Typhoid fever

Causes
Typhoid fever appears to have afflicted human beings for millennia, but the cause of the illness — a virulent and invasive bacterium called Salmonella typhi — wasn't discovered until the late 19th century. A different pathogen, Salmonella paratyphi, causes paratyphoid fever. Although they're related, these aren't the same as the bacteria responsible for salmonellosis, another serious intestinal infection.
Fecal-oral routeThe bacteria that cause typhoid and paratyphoid fever both spread through contaminated food or water and occasionally through direct contact with someone who is already infected. In developing nations, where typhoid and paratyphoid are endemic, most cases result from contaminated drinking water and poor sanitation. The majority of people in industrialized countries pick up the typhoid bacteria while traveling and spread it to others through the fecal-oral route.
This means that S. typhi and S. paratyphi are passed in the feces and sometimes in the urine of infected people. You can contract the infection if you eat food handled by someone with typhoid fever who hasn't washed carefully after using the bathroom. You can also become infected by drinking water contaminated with the bacteria.
Typhoid carriersEven after treatment with antibiotics, a small number of people who recover from typhoid fever continue to harbor the bacteria in their intestinal tract or gallbladder, often for years. These people, called chronic carriers, shed the bacteria in their feces and are capable of infecting others, although they no longer have signs or symptoms of the disease themselves.
Risk factors
Typhoid fever remains a serious threat in the developing world, where it affects more than 12 million people annually. The disease is endemic in India, Southeast Asia, Africa, South America and in certain regions of the former Soviet Union, especially Tajikistan and Uzbekistan.
Worldwide, children are at greatest risk of contracting the disease, although they generally have milder symptoms and fewer complications than adults do.
If you live in a country where typhoid and paratyphoid fevers are rare, you're at increased risk if you:
Work in or travel to areas where typhoid fever is endemic
Have close contact with someone who is infected or has recently been infected with typhoid fever
Have an immune system weakened by medications such as corticosteroids or diseases such as HIV/AIDS
Drink water contaminated by sewage that contains S. typhi
sks of complications and death increase. What's more, failure to treat an infection properly leads to longer periods in which a person is contagious and able to spread the resistant strain to others. And because bacteria mutate much more quickly than researchers can develop new antibiotics, the possibility exists that one day highly lethal strains of resistant bacteria will evolve and doctors will have no effective way to treat them.
In recent years, S. typhi has proved resistant to trimethoprim-sulfamethoxazole, ampicillin and tetracycline, in addition to chloramphenicol. In some parts of the world, such as Vietnam and Tajikistan, resistance has begun to extend even to new antibiotics such as ciprofloxacin (Cipro).
In the United States, most doctors now prescribe ciprofloxacin for adults other than pregnant women. Women who are pregnant and children most often receive ceftriaxone (Rocephin) injections. Still, all of these drugs can cause side effects and long-term use can lead to the development of antibiotic-resistant strains of bacteria.
Other treatment steps aimed at managing symptoms include:
Drinking fluids. This helps prevent the dehydration that results from a prolonged fever and diarrhea. If you're severely dehydrated, you may need to receive fluids through a vein in your arm (intravenously).
Eating a healthy diet. Nonbulky, high-calorie meals can help replace the nutrients you lose when you're sick.


