Typhoid fever Definition Typhoid fever is a bacterial infection characterized by diarrhea systemic disease and a rash most commonly

ly caused by the bacteria salmonella typhi. Causes The bacteria that causes typhoid fever, s. typhi, spreads through contaminated food , drink or water. If you eat or drink something that is contaminated , the bacteria enters your body , and goes into your intestines , and then into your bloodstream, where it can travel to your lymph nodes , gallbladder , liver,spleen ,and other parts of the body. A few people can become carriers of s. typhi and continue to release the bacteria in their stools for years, spreading the disease. Symptoms Early symptoms include fever , general ill feeling and abdominal pain. A high fever and severe diarrhea occur as the disease gets worse. Some people with typhoid fever develop a rash called -rose spots- which are small red spots on the belly and chest.

Incidence of typhoid fever Strongly endemic Endemic Sporadic cases Typhoid fever is characterized by a slowly progressive fever as high as 40 C (104 F), profuse sweating, gastroenteritis, and nonbloody diarrhea. Less commonly a rash of flat, rosecolored spots may appear.[3] Classically, the course of untreated typhoid fever is divided into four individual stages, each lasting approximately one week. In the first week, there is a slowly rising temperature with relative bradycardia, malaise, headache and cough. A bloody nose (epistaxis) is seen in a

quarter of cases and abdominal pain is also possible. There is leukopenia, a decrease in the number of circulating white blood cells, with eosinopenia and relative lymphocytosis, a positive diazo reaction and blood cultures are positive for Salmonella typhi or paratyphi. The classic Widal test is negative in the first week. In the second week of the infection, the patient lies prostrated with high fever in plateau around 40 C (104 F) and bradycardia (Sphygmo-thermic dissociation), classically with a dicrotic pulse wave. Delirium is frequent, frequently calm, but sometimes agitated. This delirium gives to typhoid the nickname of "nervous fever". Rose spots appear on the lower chest and abdomen in around 1/3 patients. There are rhonchi in lung bases. The abdomen is distended and painful in the right lower quadrant where borborygmi can be heard. Diarrhea can occur in this stage: six to eight stools in a day, green with a characteristic smell, comparable to pea-soup. However, constipation is also frequent. The spleen and liver are enlarged (hepatosplenomegaly) and tender and there is elevation of liver transaminases. The Widal reaction is strongly positive with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage. (The major symptom of this fever is the fever usually rises in the afternoon up to the first and second week.) In the third week of typhoid fever a number of complications can occur: Intestinal hemorrhage due to bleeding in congested Peyer's patches; this can be very serious but is usually non-fatal. Intestinal perforation in distal ileum: this is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicaemia or diffuse peritonitis sets in. Encephalitis Metastatic abscesses, cholecystitis, endocarditis and osteitis

The fever is still very high and oscillates very little over 24 hours. Dehydration ensues and the patient is delirious (typhoid state). By the end of third week the fever has started reducing (defervescence). This carries on into the fourth and final week. Other symptoms Abdominal tenderness Agitation

Bloody stools Chills Confusion Difficulty paying attention Delirium Fluctuating mood Hallucinations Severe fatigue, weakness , nosebleeds

Exams and tests A complete blood count will show a high number of white blood cells A blood culture during the first week of the fever can show s. typhi bacteria Other tests include stool culture Elisa Platelet count

Treatment Fluids and electrolytes may be given through a vein. Antibiotics such as cyprofloxacin , cloramfenicol.

Oral rehydration therapy (ORT) is a simple treatment for dehydration associated with diarrhea, particularly gastroenteritis, such as that caused by cholera or rotavirus. ORT consists of a solution of salts and sugars which is taken by mouth. It is used around the world, but is most important in the developing world, where it saves millions of children a year from death due to diarrheathe second leading cause of death in children under five.[1] In common usage, an antibiotic (from the Ancient Greek: anti, "against", and bios, "life") is a substance or compound that kills, or inhibits the growth of bacteria. Antibiotics belong to the broader group of antimicrobial compounds, used to treat infections caused by microorganisms, including fungus and protozoa. The term "antibiotic" was coined by Selman Waksman in 1942 to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution.[2] This original definition excluded naturally occurring substances that kill bacteria but are not produced by microorganisms (such as gastric juice and hydrogen

