parasite populations.[|[][|57][|]] Like a thief changing disguises or a spy with multiple passports, the parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system. Some merozoites turn into male and female [|gametocytes]. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the [|definitive host] of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,[|[][|59][|]] and malaria in pregnant women is an important cause of [|stillbirths], infant mortality and low birth weight,[|[][|60][|]] particularly in //P. falciparum// infection, but also in other species infection, such as //P. vivax//.[|[][|61][|]] 

Evolutionary pressure of malaria on human genes
//Further information: [|Evolution], [|Natural selection]// Malaria is thought to have been the greatest [|selective pressure] on the [|human genome] in recent history.[|[][|62][|]] This is due to the high levels of [|mortality] and [|morbidity] caused by malaria, especially the //[|P. falciparum]// species. 

Sickle-cell disease
Distribution of Malaria. The most-studied influence of the malaria parasite upon the human genome is a hereditary blood disease, [|sickle-cell disease]. The sickle-cell trait causes disease, but even those only partially affected by sickle-cell have substantial protection against malaria. In sickle-cell disease, there is a mutation in the //HBB// gene, which encodes the beta-globin subunit of [|haemoglobin]. The normal allele encodes a [|glutamate] at position six of the beta-globin protein, whereas the sickle-cell allele encodes a [|valine]. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling. In the merozoite stage of its life cycle, the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but, if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals [|heterozygous] for the mutated allele, known as sickle-cell trait, may have a low and usually-unimportant level of [|anaemia], but also have a greatly reduced chance of serious malaria infection. This is a classic example of [|heterozygote advantage]. Individuals [|homozygous] for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is [|endemic], the [|frequency] of sickle-cell genes is around 10%. The existence of four [|haplotypes] of sickle-type hemoglobin suggests that this mutation has emerged [|independently] at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions. There are also other mutations of the HBB gene that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types HbE and HbC, which are common in [|Southeast Asia] and [|Western Africa], respectively. 

Thalassaemias
Another well-documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as [|thalassaemias]. Studies in [|Sardinia] and [|Papua New Guinea] have found that the [|gene frequency] of [|β-thalassaemias] is related to the level of malarial endemicity in a given population. A study on more than 500 children in [|Liberia] found that those with β-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the α+ form of α-thalassaemia. Presumably these genes have also been [|selected] in the course of human evolution. 

Duffy antigens
The [|Duffy antigens] are [|antigens] expressed on red blood cells and other cells in the body acting as a [|chemokine] receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.). //[|Plasmodium vivax]// malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells (Fy-/Fy-). This [|genotype] confers complete resistance to //P. vivax// infection. The genotype is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.[|[][|63][|]] This is thought to be due to very high exposure to //P. vivax// in [|Africa] in the last few thousand years. 

G6PD
[|Glucose-6-phosphate dehydrogenase] (G6PD) is an [|enzyme] that normally protects from the effects of [|oxidative stress] in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria. 

HLA and interleukin-4
[|HLA-B53] is associated with low risk of severe malaria. This [|MHC class I] molecule presents [|liver] stage and [|sporozoite] [|antigens] to [|T-Cells]. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria.[|[][|64][|]] 

Diagnosis
//Further information: [|Blood film]// Blood smear from a //P. falciparum// [|culture] (K1 strain). Several red blood cells have ring stages inside them. Close to the center there is a schizont and on the left a trophozoite. Severe malaria is commonly misdiagnosed in [|Africa], leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, [|parasitemia] does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial [|retinopathy] is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial [|coma].[|[][|65][|]] 

Symptomatic diagnosis
Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).[|[][|66][|]] 

Microscopic examination of blood films
//For more details on individual parasites, see [|P. falciparum], [|P. vivax], [|P. ovale], [|P. malariae].// The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of [|blood films] because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.[|[][|67][|]] From the thick film, an experienced microscopist can detect parasite levels (or [|parasitemia]) down to as low as 0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. 