Prevention
In many developing nations, the public health goals that can help prevent and control typhoid — safe drinking water, improved sanitation and adequate medical care — may be difficult to achieve. For that reason, some experts believe that vaccinating high-risk populations is the best way to control typhoid fever.
Two vaccines are currently in use — one is injected in a single dose, and the other is administered orally over a period of days. Neither is 100 percent effective, and both require repeat vaccinations. No vaccine exists for paratyphoid fever.
If you're traveling to an area where typhoid fever is endemic, consider being vaccinated. But because the vaccine won't provide complete protection, be sure to follow these guidelines as well:
Wash your hands. Frequent hand washing is the best way to control infection. Wash your hands thoroughly with hot, soapy water, especially before eating or preparing food and after using the toilet. Carry an alcohol-based hand rub for times when water isn't available.
Avoid untreated water. Contaminated drinking water is a particular problem in areas where typhoid is endemic. For that reason, drink only bottled water or canned or bottled carbonated beverages, wine and beer. Carbonated bottled water is safer than still water is. Wipe the outside of all bottles and cans before you open them. Ask for drinks without ice. Use bottled water to brush your teeth, and try not to swallow water in the shower.
Avoid raw fruits and vegetables. Because raw produce may have been washed in unsafe water, avoid fruits and vegetables that you can't peel, especially lettuce. To be absolutely safe, you may want to avoid raw foods entirely.
Choose hot foods. Avoid food that's stored or served at room temperature. Steaming hot foods are best. And although there's no guarantee that meals served at the finest restaurants are safe, it's best to avoid food from street vendors — it's more likely to be contaminated.
To prevent infecting othersIf you're recovering from typhoid or paratyphoid, these measures can help keep others safe:
Wash your hands often. This is the single most important thing you can do to keep from spreading the infection to others. Use plenty of hot, soapy water and scrub thoroughly for at least 30 seconds, especially before eating and after using the toilet.
Clean household items daily. Clean toilets, door handles, telephone receivers and taps at least once a day with a household cleaner and paper towels or disposable cloths.
Avoid handling food. Avoid preparing food for others until your doctor says you're no longer contagious. If you work in the food service industry or a health care facility, you won't be allowed to return to work until tests show that you're no longer shedding typhoid bacteria.
Keep personal items separate. Set aside towels, bed linen and utensils for your own use and wash them frequently in hot, soapy water. Heavily soiled items can be soaked first in disinfectant.


Screening and diagnosis
Your doctor is likely to suspect typhoid or paratyphoid fever based on your symptoms and your medical and travel history. But the diagnosis is usually confirmed by identifying S. typhi or S. paratyphi in a culture of your blood or other body fluid or tissue.
For the culture, a small sample of your blood, stool, urine or bone marrow is placed on a special medium that encourages the growth of bacteria. In 48 to 72 hours, the culture is checked under a microscope for the presence of typhoid bacteria. A bone marrow culture often is the most sensitive test for S. typhi.
Your doctor may recommend other tests to help diagnose typhoid fever, such as:
Enzyme-linked immunosorbent assay (ELISA). This blood test looks for an antigen that's specific to typhoid bacteria. An antigen is any substance, such as a virus, bacterium, toxin or foreign protein, that triggers an immune system response in your body.
Fluorescent antibody test. This test checks for antibodies to S. typhi. Antibodies are proteins produced by your immune system in response to harmful substances (antigens). Each antibody is unique and defends your body against a single antigen.

AIDS

Definition of epidemiology:
The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations.
Causes and pathogenesis of AIDS in Africa:In Africa, AIDS is caused by severe starvation. An individual suffering from severe starvation usually loses up to 90% of his or her thymus size along with the capacity of the functions of their immune system. The release of endogenous cortisol plays a major role in the pathogenesis of AIDS in people suffering from malnutrition. In starvation, cortisol, a hormone released from the adrenal glands, is required for the conversion of fat and protein to glucose in the liver. Glucose is used as energy by the heart, brain, and other organs and without the endogenous cortisol, human beings are unable to survive very long without food. Any person who suffers from severe starvation has AIDS regardless if the person is HIV-positive or HIV-negative. Fortunately, AIDS in people who are suffering from severe starvation is reversible with proper nutrition and supportive medical care as shown by the following studies.

In a study involving 110 malnourished children, the thymic area was found to be 20% of the size in healthy children. The size of the thymus in these children was increased from 20% of normal to 107% of normal following 9 weeks of proper feeding ( 12).
The reversal of the reduction in CD4+T cell count in HIV+ pregnant women following proper feeding was also reported by Fawzi et al. ( 13). Briefly, the influence of diet on T cells counts in peripheral blood of 1,075 HIV-infected pregnant women who had poor nutritional status was studied. The CD4+ T cell counts of the women who received multivitamins increased from 424/µL to 596/µL during six months of proper feeding.
The prevalence of KS, lymphoma, lymphadenitis, and tuberculosis in Africa is similar or even higher than those observed in homosexual men, drug users, and AIDS patients in the United States and Europe ( 1). However, AIDS in Africa occurs almost equally in males and females because starvation affects both sexes equally. For example, Sibanda and Stanczuk reviewed all histopathology reports of lymph node biopsy submitted to the Histopathology unit in Harare, Zimbabwe in the period of January 1988 to June 1990. The most common diseases in the 2,194 lymph node specimens were: non-specific hyperplasia (33%), tuberculous lymphadenitis (27%); metastases (12%), Kaposi's sarcoma (9%); and lymphomas (7%). Kaposi's sarcoma (KS) involving the lymph nodes was reported in 176 (9%). In children, the prevalence of KS was higher in children under 5 years than in 6-15 year bracket. Approximately two thirds (65%) of all patients with KS were aged between 20 and 40 years ( 14).