peroxide) and also excluded synthetic antibacterial compounds such as the sulfonamides. Many antibiotics are relatively small molecules with a molecular weight less than 2000 .With advances in medicinal chemistry, most antibiotics are now semisyntheticmodified chemically from original compounds found in nature,[3] as is the case with beta-lactams (which include the penicillins, produced by fungus in the genus Penicillium, the cephalosporins, and the carbapenems). Some antibiotics are still produced and isolated from living organisms, such as the aminoglycosides, and others have been created through purely synthetic means: the sulfonamides, the quinolones, and the oxazolidinones. In addition to this origin-based classification into natural, semisynthetic, and synthetic, antibiotics may be divided into two broad groups according to their effect on microorganisms: those that kill bacteria are bactericidal agents, while those that only impair bacterial growth are known as bacteriostatic agents. Amoxicillin (INN), formerly amoxycillin (BAN), abbreviated AMOX, is a moderate-spectrum, bacteriolytic, -lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other -lactam antibiotics. It is also a treatment for cystic acne. [1] Amoxicillin is susceptible to degradation by -lactamase-producing bacteria, and so may be given with clavulanic acid to decrease its susceptibility. Amoxicillin acts by inhibiting the synthesis of bacterial cell wall. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell walls of both Gram-positive and Gram-negative bacteria. Amoxicillin in trihydrate form is available as capsules, chewable and dispersable tablets plus syrup and pediatric suspension for oral use, and as the sodium salt for intravenous administration. It is one of the most common antibiotics prescribed for children, and the liquid forms are helpful where the patient might find it difficult to take tablets or capsules. It has three ionizable groups. A once daily dosing form (Moxatag) was approved by the American FDA in January 2008. Side effects are as those for other beta-lactam antibiotics. Side effects include nausea, vomiting, irritability, volatile mood swings, disorientation, aggressiveness and easy fatigue. Loose bowel movements (diarrhea) also may occur. The onset of an allergic reaction to amoxicillin can be very sudden and intense - emergency medical attention must be sought as quickly as possible. The initial onset of such a reaction often starts with a change in mental state; skin rash with intense itching (often beginning in

fingertips and around groin area and rapidly spreading) and sensations of fever, nausea and vomiting. Any other symptoms that seem even remotely suspicious must be taken very seriously. Somewhere between 3% to 10% of children taking amoxicillin (or ampicillin) show a latedeveloping (>72 hours after beginning medication and having never taken penicillin-like medication previously) possibly itchy rash, which is sometimes referred to as the "amoxicillin rash." The rash can also occur in adults. The rash is described as maculopapular or morbilliform (measles-like; therefore, in medical literature, "amoxicillin-induced morbilliform rash"). It starts on the trunk and can spread from there. This rash is unlikely to be a true allergic reaction, and is not a contra-indication for future amoxicillin usage, nor should current regimen necessarily be stopped. However, as mentioned above, this common amoxicillin rash and a dangerous allergic reaction cannot easily be distinguished by inexperienced persons, and therefore a health professional should be consulted if a rash develops. (Pichichero, 2005; Schmitt 2005). Also, reliability should not be entrusted completely into the first opinion. To determine for sure the category of the rash, at least two different doctors should be consulted. A non-allergic amoxicillin rash may also be an indicator of infectious mononucleosis. Some studies indicate that approximately 80-90% of patients with acute Epstein Barr virus infection treated with amoxicillin or ampicillin develop such a rash. Amoxicillin is one of the semi-synthetic penicillins discovered by Beecham scientists. The patent for amoxicillin has expired, thus amoxicillin is marketed under many trade names including: Actimoxi, Alphamox,Amocla, AMK, Amoksibos, Amoxiclav Sandoz, Amoxidal, Amoxil, Amoxin, Amoksiklav, Amoxibiotic, Amoxicilina, Apo-Amoxi, Augmentin, Bactox, Betalaktam, Cilamox, Curam, Dedoxil, Dispermox, Duomox, E-Mox (250mg and 500 mg), Enhancin, Gimalxina, Geramox, Hiconcil, Isimoxin, Klavox, Lamoxy, Moxatag, Moxilen, Moxypen, Moxyvit, Nobactam, Novamoxin, Ospamox, Panklav, Pamoxicillin, Panamox, Polymox, Samthongcillin, Clamoxyl, Senox, Sinacilin, Trimox, Tolodina, Wymox, Yucla, Zerrsox and Zimox. Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company, Beecham,

