【素材】Unit 1 文档Cholera（人教）.doc

CholeraScanning Electron Microscope image of Vibrio choleraeICD-10A00.,ICD-9001DiseasesDB29089MedlinePlus000303eMedicinemed/351MeSHD002771Distribution of choleraCholera, sometimes known as Asiatic or epidemic cholera, is an infectious gastroenteritis caused by enterotoxin-producing strains of the bacterium Vibrio cholerae.12 Transmission to humans occurs through eating food or drinking water contaminated with cholera vibrios from other cholera patients. 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.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 diseases infamous characteristic, exhaustive diarrhea.1 In its most severe forms, cholera is one of the most rapidly fatal illnesses known, and a healthy persons 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.34TreatmentHand 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 The outdated public health advice demonstrates the lack of understanding of the disease and its actual causative factors.Cholera patient being treated by medical staff in 1992In 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 homemade solutions using various formulas of water, sugar, table salt, baking soda, and fruit offer less expensive methods of electrolyte repletion. In severe cholera cases with significant dehydration, 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 principal 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.5 Fluoroquinolones such as norfloxacin also may be used, but resistance has been reported.6 Recently Hemendra Yadav reported findings at the All India Institute of Medical Sciences, New Delhi, noting 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.7 New generation antimicrobials have been discovered which are effective against V. cholerae in in vitro studies.8The success of treatment is significantly affected by the speed and method of treatment. If cholera patients are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera the mortality rate rises to 5060%.910EpidemiologyPreventionAlthough cholera can be and is, if left untreated, life-threatening, prevention of the disease is normally straightforward if proper sanitation practices are followed. In the first world, due to nearly universal advanced water treatment and sanitation practices, cholera is no longer a major health threat. The last major outbreak of cholera in the United States occurred in 1910-1911 .1112 Travelers should be aware of how the disease is transmitted and what can be done to prevent it. Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. The main procedure involves exposing as many microbes as possible to treatments or processes that kill or remove them. Heat, chlorine, ozone, ultra-violet light, and microbal filters are all some of the methods used to kill or remove the germs. There are several points along the cholera transmission path at which its spread may be (and should be) halted:Cholera hospital in Dhaka, showing typical cholera beds. Sterilization: Proper disposal and treatment of the germ infected fecal waste water produced by cholera victims (and all clothing, bedding, people, etc. that come in contact with it) is of primary importance. All materials that come in contact with cholera patients should be sterilized by washing in hot water using chlorine bleach if possible. Hands that touch cholera patients or their clothing, bedding etc. should be thoroughly cleaned and sterilized with chlorinated water or other effective anti-microbal. Sewage: anti-bacterial treatment of general sewage by chlorine, ozone, ultra-violet light or other effective treatment before it enters the waterways or underground water supplies helps prevent undiagnosed patients from inadvertently spreading the disease. Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to decontaminate the water (boiling, chlorination etc.) for possible use. Water purification: All water used for drinking, washing, or cooking should be sterilized by boiling,chlorination, ozone water treatment, ultra-violet light sterilization, or anti-microbal filtration in any area where cholera may be present. Chlorination, and boiling are nearly always the cheapest and 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. Better anti-microbal filters like those present in up-scale individual water treatment hiking kits are required to remove all microbes. Public health education and adherence to appropriate sanitation practices are of primary importance to help prevent and control transmission of cholera and other diseases. A vaccine is available in some countries (not the U.S.), but this prophylactic is not currently recommended for routine use by the U.S. Centers for Disease Control and Prevention (CDC)13. 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.14 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.13 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.15Sensitive 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.16SusceptibilityRecent epidemiologic research suggests that an individuals susceptibility to cholera (and other diarrheal infections) is affected by their blood type: those with type O blood are the most susceptible,1718 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 neededAbout 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.19 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.TransmissionDrawing of Death bringing the cholera, in Le Petit JournalPeople infected with cholera suffer acute diarrhea. This highly liquid diarrhea, colloquially 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.20 Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage.21 Coastal cholera outbreaks typically follow zooplankton blooms, thus making cholera a Potential human contribution to transmissibilityCholera 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.22 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.DiagnosisIn 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.14A number of special media have been employed for the cultivation for cholera vibrios. They are classified as follows:Holding or transport media1. 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 Enrichment media1. Alkaline peptone water at pH 8.6 2. Monsurs taurocholate tellurite peptone water at pH 9.2 Plating media1. Alkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar. 2. Monsurs 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 2-3mm in diameter, yellow nucleated colonies. 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.BiochemistryTEM image of Vibrio choleraeMost of the V. cholerae bacteria in the contaminated water consumed by the host do not survive the highly acidic conditions of the human stomach.23 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 hostif 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.24 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 bloods 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.24 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.24HistoryOrigin and spreadCholera likely has its origins in and is endemic to the Indian subcontinent, with the River Ganges 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. Cholera is now no longer considered a