orating centers, including CDC in the United States, the WHO Collaborating Centre in Paris, and WHO regional offices and ministries of health. Accuracy and completeness of AIDS reporting vary in different areas of the world.
Epidemiologic studies indicate three broad yet distinct geographic patterns of transmission.Pattern I is typical of industrialized countries with large numbers of reported AIDS cases, such as North America, Western Europe, Australia, New Zealand, and parts of Latin America. In these areas, most cases occur among homosexual or bisexual males and urban IV drug users. Heterosexual transmission is responsible for only a small percentage of cases but is increasing.Pattern II is observed in areas of central, eastern, and southern Africa and in some Caribbean countries. In these areas, most cases occur among heterosexuals; the male to female ratio is approximately 1:1 and perinatal transmission is relatively more common than in other areas. IV drug use and homosexual transmission either do not occur or occur at a very low level.Pattern III is found in areas of Eastern Europe, the Middle East, Asia, and most of the Pacific. HIV appears to have been introduced into these areas in the early to mid-1980s, and only small numbers of cases have been reported. Homosexual and heterosexual transmission has only recently been documented. Generally, cases have occurred among persons who have traveled to endemic areas or who have had sexual contact with individuals from endemic areas, such as homosexual men and female prostitutes.

HIV-2

UNAIDS and the WHO estimate that AIDS has killed more than 25 million people since it was first recognized in 1981, making it one of the most destructive epidemics in recorded history. Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS epidemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.^[6]

Globally, between 33.4 and 46 million people currently live with HIV.^[6] In 2005, between 3.4 and 6.2 million people were newly infected and between 2.4 and 3.3 million people with AIDS died, an increase from 2003 and the highest number since 1981.^[6]

Sub-Saharan Africa remains by far the worst affected region, with an estimated 21.6 to 27.4 million people currently living with HIV. Two million [1.5–3.0 million] of them are children younger than 15 years of age. More than 64% of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (76%) of all women living with HIV. In 2005, there were 12.0 million [10.6–13.6 million] AIDS orphans living in sub-Saharan Africa 2005.^[6] South Africa has the largest population of HIV patients in the world, followed by Nigeria.^[120] South & South East Asia are second worst affected with 15%. AIDS accounts for the deaths of 500,000 children in this region. India has an estimated 2.5 million infections (0.02% of population) making it the country with the third highest number of HIV infections in the world. In the 35 African nations with the highest prevalence, average life expectancy is 48.3 years— 6.5 years less than it would be without the disease.^[121]

The latest evaluation report of the World Bank's Operations Evaluation Department assesses the effectiveness of the World Bank's country-level HIV/AIDS assistance, defined as policy dialogue, analytic work, and lending, with the explicit objective of reducing the scope or impact of the AIDS epidemic.^[122] This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank's assistance is for implementation of government programs by government, it provides important insights on how national AIDS programs can be made more effective.

The development of HAART as effective therapy for HIV infection and AIDS has substantially reduced the death rate from this disease in those areas where it is widely available. This has created the misperception that the disease has gone away. In fact, as the life expectancy of persons with AIDS has increased in countries where HAART is widely used, the number of persons living with AIDS has increased substantially. In the United States, the number of persons with AIDS increased from about 35,000 in 1988 to over 220,000 in 1996.^{[citation needed]}

In Africa, the number of MTCT and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival.^{[citation needed]} Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counseling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.

Cholera

Although cholera can be life-threatening, the disease is fairly simple to prevent, in principle, if proper sanitation practices are followed. In the United States and Western Europe, 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 1911. Travelers, however, 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.