penicillin therapies had only been effective against Gram-positive organisms such as Staphylococci and Streptococci. Ampicillin (originally branded as 'Penbritin') also demonstrated activity against Gram-negative organisms such as H. influenzae, coliforms and Proteus spp. Ampicillin was the first of a number of so-called broad spectrum penicillins subsequently introduced by Beecham. Ampicillin is part of the aminopenicillin family and is roughly equivalent to its successor, amoxicillin in terms of spectrum and level of activity. It can sometimes result in reactions that range in severity from a non-in allergic rash (in the case of patients that may unwitting have mononucleosis) to potentially lethal allergic reactions such as anaphylaxis. However, as with other penicillin drugs, it is relatively nontoxic and adverse effects of a serious nature are encountered only infrequently. Mechanism of action Belonging to the penicillin group of beta-lactam antibiotics, ampicillin is able to penetrate Gram-positive and some Gram-negative bacteria. It differs from penicillin only by the presence of an amino group. That amino group helps the drug penetrate the outer membrane of gram-negative bacteria. Ampicillin acts as a competitive inhibitor of the enzyme transpeptidase, which is needed by bacteria to make their cell walls. It inhibits the third and final stage of bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis. Effects on chloroplasts division Ampicillin, like other -lactam antibiotics, not only blocks the division of bacteria, but also the division of chloroplasts of the Glaucophytes (called cyanelles) and chloroplasts of the moss Physcomitrella patens, a bryophyte. In contrast, it has no effect on the plastids of the highly developed vascular plant Lycopersicon esculentum L. Application Ampicillin is closely related to amoxicillin, another type of penicillin, and both are used to treat urinary tract infections, otitis media, uncomplicated community-acquired pneumonia, Haemophilus influenzae, salmonellosis and Listeria meningitis. It is used with flucloxacillin in the combination antibiotic co-fluampicil for empiric treatment of cellulitis; providing cover against Group A streptococcal infection whilst the flucloxacillin acts against the

Staphylococcus aureus bacterium. Of concern is the number of bacteria that become resistant to Ampicillin necessitating combination therapy or use of other antibiotics. All Pseudomonas and most strains of Klebsiella and Aerobacter are considered resistant. Use in research Ampicillin is often used as a selective agent in molecular biology to select for and to confirm the uptake of genes (e.g., of plasmids) by bacteria (e.g., E. coli). A gene that is to be inserted into a bacterium is coupled to a gene coding for an ampicillin resistance (in E. coli, usually the bla (TEM-1) gene, coding for -lactamase). The treated bacteria are then grown in a medium containing ampicillin (typically 50100 mg/L). Only the bacteria that successfully take up the desired genes become ampicillin resistant, and therefore contain the other desired gene as well. It can be used with Cloaxicillin as well. As a powder, ampicillin is white with slight yellow cast and is soluble in water (150 mg/ml). Chloramphenicol (INN) is a bacteriostatic antimicrobial. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines. Chloramphenicol is effective against a wide variety of Gram-positive and Gram-negative bacteria, including most anaerobic organisms. Due to resistance and safety concerns, it is no longer a first-line agent for any indication in developed nations, although it is sometimes used topically for eye infections; nevertheless, the global problem of advancing bacterial resistance to newer drugs has led to renewed interest in its use. In low-income countries, chloramphenicol is still widely used because it is exceedingly inexpensive and readily available. The most serious adverse effect associated with chloramphenicol treatment is bone marrow toxicity, which may occur in two distinct forms: bone marrow suppression, which is a direct toxic effect of the drug and is usually reversible, and aplastic anemia, which is idiosyncratic (rare, unpredictable, and unrelated to dose) and generally fatal. Spectrum of activity Because it functions by inhibiting bacterial protein synthesis, chloramphenicol has a very broad spectrum of activity: it is active against Gram-positive bacteria (including most strains

