HIV, the virus that causes AIDS, poses a particularly difficult challenge to vaccine developers. For one thing, there are several strains of the virus circulating in the world, and an effective vaccine would need to immunize the public against all of the major strains. Second, the virus is constantly mutating as part of its strategy to elude the immune system, so an effective vaccine would need to disable the virus in spite of these mutations. Early candidate vaccines targeted one strain of the virus, and tended to attack or block the virus on one front only. The new generation of vaccines are designed to block the virus on several fronts.

Most HIV vaccine candidates that have been developed so far have been designed to generate antibodies to a protein called gp120 that is found on the surface of the AIDS virus. While some of the vaccines have elicited immune responses to some forms of gp120, researchers have a had a hard time developing a vaccine that can generate antibodies against the many forms of gp120 that occur naturally.

In November of this year, clinical trials began with a new vaccine that targets the three most globally important HIV subtypes, or clades. The vaccine incorporates genetic material from the A, B and C clades of HIV, which together are associated with some 90 percent of all HIV infections worldwide.

"This is the first multigene, multiclade HIV vaccine to enter human trials. It marks an important milestone in our search for a single vaccine that targets US subtypes of HIV as well as clades causing the global epidemic," said Anthony S. Fauci, M.D, Director of the National Institute of Allergic and Infectious Diseases.

The novel vaccine incorporates modified elements of four HIV genes known as gag, pol, nef and env. Previous clinical trials have shown that this type of DNA vaccine is very safe and cannot induce HIV infection. Each of the HIV genes play an important role in infection. For example, the env gene codes for a protein on the outer coat of the virus that allows it to recognize and attach to human cells. The current candidate vaccine includes env components from several HIV subtypes.

The researchers say that the current trial represents an important step in an ongoing process of HIV vaccine development. If an when the multicalde vaccine is shown to be safe and to elicit an effective immune response, the researchers would then add additional HIV protein components in an attempt to increase the immune response even further.

"Ultimately, we aim to build a potent vaccine designed to prevent HIV infection. Any HIV vaccine must hit a constantly moving target. Essentially, we are trying to enlarge that target through a multiclade vaccine," notes Gary Nabel, M.D., Ph.D., director of the Dale and Betty Bumpers Vaccine Research Center where the vaccine was developed.

The initial stage of the trial is being conducted at the National Institutes of Health in Bethesda, MD. The Phase I trial will enroll 50 volunteers who are not infected with HIV and is designed solely to confirm the safety of the vaccine. Volunteers between the ages of 18 and 40 years old will be vaccinated with either the test vaccine or an inactive placebo solution in a series of increasing doses. The trial is a double-blind design, meaning neither the volunteers nor the doctors will know which group receives the active compound. The researchers will check the volunteers regularly for one year to look for immune responses and adverse effects. Once the safety of the vaccine has been established, the trial will be expanded to include volunteers in the US, Haiti and South Africa

"We want the community to understand and support the process of vaccine development so that together we can attain the goal of stopping or slowing the AIDS pandemic. Although thousands have already volunteered to take part in HIV vaccine trials, many more are needed. The importance of community participation cannot be overemphasized," notes Barney Graham, M.D., Ph.D., lead investigator in the multiclade vaccine trial.

Clinical trials are ongoing around the world with both therapeutic and prophylactic HIV vaccine candidates. Prophylactic vaccines are the more familiar kind that are designed to prevent infection with a virus, e.g. the small pox, influenza and varicella vaccines. Therapeutic vaccines are those which might prove useful in bolstering the immune response of those already infected with HIV. There have been more than 50 HIV vaccine clinical trials since 1988, involving more than 26 different vaccine candidates. More than two dozen clinical trials are now underway, although only one has reached the final Phase III stage.

There is a growing consensus among researchers that an effective vaccine against HIV infection will be developed within the next ten years. Public health authorities will then face a new set of logistic and political challenges as they determine how to get the vaccine to where it is needed most in a long-term global effort both in the the developed world and in areas of the developing world already decimated by the effects of the pandemic.

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Hormone Replacement Therapy

Once considered a boon to women during and after menopause, the risks of hormone supplementation now appear to outweigh the putative benefits, at least in some patients, according to the results of a huge clinical trial.

Federal health authorities stopped the trial, part of the Women's Health Initiative (WHI), when it became clear that post-menopausal women who were taking a common combination of estrogen and progestin had an increased risk for developing breast cancer and cardiovascular disease. The study involved 16,608 women across the United States. It is the first randomized trial to study the effects of long-term treatment with the hormone combination on these risks.