Field tests
In areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are [|antigen detection tests] that require only a drop of blood.[|[][|68][|]] Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") have been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and a laboratory is not needed. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood compared to 5 by thick film microscopy. The first rapid diagnostic tests were using P. falciparum [|glutamate dehydrogenase] as antigen.[|[][|69][|]] PGluDH was soon replaced by P.falciparum [|lactate dehydrogenase], a 33 kDa oxidoreductase [EC 1.1.1.27]. It is the last enzyme of the glycolytic pathway, essential for ATP generation and one of the most abundant enzymes expressed by P.falciparum. PLDH does not persist in the blood but clears about the same time as the parasites following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. The OptiMAL-IT assay can distinguish between P. falciparum and P. vivax because of antigenic differences between their pLDH isoenzymes. OptiMAL-IT will reliably detect //falciparum// down to 0.01% [|parasitemia] and non-//falciparum// down to 0.1%. //Para//check-Pf will detect parasitemias down to 0.002% but will not distinguish between //falciparum// and non-//falciparum// malaria. Parasite nucleic acids are detected using [|polymerase chain reaction]. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).[|[][|70][|]] 

Molecular methods
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, [|QT-NASBA] based on the polymerase chain reaction)[|[][|71][|]] are being developed with the hope of being able to deploy them in endemic areas. 

Laboratory tests
OptiMAL-IT will reliably detect //falciparum// down to 0.01% [|parasitemia] and non-//falciparum// down to 0.1%. //Para//check-Pf will detect parasitemias down to 0.002% but will not distinguish between //falciparum// and non-//falciparum// malaria. Parasite nucleic acids are detected using [|polymerase chain reaction]. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. [|[][|72][|]] 

Treatment
Active malaria infection with //P. falciparum// is a [|medical emergency] requiring [|hospitalization]. Infection with //P. vivax//, //P. ovale// or //P. malariae// can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete recovery.[|[][|73][|]] 

Antimalarial drugs
//Further information: [|Antimalarial drugs]// There are several families of drugs used to treat malaria. [|Chloroquine] is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of //Plasmodium falciparum// to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world.[|[][|74][|]] In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as [|quinine] and [|amodiaquine].[|[][|75][|]] There are several other substances which are used for treatment and, partially, for prevention ([|prophylaxis]). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug currently[|[update]] being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the [|beta blocker] [|propranolol]. Propranolol has been shown to block both //Plasmodium'//s ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by [|Northwestern University] researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against //P. falciparum// by 5- to 10-fold, suggesting a role in combination therapies.[|[][|76][|]] Currently available anti-malarial drugs include:[|[][|77][|]] The development of drugs was facilitated when //Plasmodium falciparum// was successfully [|cultured].[|[][|78][|]] This allowed in vitro testing of new drug candidates. Extracts of the plant //[|Artemisia annua]//, containing the compound [|artemisinin] or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand.[|[][|79][|]] In 2007, the [|Bill & Melinda Gates Foundation] contributed $13.6m to support research at the [|University of York] to develop fast and high-yield strains of artemisia, with researchers predicting an increase in yield of up to 1000% compared to current varieties.[|[][|80][|]] One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with [|artesunate], rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted.[|[][|81][|]] Since 2001 the [|World Health Organization] has recommended using [|artemisinin]-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent [|WHO] [|treatment guidelines for malaria] recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that [|SERCA], a calcium pump in the [|endoplasmic reticulum] may be associated with artemisinin resistance.[|[][|82][|]] Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.[|[][|83][|]] However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.[|[][|84][|]] In February 2002, the journal //[|Science]// and other press outlets[|[][|85][|]] announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25".[|[][|86][|]] It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3".[|[][|87][|]] As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available. In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts,[|[][|88][|]] an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that any number of herbicides may in fact be successful in the fight against malaria, and so he set about trialing large numbers of them, and enjoyed a 75% success rate. These "[|apicoplasts]" are thought to have originated through the endosymbiosis of algae[|[][|89][|]] and play a crucial role in fatty acid bio-synthesis in plasmodia.[|[][|90][|]] To date, 466 proteins have been found to be produced by apicoplasts[|[][|91][|]] and these are now being looked at as possible targets for novel anti-malarial drugs. Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles. [|Médecins Sans Frontières] estimates that the cost of treating a malaria-infected person in an endemic country was between [|US$]0.25 and $2.40 per dose in 2002.[|[][|92][|]] 
 * [|Artemether]-[|lumefantrine] (Therapy only, commercial names //[|Coartem]// and //Riamet//)
 * [|Artesunate]-[|amodiaquine] (Therapy only)
 * [|Artesunate]-[|mefloquine] (Therapy only)
 * [|Artesunate]-[|Sulfadoxine]/[|pyrimethamine] (Therapy only)
 * [|Atovaquone]-[|proguanil], trade name [|Malarone] (Therapy and prophylaxis)
 * [|Quinine] (Therapy only)
 * [|Chloroquine] (Therapy and prophylaxis; usefulness now reduced due to resistance)
 * [|Cotrifazid] (Therapy and prophylaxis)
 * [|Doxycycline] (Therapy and prophylaxis)
 * [|Mefloquine], trade name Lariam (Therapy and prophylaxis)
 * [|Primaquine] (Therapy in //P. vivax// and //P. ovale// only; not for prophylaxis)
 * [|Proguanil] (Prophylaxis only)
 * [|Sulfadoxine]-[|pyrimethamine] (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
 * [|Hydroxychloroquine], trade name Plaquenil (Therapy and prophylaxis)