of MRSA), Gram-negative bacteria and anaerobes. It is not active against Pseudomonas aeruginosa, Chlamydiae, or Enterobacter species. It has some activity against Burkholderia pseudomallei, but is no longer routinely used to treat infections caused by this organism (it has been superseded by ceftazidime and meropenem). In the West, chloramphenicol is mostly restricted to topical uses because of the worries about the risk of aplastic anaemia. Therapeutic uses The original indication of chloramphenicol was in the treatment of typhoid, but the now almost universal presence of multi-drug resistant Salmonella typhi has meant that it is seldom used for this indication except when the organism is known to be sensitive. Chloramphenicol may be used as a second-line agent in the treatment of tetracycline-resistant cholera. Because of its excellent CSF penetration (far superior to any of the cephalosporins), chloramphenicol remains the first choice treatment for staphylococcal brain abscesses. It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known. Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe penicillin or cephalosporin allergy and GPs are recommended to carry intravenous chloramphenicol in their bag. In low income countries, the WHO recommend that oily chloramphenicol be used first-line to treat meningitis. Chloramphenicol has been used in the U.S. in the initial empirical treatment of children with fever and a petechial rash, when the differential diagnosis includes both Neisseria meningitidis septicaemia as well as Rocky Mountain spotted fever, pending the results of diagnostic investigations. Chloramphenicol is also effective against Enterococcus faecium, which has led to it being considered for treatment of vancomycin-resistant enterococcus. Although unpublished, recent research suggests that chloramphenicol could also be applied to frogs to prevent their widespread destruction from fungal infections.

Chloramphenicol has recently been discovered to be a life saving cure for chytridiomycosis in amphibians. Chytridiomycosis is a fungal disease that has been blamed for the extinction of one-third of the 120 frog species lost since 1980.

Complications Intestinal hemorrhage Intestinal perforation Kidney failure Peritonitis

Diagnosis Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal test (demonstration of salmonella antibodies against antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of Widal test and cultures of the blood and stool. The term "enteric fever" is a collective term that refers to typhoid and paratyphoid. Resistance Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and streptomycin is now common, and these agents have not been used as first line treatment for almost 20 years. Typhoid that is resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid). Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are therefore moving away from using ciprofloxacin as first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand or Vietnam. For these patients, the recommended first line treatment is ceftriaxone. It has also been suggested that Azithromycin is better at treating typhoid in resistant

populations than both fluoroquinolone drugs and ceftriaxone. Azithromycin significantly reduces relapse rates compared with ceftriaxone. There is a separate problem with laboratory testing for reduced susceptibility to ciprofloxacin: current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to ciprofloxacin (MIC 0.1251.0 mg/l) would not be picked up by this method. It is not certain how this problem can be solved, because most laboratories around the world (including the West) are dependent on disc testing and cannot test for MICs.

Prevention

Sanitation and hygiene are the critical measures that can be taken to prevent typhoid. Typhoid does not affect animals and therefore transmission is only from human to human. Typhoid can only spread in environments where human feces or urine are able to come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to preventing typhoid. There are two vaccines currently recommended by the World Health Organization for the prevention of typhoid: these are the live, oral Ty21a vaccine (sold as Vivotif Berna) and the injectable Typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). Both are between 50 to 80% protective and are recommended for travelers to areas where typhoid is endemic. There exists an older killed whole-cell vaccine that is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use, because it has a higher rate of side effects (mainly pain and inflammation at the site of the injection). The World Health Organization (WHO) is a specialized agency of the United Nations (UN) that acts as a coordinating authority on international public health. Established on 7 April 1948, and headquartered in Geneva, Switzerland, the agency inherited the mandate and

resources of its predecessor, the Health Organization, which had been an agency of the League of Nations. The Vi capsular polysaccharide vaccine (or ViCPS) is one of two vaccines recommended by the World Health Organisation for the prevention of typhoid (the other is Ty21a). It was first licensed in the US in 1994 and is made from the purified Vi capsular polysaccharide from the Ty2 Salmonella Typhi strain. The vaccine is only 60 to 80% protective and the traveller should still be warned to take all usual precautions (careful hygiene, hand washing and food preparation). Indications The vaccine may be used in endemic areas in order to prevent typhoid. It is also commonly used to protect people who are traveling to parts of the world where typhoid is endemic. Dosing The vaccine is injected either under the skin or into a muscle at least seven days before traveling to the typhoid-affected area (the CDC recommend 14 days). The vaccine is not effective in children under the age of two; children under the age of two would normally have all their food regulated by their parents and should therefore be expected to be at low risk of exposure to typhoid. To maintain immunity, the vaccine should be repeated every three years.