"We have long sought the answer to the question: Does postmenopausal hormone therapy prevent heart disease and, if it does, what are the risks? The bottom-line answer from WHI is that this combined form of hormone therapy is unlikely to benefit the heart. The cardiovascular and cancer risks of estrogen plus progestin outweigh any benefits--and a 26 percent increase in breast cancer risk is too high a price to pay, even if there were a heart benefit. Similarly, the risks outweigh the benefits of fewer hip fractures," said NHLBI Director Claude Lenfant, M.D

In brief, the study revealed that when compared with placebo, women taking the hormone combination had:

A 41% increase in strokes A 29 % increase in heart attacks A doubling of rates of venous thromboembolism (blood clots) A 22 % increase in total cardiovascular disease A 26% increase in breast cancer

The study also showed some apparent benefits associated with hormone use. These included:

A 37 % reduction in cases of colorectal cancer A one-third reduction in hip fracture rates A 24 % reduction in total fractures In editorial accompanying the publication in JAMA, Suzanne W. Fletcher, MD, M. Sc., and Graham A. Colditz, MD Dr.P.H., of the Harvard Medical School, suggest that the time may have come to stop prescribing estrogen/progestin for preventive purposes.

"The whole purpose of healthy women taking long-term estrogen/progestin therapy is to preserve health and prevent disease. The results of this study provide strong evidence that the opposite is happening for important aspects of women's health, even if the absolute risk is low. Given these results, we recommend that clinicians stop prescribing this combination for long-term use."

Ovarian Cancer Risk

In a related report in the same issue of the journal JAMA that announced the results, researchers from the National Cancer Institute reported an increased risk of ovarian cancer among women receiving estrogen replacement therapy. In a study that tracked the health of 44,241 women for approximately 20 years, the researchers found women taking estrogen had a 60% increased risk of ovarian cancer compared to those who were not. The risk increased with length of estrogen use.

"The main finding of our study was that postmenopausal women who used estrogen replacement therapy for 10 or more years were at significantly higher risk of developing ovarian cancer than women who never used hormone replacement therapy," said James V. Lacey, Jr., Ph.D., lead author of the study from National Cancer Institute's Division of Cancer Epidemiology and Genetics.

The NCI study primarily looked at the long-term effects of estrogen use alone. The study did not report an increased risk for ovarian cancer among women who used combination hormone replacement therapy. However, Dr. Lacey cautioned that the study had not followed enough women for a long enough period to say whether taking the combined therapy has any effect on ovarian cancer.

Caveats and Limitations

It is important to keep the WHI study in perspective. The study looked at the effect of one combination of hormones taking for a long period of time. The findings may not apply to women who take hormone replacement therapy for only a short-period to ease the symptoms of the menopausal transition. The WHI investigators stress that the current results do not necessarily apply to lower dosages of these drugs, to other formulations of oral estrogens and progestins, or to estrogens and progestins administered through the transdermal route. Indeed, they say it is still possible that transdermal estradiol with progesterone, may provide a different risk-benefit profile.

A parallel WHI trial of estrogen only in women who have had a hysterectomy will continue. The trial is scheduled to end in March 2005, by which time the average follow-up with be about 8.5 years.

During the time in which the WHI trial has been conducted, many new treatments have been found that offer an alternative to hormone replacement for reducing fracture risk associated with osteoporosis. In addition, there has been a growing awareness of the need to inform women of strategies to reduce the risk for cardiovascular disease.

"Menopausal women who might have been candidates for estrogen plus progestin should now focus on well-proven treatments to reduce the risk of cardiovascular disease, including measures to prevent and control high blood pressure, high blood cholesterol, and obesity. This effort could not be more important: heart disease remains the number one killer of American women,"

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ORIGINS OF MODERN HUMAN BEHAVIOUR:

THE DEBATE

The origins of anatomically modern people (Homo sapiens) almost certainly lie in Africa at about 300,000 – 150,000 years ago and genetic evidence shows that all living people are related to these African ancestors. The origins of 'modern' human behaviour, however, are a more contentious issue and the subject of ongoing and extensive debate. A link between early anatomical modernity and early 'modern behaviour' in Africa is not generally accepted and there is also disagreement on how 'modern behaviour' is defined. In essence, there are two opposing viewpoints: 1) A late African origin with 'modern' behaviour rapidly appearing at ~ 50,000 years ago, an event closely linked to behavioural modernity in the European Upper Palaeolithic at about 40,000 years; 2) Modern human behaviour developed in Africa at a much earlier stage, and this development is linked to anatomical modernity - a gradual process that perhaps started more than 200,000 years ago but certainly long before the start of the European Upper Palaeolithic. Most 'late origin' models draw heavily on the European Middle / Upper Palaeolithic transition (about 40,000 years ago) for their construction, but applying eurocentric evidence for 'modern behaviour' to an African context has drawn considerable criticism. Until recently archaeological evidence for modern human behaviour in Africa has been limited and, consequently, the model for a late European linked development of 'modern behaviour' is widely accepted. Unfortunately only a small number of archaeological sites that date to this time range have been well excavated in Africa and evidence supporting an early African origin has been limited – in comparison there are many hundreds of well excavated European sites demonstrating a florescence of modern behaviour traits from about 40,000 years ago.