• Sickbed: Proper disposal and treatment of the germ infected fecal waste (and all clothing and bedding that come in contact with it) produced by cholera victims is of primary importance.
• 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.
• Sterilization: Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections from spreading. 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. All water used for drinking, washing, or cooking should be sterilized by boiling or chlorination in any area where cholera may be present. 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 can help prevent transmission.

A vaccine is available outside the US, but this prophylactic is short-lived in efficacy and not currently recommended by the CDC.^[8]

[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,^[9][10] 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.^[11]

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.^[12] 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.

Persons infected with cholera have massive diarrhea. This highly-liquid diarrhea is loaded with bacteria that can spread under unsanitary conditions to infect water used by other people. Cholera is transmitted from person to person through ingestion of water contaminated with the cholera bacterium, usually from feces 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 supply. 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 plankton of fresh, brackish, and salt water, attached primarily to copepods in the zooplankton. Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage.^[13] Coastal cholera outbreaks typically follow zooplankton blooms, thus making cholera a zoonotic disease.

[edit] Laboratory diagnosis

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. 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

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. Also in oysters and lobster in some cases. Cholera vibrios produce flat 2-3 mm 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.

[edit] Biochemistry of the V. cholerae bacterium

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.^[14] 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 mucous 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.^[15] 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 choride 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.^[16]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 separately, 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. ^[17] 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." ^[18]

Epidemiology of AIDS- 1

Epidemiologically, the Acquired Immune Deficiency Syndrome, AIDS, is transmitted and distributed in the USA and Europe almost entirely in well­defined subsets of populations engaging in, or subjected to, the effects of behaviours which carry high risks of genital and systemic infections. The persons predominantly affected are those engaging in promiscuous homosexual and bisexual activity, regular use of addictive drugs, and their sexual and recreational partners. In such persons and in subsets of populations with corresponding life­styles, the risk of AIDS increases by orders of magnitude. Because of continuity of risk behaviour and of associated indicator infections; the incidence of AIDS over 3­5 year periods is predictable to within 10% of actual totals of registered cases in the USA and UK. Secondary transmission of AIDS beyond these groups is minimal or, in many locations, absent. There is no indication of appreciable spread by heterosexual transmission to the general population.
The Human Immunodeficiency Virus, HIV, is transmissible to some extent in general populations, and more so among promiscuous persons. It may cause viraemia, lymphadenopathy and latent infection (HIV disease) in anyone. In persons engaging in risk behaviours which themselves alter or suppress immune responses, it can interact with MHC, antibodies to other organisms and to semen, and other allogenic antigens to initiate a programmed death of CD4 lymphocytes and other defensive cells, as in graft­host rejections. This occurs also in haemophiliacs receiving transfusions of blood products, and is more pronounced in persons with reactive HLA haplotypes. The susceptibility of particular subsets of populations to AIDS is thereby largely explained. But these changes occur in the absence of HIV, and so do Kaposi's sarcoma, lymphadenopathies and opportunistic infections which are regarded as main indicators of AIDS. The hypothesis that HIV­I can do all this by itself and thereby cause AIDS is falsifiable on biological as well as epidemiological grounds.
An alternative hypothesis is proposed, linking the incidence of AIDS to the evolution of contemporary risk behaviour in particular communities and locations in the USA, UK and probably in most of Europe. It does not pretend to explain the reported incidence of AIDS in Africa and other developing regions where data are insufficient to provide validation of the pattern of disease and contributory variables.
The immediate, practical implication of this alternative hypothesis is that existing programmer for the control of AIDS are wrongly orientated, extremely wasteful of effort and expenditure, and in some respects harmful.