Counterfeit drugs
Sophisticated [|counterfeits] have been found in several Asian countries such as [|Cambodia],[|[][|93][|]] [|China],[|[][|94][|]] [|Indonesia], [|Laos], [|Thailand], [|Vietnam] and are an important cause of avoidable death in these countries.[|[][|95][|]] [|WHO] have said that studies indicate that up to 40% of [|artesunate] based malaria medications are counterfeit, especially in the Greater [|Mekong] region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries.[|[][|96][|]] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution. 

Prevention and disease control
//[|Anopheles] albimanus// mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria. Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density, and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in [|North America], [|Europe] and much of [|Middle East]. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favors the parasite's reproduction. Many countries are seeing an increasing number of imported malaria cases due to extensive travel and migration. (See [|Anopheles].) There is currently no [|vaccine] that will prevent malaria, but this is an active field of research. Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser [|Jeffrey Sachs] estimates that malaria can be controlled for US$3 billion in aid per year. It has been argued that, in order to meet the [|Millennium Development Goals], money should be redirected from [|HIV]/[|AIDS] treatment to malaria prevention, which for the same amount of money would provide greater benefit to African economies.[|[][|97][|]] The distribution of funding varies among countries. Countries with large populations do not receive the same amount of support. The 34 countries that received a per capita annual support of less than $1 included some of the poorest countries in Africa. Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.[|[][|98][|]] 

Vector control
//Further information: [|Mosquito control]// Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.[|[][|99][|]] Efforts to [|eradicate] malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the [|United States] and southern [|Europe], but the draining of wetland breeding grounds and better sanitation, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the [|pesticide] [|DDT] eliminated it from the South by 1951. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant.[|[][|100][|]] However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa. [|Sterile insect technique] is emerging as a potential mosquito control method. Progress towards transgenic, or [|genetically modified], insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at [|Imperial College London] created the world's first transgenic malaria mosquito,[|[][|101][|]] with the first plasmodium-resistant species announced by a team at [|Case Western Reserve University] in [|Ohio] in 2002.[|[][|102][|]] Successful replacement of existent populations with genetically modified populations, relies upon a drive mechanism, such as [|transposable elements] to allow for non-Mendelian inheritance of the gene of interest. However, this approach contains many difficulties and 34% of the malaria research and control community say that such an approach “will never fly” . Furthermore, such an approach is at least 5 to 10 years away from introduction and the progress which has been made in developing a vaccine could influence further research in genetic modification of malaria mosquitoes negatively <Knols et al., 2007>. On December 21, 2007, a study published in [|PLoS Pathogens] found that the hemolytic C-type [|lectin] CEL-III from //[|Cucumaria echinata]//, a [|sea cucumber] found in the [|Bay of Bengal], impaired the development of the malaria parasite when produced by transgenic mosquitoes.[|[][|103][|]][|[][|104][|]] This could potentially be used one day to control malaria by using genetically modified mosquitoes refractory to the parasites, although the authors of the study recognize that there are numerous scientific and ethical problems to be overcome before such a control strategy could be implemented. 