Evidence emerging from a few recently excavated African sites is beginning to change the picture. One of these sites, Blombos Cave, located in the southern Cape, South Africa, contains excellently preserved Middle Stone Age (MSA) deposits that date to older than 70,000 years. Excavations at this site between1992 – 2000 have yielded remarkable, yet anomalous finds that are directly relevant to the 'modern' human behaviour debate. These finds include a range of bone tools, finely crafted bifacial stone points, an engraved bone fragment and evidence.

African Trypanosomiasis

Zoomastigina: The Zoomastigotes

The zomastigotes are unicellular, heterophic organism that are highly variable in form. Each has at least one flagellum, with some species having thousands.

They include both free-living and parasitic organisms. Many zoomastigotes apparently reproduce only asexually, but sexual reproduction by gametes occurs in some species. Members of one group, the amoeboflagellates, alternate between an amoeboid stage and a flagellated one, depending on environmental conditions.

The members of another group, the trypanosomes, include the genera Trypanosoma and Critbidia, which are important pathogens of human, and domestic animals. The euglenoids can in many respect be viewed as a specialized group of zoomastigotes, some of which have acquired chloroplasts during the course of their evolution.

Among the diseases for which the trypanosomes are responsible are sleeping sickness (trypanosomiasis), East Coast fever, and Chagas' diease, all of great importance in tropical areas. Another tropical disease, leishmaniasis, which is transmitted by sand flies, afflicts about 4 million people a year.

Its effects range from skin sores to deep, eroding lesions that can almost obliterate the face. The trypanosomes that cause these diseases are spred by biting insects, including testse flies, and assassin bugs.

Serious effort has been made to produce a vaccine for trypanosome-caused diseases. These diseases make it almost impossible to rse domestic cattle for meat or milk in a large portion of Africa, and thus pose an obstacle to the alleviation of hunger.

Control is especially difficult because of the unique attributes of thes organism. Example: testse flt-transmitted trypanosomes have evolved an elaborate genetic mechanism for repeatedly changing the antigenic nature of their protective glycoprotein coat, thus avoiding the effects of the antibodies that their host produce against them.

Only a single one out of some 1000 to 2000 variable antigen genes is expressed at a time. The expressed gene is located in a specific position near the end of the chromosome. Rearrangements of these genes occur during the asexual cycle of the organism and provides a system that allows for the expression of a seemingly endless variety of different antigen genes and, thus, the maintenance of infectivity by the trypanosomes.

When the trypanosomes are ingested by a tsetse fly, they embark on a complicated cycle of development and multiplication, first in the fly's gut, and later in its salivary glands. Recombination has been observed between different strains of trypanosomes introduced into a single fly, thus suggesting that mating and meiosis occure, even though they have not been observed directlt.

Although most trypanosome reproduction is asexual, this sexual cycle, reported for the first time in 1986, affords still further possibilities for recombination in these organisms. In the guts of the flies that spread them, trypanosomes are noninfective. When they are prepared for transfer to a mammalian skin or bloodstream, trypanosomes acquire a thick coat of glycoprotein antigens that protect them from the host'santibodies.

When they are taken up by a fly, the trypanosomes again shed their coats. The production of vaccines against such a system is complex, but field tests has occurred. Releasing sterilized flies to impede the reproduction of populations is another technique used to try to control the fly population. Traps made of dark cloth and scented like cows, but poisoned with insecticides, have likewise proved effective.

Research is proceeding at a rapid rate because the presence of tsetst flies with their associated trypanosomes blocks the use of some 11 million square kilometers of potential grazing land in Africa.

Some zoomastigotes occur in the guts of termites and other wood-eating insects. They possess the enzymes that allow them to digest the wood and thus make it available to their host. The relationship is similar to that between certain bacteria and protozoa that function in the rumens of cattle and related mammals.

Another group of zoomastigotes, the choanoflagellates, is certainly the groupe from which the sponges (phylum Porifera) and probably all other animals derived. Choanoflagellates have a single emergent flagellum surrounded by a funnel-shaped, contractile collar composed of closely placed filaments, a unique structure that is exactly matched in the sponges.

These protists feed mostly on bacteria, which are strained out of water by the collar.