Efficacy and duration of protection In a randomised controlled trial of more than 11,000 children in South Africa, the vaccine was 64% efficacious after 21 months and 55% efficacious 3 years after vaccination; more than half the children still had protective levels of antibodies 10 years after vaccination. A randomised controlled trial of 6900 subjects in Nepal showed that the vaccine conferred 72% protection after 17 months. A randomised controlled trial of 131,000 subjects in southwestern China showed the vaccine to be 69% protective over a 19-month observation period. Follow

up of this population in the third year after vaccination showed evidence of protection in approximately 50% of the vaccinees.

Transmission Flying insects feeding on feces may occasionally transfer the bacteria through poor hygiene habits and public sanitation conditions. Public education campaigns encouraging people to wash their hands after defecating and before handling food are an important component in controlling spread of the disease. According to statistics from the United States Center for Disease Control, the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the U.S. A person may become an asymptomatic carrier of typhoid fever, suffering no symptoms, but capable of infecting others. According to the Centers for Disease Control approximately 5% of people who contract typhoid continue to carry the disease after they recover. The most famous asymptomatic carrier was Mary Mallon (commonly known as "Typhoid Mary"), a young cook who was responsible for infecting at least 53 people with typhoid, three of whom died from the disease. Mallon was the first apparently perfectly healthy person known to be responsible for an "epidemic".

Death rates for typhoid fever in the U.S. 19061960 Many carriers of typhoid were locked into an isolation ward never to be released in order to prevent further typhoid cases. These people are often deteriorated mentally, driven mad by the conditions they lived in. An asymptomatic carrier (healthy carrier or just carrier) is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others. A number of animal species can also act as carriers of human disease.

In humans, the HIV virus goes through a long latency period, during which the host is asymptomatic. Many carriers are infected with persistent viruses such as EBV and Cytomegalovirus that only rarely progress to a disease state. Mary Mallon, known as "Typhoid Mary", was an asymptomatic carrier of typhoid fever. She worked as a cook for several families in New York City at the beginning of the twentieth century. Several cases of typhoid fever in members of those families were traced to her by the Health Department. It appeared that she "carried" the infectious agent without becoming sick. There was at the time no way of eradicating the disease, and an attempt was made to restrict her from continuing to work as a cook to avoid spreading it to others. It is also believed that Edgar Allan Poe was a carrier of Tuberculosis, because most of his family died of the disease, though he exhibited no symptoms himself. The Centers for Disease Control and Prevention (or CDC) is a United States federal agency under the Department of Health and Human Services based in Atlanta, Georgia. It works to protect public health and safety by providing information to enhance health decisions, and it promotes health through partnerships with state health departments and other organizations. The CDC focuses national attention on developing and applying disease prevention and control (especially infectious diseases), environmental health, occupational safety and health, health promotion, prevention and education activities designed to improve the health of the people of the United States. Chlorination is the process of adding the element chlorine to water as a method of water purification to make it fit for human consumption as drinking water. Water which has been treated with chlorine is effective in preventing the spread of water born disease. The chlorination of public drinking supplies was originally met with resistance, as people were concerned about the health effects of the practice. The use of chlorine has greatly reduced the prevalence of waterborne disease as it is effective against almost all bacteria and viruses, as well as amoeba. Chlorination is also used to sanitize the water in swimming pools and as a disinfection stage in sewage treatment.

Epidemiology With an estimated 1633 million cases of annually resulting in 500,000 to 600,000 deaths in endemic areas, the World Health Organization identifies typhoid as a serious public health problem. Its incidence is highest in children and young adults between 5 and 19 years old. The World Health Organization (WHO) is a specialized agency of the United Nations (UN) that acts as a coordinating authority on international public health. Established on 7 April 1948, and headquartered in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health Organization, which had been an agency of the League of Nations. Constitution and history The WHO's constitution states that its objective "is the attainment by all peoples of the highest possible level of health". Its major task is to combat disease, especially key infectious diseases, and to promote the general health of the people of the world. The World Health Organization (WHO) is one of the original agencies of the United Nations, its constitution formally coming into force on the first World Health Day, (7 April 1948), when it was ratified by the 26th member state. Prior to its operations, as well as the remaining activities of the League of Nations Health Organization, were under the control of an Interim Commission following an International Health Conference in the summer of 1946. The transfer was authorized by a Resolution of the General Assembly. The epidemiological service of the French Office International d'Hygine Publique was incorporated into the Interim Commission of the World Health Organization on January 1st, 1947. Activities Apart from coordinating international efforts to monitor outbreaks of infectious diseases, such as SARS, malaria, swine flu, and AIDS, the WHO also sponsors programs to prevent and treat such diseases. The WHO supports the development and distribution of safe and effective vaccines, pharmaceutical diagnostics, and drugs. After over 2 decades of fighting smallpox, the WHO declared in 1980 that the disease had been eradicated the first disease in history to be eliminated by human effort.