Prophylactic drugs
//Main article: [|Malaria prophylaxis]// Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative [|side effects] from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations. [|Quinine] was used starting in the seventeenth century as a prophylactic against malaria. The development of more effective alternatives such as [|quinacrine], [|chloroquine], and [|primaquine] in the twentieth century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant //[|Plasmodium falciparum]//, as well as severe and cerebral stages of malaria, but is not generally used for prophylaxis. Of interesting historical note is the observation by [|Samuel Hahnemann] in the late 18th century that over-dosing of quinine leads to a symptomatic state very similar to that of malaria itself. This lead Hahnemann to develop the [|Law of Similars], and the subsequent pseudo-medical system of [|Homeopathy]. Modern drugs used preventively include [|mefloquine] (**Lariam**), [|doxycycline] (available generically), and the combination of [|atovaquone] and [|proguanil] hydrochloride (**Malarone**). The choice of which drug to use depends on which drugs the parasites in the area are [|resistant] to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards). 

Indoor residual spraying
Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria affected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can bite another victim, transferring the malaria parasite. The first and historically the most popular insecticide used for IRS is [|DDT]. While it was initially used exclusively to combat malaria, its use quickly spread to [|agriculture]. In time, pest-control, rather than disease-control, came to dominate DDT use, and this large-scale agricultural use led to the [|evolution] of resistant mosquitoes in many regions. If the use of DDT was limited agriculturally, DDT may be more effective now as a method of disease-control. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. The overuse of anti-bacterial soaps and antibiotics have led to antibiotic resistance in bacteria, similar to how overspraying of DDT on crops have led to DDT resistance in Anopheles mosquitoes. During the 1960s, awareness of the negative consequences of its indiscriminate use increased ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s. Though DDT has never been banned for use in malaria control and there are several other insecticides suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries where DDT had once been effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in [|public health].[|[][|105][|]] The [|World Health Organization] (WHO) currently advises the use of 12 different insecticides in IRS operations. These include DDT and a series of alternative insecticides (such as the pyrethroids [|permethrin] and [|deltamethrin]) to both combat malaria in areas where mosquitoes are DDT-resistant, and to slow the evolution of resistance.[|[][|106][|]] This public health use of small amounts of DDT is permitted under the [|Stockholm Convention] on [|Persistent Organic Pollutants] (POPs), which prohibits the agricultural use of DDT.[|[][|107][|]] However, because of its legacy, many developed countries discourage DDT use even in small quantities.[|[][|108][|]][|[][|109][|]] One problem with all forms of Indoor Residual Spraying is insecticide [|resistance] via evolution of mosquitos. According to a study published on Mosquito Behavior and Vector Control, mosquito breeds that are affected by IRS are endophilic species(Species which tend to rest and live indoors), and due to the irritation caused by spraying, their evolutionary descendants are trending towards becoming exophilic(Species which tend to rest and live out of doors), meaning that they are not as affected--if affected at all-- by the IRS, rendering it somewhat useless as a defense mechanism [|[][|110][|]]. 