The current hypothesis

The hypothesis that HIV is the unique cause of AID is an inductive generalisation based on a few agree facts and an acceptance in medical, sociological an political circles of corroborative reasoning, conjectur and consensus. The facts (Barre­Sinoussi, Cherman & Rey, 1983; Gallo, Salahuddin & Popvic, 1984; Dal gleish et al., 1984; Levy & Chimabukuro 1985; He Pomerantz & Kaplan, 1987; Hanafusa, Pinter & Pull man, 1987; Gallo, 1987) are that (i) HIVs can be isolated from, or identified by biochemical probes in celh blood and secretion of an (unknown) proportion c patients with AIDS; (ii) in patients with AIDS wh are tested serologically, antibodies specific for antigens prepared from envelopes of the original isolate of LAV 1/HTLV III are usually detectable; (iii) in term of this test, there is a correlation between the presenc of HIV and AIDS in a community; (iv) HIVs appec to be transmitted from person­to­person by anal an vaginal intercourse, or parenterally via infected needles or blood transfusion, or congenitally; and (v) HIVs have high affinity for, and fuse with specific CD4 membrane receptors on helper T­lymphocyte and other mononuclear cells, transcribe their RNA int the DNA of the cells' nuclei and form virions which can infect other T­lymphocytes. The reasoning (Ho Pomerantz & Kaplan, 1987; Blattner, Gallo & Tenil 1988; Institute of Medicine, 1988; Baltimore & Feir berg, 1989; Fauci, 1988) is that HIVs can thereby weaken or destroy cell­mediated immunity, and that persons thus affected always or almost always succumb to a specific syndrome of generalised immune deficiency which then renders them susceptible to other, opportunistic infections and to various disorders of lymphoid cells and vital processes with fatal or near­fatal results. The conjecture of these authors and very many others is that infection with HIV is necessary and sufficient to explain this pathogenesis, irrespective of risk­behaviour. The consensus of the medical and scientific establishment, and practically all health authorities is that epidemiological evidence and predictions support this reasoning, and that any departure from it is heresy, a threat to public safety and efforts to control a dangerous epidemic, and to dedicated research.

The need for an alternative hypothesis
This has been raised on several occasions especially by Duesberg (1987, 1989), Sonnabend (1989), Evans (1989a) and by the author (1989, 1992a). Sonnabend, working with patients in Manhattan, was the first to explain the vunerability of homosexual men, in particular the effect of spermatozoa in the rectum on immunity. He suggested that risk factors for seroconversion are different from those for AIDS in which autoimmunisation, release of interferon, massive inocula in tranfused blood and blood­products, and a trigger effect of coincident viral infections might account for the pathogenesis of ARCs and AIDS.