The WHO aims to eradicate polio within the next few years. The organization has already endorsed the world's first official HIV/AIDS Toolkit for Zimbabwe (from 3 October 2006), making it an international standard. In addition to its work in eradicating disease, the WHO also carries out various health-related campaigns for example, to boost the consumption of fruits and vegetables worldwide and to discourage tobacco use. Experts met at the WHO headquarters in Geneva in February 2007, and reported that their work on pandemic influenza vaccine development had achieved encouraging progress. More than 40 clinical trials have been completed or are ongoing. Most have focused on healthy adults. Some companies, after completing safety analysis in adults, have initiated clinical trials in the elderly and in children. All vaccines so far appear to be safe and well-tolerated in all age groups tested. The WHO also promotes the development of capacities in Member States to use and produce research that addresses national needs, by bolstering national health research systems and promoting knowledge translation platforms. WHO and its regional offices are working to develop regional policies on research for health -the first one being the Regional Office for the Americas PAHO/AMRO that had its Policy on Research for Health approved in September 2009. WHO also conducts some research; for example, whether the electromagnetic field surrounding cell phones has an impact on health. Some of this work can be controversial, as illustrated by the April, 2003, joint WHO/FAO report, which recommended that sugar should form no more than 10% of a healthy diet.

Heterozygous advantage It is thought that cystic fibrosis may have risen to its present levels (1 in 1600 in UK) due to the heterozygous advantage that it confers against typhoid fever. The CFTR protein is present in both the lungs and the intestinal epithelium, and the mutant cystic fibrosis form of the CFTR protein prevents entry of the typhoid bacterium into the body through the intestinal epithelium.

Cystic fibrosis (also known as CF or mucoviscidosis) is a common hereditary disease which affects the entire body, causing progressive disability and often, early death. The name cystic fibrosis refers to the characteristic: scarring (fibrosis) and cyst hairy within the pancreas, first recognized in the 1930s. Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body. CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). This gene helps create sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally. Therefore, CF is considered an autosomal recessive disease. CF is most common among Caucasians; one in 25 people of European descent carry one gene for CF. Approximately 30,000 Americans have CF, making it one of the most common lifeshortening inherited diseases. Individuals with cystic fibrosis can be diagnosed prior to birth by genetic testing or in early childhood by a sweat test. There is no cure for CF, and most individuals with cystic fibrosis die young many in their 20s and 30s from lung failure. Ultimately, lung transplantation is often necessary as CF worsens.

Signs and symptoms

The hallmarks of cystic fibrosis are salty tasting skin, normal appetite but poor growth and poor weight gain, excess mucus production, frequent chest infections and coughing/shortness of breath. Males can be infertile due to congenital absence of the vas deferens. CF symptoms often appear in infancy and childhood, with meconium ileus being a typical finding in newborn babies. As the child grows, he or she will have to exercise to release mucus stuck to the alveoli. Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multifactorial and include

chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness. Heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. This selection favoring the heterozygote is one of the mechanisms that maintain polymorphism and help to explain some kinds of genetic variability. There are several cases in which the heterozygote conveys certain advantages and some disadvantages while both versions of homozygotes are only at disadvantages. A well-established case of heterozygote advantage is that of the gene involved in sickle cell anaemia. Often, the advantages and disadvantages conveyed are rather complicated, because more than one gene may influence a given trait. Major genes almost always have multiple effects (pleiotropism), which can simultaneously convey separate advantageous traits and disadvantageous traits upon the same organism. In this instance, the state of the organism's environment will provide selection, with a net effect either favoring or working in opposition to the gene, until an environmentally-determined equilibrium is reached. Heterozygote advantage in theory When two populations of any sexual organism are separated and kept isolated from each other, the frequencies of deleterious mutations in the two populations will differ over time, by genetic drift. It is highly unlikely, however, that the same deleterious mutations will be prevalent in both populations after a long period of separation. Since loss-of-function mutations tend to be recessive (given that dominant mutations of this type generally prevent the organism from reproducing and thereby passing the gene on to the next generation), the result of any cross between the two populations will be fitter than the parent.