Mosquito nets and bedclothes
Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets,[|[][|97][|]] and offer greater than 70% protection compared with no net.[|[][|111][|]]. Although ITN are proven to be very effective against malaria, less than 2% of children in urban areas in Sub-Saharan Africa are protected by ITNs. Since the //[|Anopheles]// mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely. The distribution of mosquito nets impregnated with insecticide (often [|permethrin] or deltamethrin) has been shown to be an extremely effective method of malaria prevention, and it is also one of the most cost-effective methods of prevention. These nets can often be obtained for around [|US$]2.50 - $3.50 (2-3 [|euro]) from the [|United Nations], the World Health Organization (WHO), and others. ITNs have been shown to be the most cost-effective prevention method against malaria and are actively part of WHO’s Millennium Development Goals (MDGs). For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years,[|[][|112][|]] and cost about US$5.50. ITNs have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net. Unfortunately, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net.[|[][|97][|]] Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish.[|[][|113][|]] Nets are also often distributed though vaccine campaigns using vouchers subsidies, such as the measles campaign for children. Vouchers subsidies are an effective way of getting protective nets to those who cannot afford them off the market. A study among [|Afghan refugees] in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper.[|[][|114][|]] A new approach, announced in //Science// on June 10, 2005, uses spores of the [|fungus] //[|Beauveria bassiana]//, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to fungal infections.[|[][|115][|]] 

Vaccination
//Further information: [|Malaria vaccine]// [|Vaccines] for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-[|attenuated] [|sporozoites], providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites.[|[][|116][|]] Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a //P. falciparum// infection if they receive over 1000 bites from infected, irradiated mosquitoes.[|[][|117][|]] It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman of [|Sanaria], one of the key researchers who originally sequenced the genome of //[|Plasmodium falciparum]//. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the [|Bill & Melinda Gates Foundation] and the U.S. government to begin early clinical studies in 2007 and 2008.[|[][|118][|]] The Seattle Biomedical Research Institute (SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials won't be a life-threatening experience. While many volunteers [in Seattle] will actually contract malaria, the cloned strain used in the experiments can be quickly cured, and does not cause a recurring form of the disease." "Some participants will get experimental drugs or vaccines, while others will get placebo."[|[][|119][|]] Instead, much work has been performed to try and understand the [|immunological] processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967,[|[][|116][|]] it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating [|antibodies] against the parasite. It was determined that the immune system was creating antibodies against the [|circumsporozoite] protein (CSP) which coated the sporozoite.[|[][|120][|]] Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.[|[][|121][|]] CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines. Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood [|venules] and [|placenta]; and [|transmission]-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person.[|[][|122][|]] It is hoped that the sequencing of the //P. falciparum// [|genome] will provide targets for new drugs or vaccines.[|[][|123][|]] The first vaccine developed that has undergone field trials, is the SPf66, developed by [|Manuel Elkin Patarroyo] in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in The Gambia did not show any effect. Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified //[|Pseudomonas aeruginosa]// toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed. The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in [|The Lancet] (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country. The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the [|Gates Foundation]), the [|pharmaceutical company], [|GlaxoSmithKline], and the Walter Reed Army Institute of Research[|[][|124][|]] In the vaccine, a portion of CSP has been fused to the [|immunogenic] "S [|antigen]" of the [|hepatitis B] virus; this [|recombinant] protein is injected alongside the potent AS02A [|adjuvant].[|[][|122][|]] In October 2004, the RTS,S/AS02A researchers announced results of a [|Phase IIb trial], indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2,000 [|Mozambican] children.[|[][|125][|]] More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a [|phase I/IIb trial] conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection.[|[][|126][|]] Further research will delay this vaccine from commercial release until around 2011.[|[][|127][|]] 

Other methods
Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%. Recognizing the disease in the early stages can also stop the disease from becoming a killer. Education can also inform people to cover over areas of stagnant, still water e.g. Water Tanks which are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is most put in practice in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas. The [|Malaria Control Project] is currently using downtime computing power donated by individual volunteers around the world (see [|Volunteer computing] and [|BOINC]) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.[|[][|128][|]] An example of the importance of computer modeling in planning malaria eradication programs is shown in the paper by Águas and others. They showed that eradication of malaria is crucially dependent on finding and treating the large number of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection.[|[][|129][|]] The malaria parasites do not affect animal species and therefore eradication of the disease from the human population would be expected to be effective. 

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