Conclusion
An alternative hypothesis must explain not only the pathogenesis of immune deficiency in AIDS, but also the pattern of transmission and epidemiology. In the hypothesis presented here, AIDS is presented as a disease acquired in the first place by self­preferred or imposed behaviours, which in themselves dysregulate immunity and homeostasis while also leading to exposure to various pathogenic and opportunistic infections. The complex syndrome which follows has infectious, immunological and metabolic features. The hypothesis rejects HIV as a unique and sufficient cause of all this but agrees that it is transmissible in sexual secretions and blood, causing HIV disease: lymphadenopathy and febrile illness followed by latency or minimal pathological change during which there is evidence of direct cell­to­cell transmission of virus to migrant mononuclears and neural cells, of direct encephalopathy and of immune activation.
AIDS and AIDS­related complexes (ARCs) develop, with and without HIV, because heterologous antigens in spermatozoa enter the rectum and bloodstream, or in whole blood and blood concentrates given as transfusions, provoke allogenic responses and elicit antibodies which are toxic to lymphocytes, and cause a fall in CD4 counts. HIV can do the same by joining with CD4 receptors on T­helper lymphocytes presented along with MHC Class II proteins because of molecular affinities. This complex is tolerated, because it is recognisable at first as self, so HIV survives in clones of activated lymphocytes and monocytes in the presence of neutralising antibodies. But repeated infections of the genital, alimentary and respiratory tracts conveyed with various heterologous antigens, as above, maintain the T­cell activation while antilymphocyte antibodies are being formed. This leads to auto­immunity with a fall in CD4 count, reversal of the T4/T8 ratio, energy and programmed cell death of T­ and B­lymphocytes, consistent with the collapse of immunity, and atrophy of thymic and splenic follicles found post­mortem in patients dying with AIDS. It explains the general absence of AIDS in immunocompetent persons, the special susceptibility of homosexual men and haemophiliacs, and the risk to the foetus of a mother with AIDS; and it is entirely consistent with the epidemiological pattern of AIDS in the USA and most of Europe to date.
The occurrence of AIDS in drug users is attributable, firstly, to the general immunosuppressive properties of most of the major psycho­active drugs at present in use and secondly, to contaminants and impurities which cause refractory infections and dysregulate immunity. Persons in this risk category often overlap with the male homosexual group. Girls and women place themselves at high risk by taking drugs or by having intercourse with men in high risk groups. If they are pregnant, their infants share these risks by intra­uterine or perinatal exposure. Otherwise, the spread of AIDS by heterosexual transmission in either direction is minimal or absent except in sub­Saharan Africa where registrations are increasing rapidly, but in a totally different clinical and epidemiological pattern which overlaps with other, prevalent infections and with malnutrition.
Predictions made on this basis are accurate to within 10% of registered totals of current and cumulative incidence in the USA and UK. The risk­behaviour hypothesis postulates that, for these reasons, AIDS will continue to occur in persons and communities in defined susceptibility groups although HIV disease will be much more widely prevalent. Along with other organisms (HSV, CMV, VZ, EBV, various protozoa, fungi and bacteria), HIV can be activated from latency by various forms of risk behaviour, as described above, because this leads to an overload of genital, alimentary, pulmonary and systemic infections compounded by dysregulation of natural immunity, either by spermatozoa in the rectum and blood in persons of either sex experiencing traumatic anal intercourse, or from organisms acquired in oral sex, or from the immuno­toxic effects of injected or ingested drugs or from self­medication by broad­spectrum antimicrobial agents or, frequently, from al1 of these in life­styles which disregard elementary rules of hygiene and nutrition. In persons choosing these life­styles, AIDS is essentially a self­inflicted disease which can only be prevented by awareness and self­control. For persons upon whom these risks are inflicted, one way or another, it is becoming increasingly and tragically obvious that protection is imperative.
Impact of this new hypothesis on research and control of AIDS
The monopolistic hypothesis that HIV­ I is the unique cause of AIDS has, since 1984, led not only to erroneous predictions, but also to widespread misinformation and grotesque errors in prognosis, treatment, allocation of resources and strategy for research (Rubin, 1988; Adams, 1988; Eigen, 1989; Stewart, 1989, 1992a; Craven, Stewart & Taghavi, 1994). Resources and funds for the longer term are allocated mainly for single­factor strategy based on the false assumptions (Montagnier, 1994) that a specific vaccine or drug will eliminate or cure AIDS. Even if this were possible, the ethical and logistic problems would be immense. To whom would the vaccine be given? Would recipients be encouraged to continue risk­behaviour? How else would exposure and efficacy be measured? Or will the vaccine or vaccines be used as shot­guns on the blind guess that everyone is already at risk? Since heterosexual spread is not occurring in developed countries on anything approaching the scale envisaged in official predictions, it is easy to see how a vaccine used widely at this stage could be given credit for control of a pandemic which is not occurring. On the drug front, the consensus jumped the gun by promoting the use of Azidothymidine (AZT, Zidovudine), a highly cytotoxic drug, for prophylaxis in seropositive pregnant women and infants on the assumption that without it, they would all develop AIDS and die. This policy continues, despite the evidence in the prolonged Anglo­French Trial (Aboulker & Swart, 1993; Concorde,1994) which showed no significant prophylactic effect in symptom­free HIV­positive subjects in terms of survival or disease progression after five years.
If the HIV hypothesis is inadequate or wrong, the risks and misplacement of effort and research since 1984 will be enormous. The alternative hypothesis offered here differentiates HIV infection and disease from AIDS which, in developed countries at least, is a complex amalgam of diseases determined first and foremost by high risk behaviour in subsets of populations in restricted social, ethnic and geographic locations. It postulates that prevention depends essentially upon recognition and control of these existential determinants by education, notification, contact tracing and, if necessary, by legal constraints upon behaviour which places unaware or passive persons, including unborn infants, at equally high or higher risks. The situation in the developing world is even more serious but is different in ways which cannot be understood without a more informative data­base about the distribution and pattern of AIDS and other life­threatening and sexually­transmitted diseases, and about life styles in affected countries.
The data and predictions supporting the alternative risk­behaviour hypothesis are presented here in a manner which opens them in the short term to falsification and correction, for instance, by factual data excluding other diagnoses and confirming the occurrence of destruction of immunity with unremitting signs of AIDS and HI­viraemia by secondary transmissions to and between persons not engaging in risk­behaviour, or in infants of seropositive mothers not exposed to direct or indirect risks.

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