Experimental confirmation Cases of heterozygote advantage have been demonstrated in several organisms, including humans. The first experimental confirmation of heterozygote advantage was with Drosophila melanogaster, a fruit fly that has been a model organism for genetic research. In a classic

study, Kalmus demonstrated how polymorphism can persist in a population through heterozygote advantage. Kalmus discovered a mutant allele of an autosomal gene that expressed ebony body color and other selective advantages in a pattern that was autosomal dominant. The same allele also conveyed harsh disadvantages in a pattern that was completely recessive. When a fly inherited two copies of the mutation (homozygous), it expressed the dark ebony color, but it was also particularly weak, and was placed at a harsh reproductive disadvantage. If weakness were the only effect of the mutant allele, so that it conveyed only disadvantages, natural selection would weed out this version of the gene until it became extinct from the population. However, the same mutation also conveyed advantages, providing improved viability for individuals that were heterozygotes. The heterozygote expressed none of the disadvantages of homozygotes, yet gained improved viability. The homozygote wild type was perfectly healthy, but did not possess the improved viability of the heterozygote, and was thus at a disadvantage compared to the heterozygote in survival and reproduction. This mutation, which at first glance appeared to be harmful, conferred enough of an advantage to heterozygotes to make it beneficial, so that it remained at dynamic equilibrium in the gene pool. Kalmus introduced flies with the ebony mutation to a wild-type population. The ebony allele persisted through many generations of flies in the study, at genotype frequencies that varied from 8% to 30%. In experimental populations, the ebony allele was more prevalent and therefore advantageous when flies were raised at low, dry temperatures, but less in warm, moist environments. Heterozygote advantage in human genetics Sickle-cell anemia (SCA) is a genetic disorder that is caused by the presence of two incompletely recessive alleles. When a sufferer's red blood cells are exposed to low-oxygen conditions, the cells lose their healthy round shape and become sickle-shaped. This deformation of the cells can cause them to become lodged in capillaries, depriving other parts of the body of precious oxygen. When untreated, a person with SCA may suffer from painful periodic bouts, often causing damage to internal organs, strokes, or anemia. Typically the disease results in premature death.

Because the genetic disorder is incompletely recessive, a person with only one SCA allele and one unaffected allele will have a "mixed" phenotype. The sufferer will not experience the ill effects of the disease, yet will still possess a sickle cell trait, whereby some of the red blood cells undergo benign effects of SCA, but nothing severe enough to be harmful. Those afflicted with sickle-cell trait are also known as carriers. If two carriers have a child, there is a twenty-five percent chance that their child will have SCA, a fifty percent chance that their child will be a carrier, and a twenty-five percent chance that the child will neither have SCA nor be a carrier. Where the presence of the SCA allele confers only negative traits, we would expect its allele frequency to decrease generation after generation, until its presence were completely eliminated by selection and by chance. However, there is convincing evidence indicating that, in areas with persistent malaria outbreaks, individuals with the heterozygous state have a distinct advantage (and this is why individuals with heterozygous alleles are far more common in these areas). Those with the benign sickle trait possess a resistance to malarial infection. The pathogen that causes the disease spends part of its cycle in the red blood cells, and those with sickle cells effectively stop the pathogen in its tracks, until the immune system destroys the foreign bodies. These individuals have a great immunity to infection and have a greater chance of surviving outbreaks. However, those with two alleles for SCA may survive malaria but will typically die from their genetic disease unless they have access to advanced medical care. Those of the homozygous normal or wild-type case will have a greater chance of passing on their genes successfully, in that there is no chance of their offspring's suffering from SCA; yet, they are more susceptible to dying from malarial infection before they have a chance to pass on their genes. This resistance to infection is the main reason that we still see the SCA allele and SCA disease. It is found in greatest frequency in populations where malaria was and often still is a serious problem. Approximately one in 13 African-Americans is a carrier, as their recent ancestry is from malaria-stricken regions. Other populations in Africa, India, the Mediterranean and the Middle East have higher allele frequencies as well. As effective antimalarial treatment becomes increasingly available to malaria-stricken populations, we can expect the allele frequency for SCA to decrease, so long as SCA treatments are unavailable or only partially effective. If effective Sickle-cell anemia treatments become available to the same degree, we can expect allele frequencies to remain at their present levels in these

populations. In this context, 'treatment effectiveness' refers to the reproductive fitness that it grants, rather than the degree of suffering alleviation. Heterozygote advantage and cystic fibrosis Cystic fibrosis, or CF, is an autosomal recessive hereditary disease of the lungs, sweat glands and digestive system. The disorder is caused by the malfunction of the CFTR protein, which controls inter-membrane transport of chloride ions, which is vital to maintaining equilibrium of water in the body. The malfunctioning protein causes viscous mucus to form in the lungs and intestinal tract. Before modern times, children born with CF would have a life expectancy of only a few years, but modern medicine has made it possible for these people to live into adulthood. However, even in these individuals, male and female, CF typically causes sterility. It is the most common genetic disease among people of European descent. The presence of a single CF mutation may influence survivorship of people affected by diseases involving loss of body fluid, typically due to diarrhea. The most common of these maladies is cholera, which throughout history has killed many Europeans. Those with cholera would often die of dehydration due to intestinal water losses. A mouse model of CF was used to study resistance to cholera, and the results were published in Science in 1994 (Gabriel, et al.). The heterozygote (carrier) mouse had less secretory diarrhea than normal, non-carrier mice. Thus it appeared for a time that resistance to cholera explained the selective advantage to being a carrier for CF and why the carrier state was so frequent. This theory has been called into question. Hogenauer, has challenged this popular theory with a human study. Prior data were based on solely on mouse experiments. These authors found that the heterozygote state was indistinguishable from the non-carrier state. Another theory for the prevalence of the CF mutation is that it provides resistance to tuberculosis. Tuberculosis was responsible for 20% of all European deaths between 1600 and 1900, so even partial protection against the disease could account for the current gene frequency. As of 2007, the selective pressure for the high gene prevalence of CF mutations is still uncertain. Approximately 1 in 25 persons of European descent is a carrier of the disease, and 1 in 2500 to 3000 children born is affected by cystic fibrosis.

History Around 430424 B.C., a devastating plague, which some believe to have been typhoid fever, killed one third of the population of Athens, including their leader Pericles. The balance of power shifted from Athens to Sparta, ending the Golden Age of Pericles that had marked Athenian dominance in the ancient world. Ancient historian Thucydides also contracted the disease, but he survived to write about the plague. His writings are the primary source on this outbreak. The cause of the plague has long been disputed, with modern academics and medical scientists considering epidemic typhus the most likely cause. However, a 2006 study detected DNA sequences similar to those of the bacterium responsible for typhoid fever.The disease is most commonly transmitted through poor hygiene habits and public sanitation conditions; during the period in question, the whole population of Attica was besieged and lived in tents. Mary Mallon ("Typhoid Mary") in a hospital bed. She was forcibly quarantined as a carrier of typhoid fever in 1907 for three years and then again from 1915 until her death in 1938. In the late 19th century, typhoid fever mortality rate in Chicago averaged 65 per 100,000 people a year. The worst year was 1891, when the typhoid death rate was 174 per 100,000 people. The most notorious carrier of typhoid feverbut by no means the most destructive was Mary Mallon, also known as Typhoid Mary. In 1907, she became the first American carrier to be identified and traced. She was a cook in New York. She is closely associated with fifty-three cases and three deaths. Public health authorities told Mary to give up working as a cook or have her gall bladder removed. Mary quit her job but returned later under a false name. She was detained and quarantined after another typhoid outbreak. She died of pneumonia after 26 years in quarantine. In 1897, Almroth Edward Wright developed an effective vaccine. In 1909, Frederick F. Russell, a U.S. Army physician, developed an American typhoid vaccine and two years later his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military.

Most developed countries saw declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. Antibiotics were introduced in clinical practice in 1942, greatly reducing mortality. Today, incidence of typhoid fever in developed countries is around 5 cases per 1,000,000 people per year. An outbreak in the Democratic Republic of Congo in 200405 recorded more than 42,000 cases and 214 deaths. Typhoid fever was also known as suette milliaire in nineteenth-century France.