New hope for HIV sufferers

A drug that suppresses the immune system delays the onset of AIDS in patients with HIV, according to a study published in May in BMC Medicine. Predni-solone, taken without any antiviral therapy, postponed the loss of T-cells that leads to AIDS in 50 per cent of HIV sufferers by between two and 10 years.

HIV leads to a complex disorder that combines an initial chronic activation of the immune system with a progressive decrease in the number of CD4+ T cells, which are involved in the immune response. If the number of CD4+ T cells falls below a certain level, the weakened immune system is less able to fight infections and the symptoms of AIDS develop.

Rejecting the commonly accepted view that the CD4+ T cells are killed solely by the HIV virus, Jean-Marie Andrieu and Wei Lu of Université René Descartes in Paris believe that the hyperactivity of the immune system is part of the problem. To test whether reducing the activity of the immune system can protect patients’ CD4+ T-cell numbers and hence delay the onset of AIDS, the researchers initiated a trial where 44 patients with HIV were given the immunosuppressant drug, prednisolone.

After two years of taking the drug, 50 per cent of patients had higher CD4+ T-cell counts than they did at the start of the trial. This compares with five per cent of the control group patients that did not take prednisolone.

After five years, more than 10 per cent of the patients taking prednisolone had higher CD4+ T-cell counts than they did at the start of the trial, compared with virtually no patients in the control group.

Prednisolone was particularly effective at maintaining high CD4+ T-cell counts and delaying AIDS onset in patients that initially had a low level of virus in their body. Importantly, despite sup-pressing patients’ immune response, prednisolone did not cause the HIV virus to replicate more vigorously.

Prednisolone is a very inexpensive drug belonging to the class of glucocorticoids. The side effects were mild at the low daily dose it was given.

The authors expect their study to prompt further clinical trials. These should test different doses of prednisolone or other glucocorticoids, to define the lowest dose that can maintain the population of CD4+ T-cells. In addition, researchers could investigate whether the antiretroviral therapy for AIDS, HAART, is more effective if given in conjunction with glucocorticoids.

For further information about this research, email Jean-Marie Andrieu at:
Jean-marie.andrieu@biomedicale.univ-paris5.fr

HIV gene therapy

Three people with drug-resistant strains of HIV have become the first to undergo a new form of gene therapy designed to block the virus.

The idea is to use a modified form of HIV to deliver an “antisense” gene to the immune cells that HIV infects. This is integrated into the cells’ genome, and stays there until a cell is infected. Then it is switched on, and produces RNA complementary to the “sense” RNA encoding a viral protein. In theory, the RNAs should bind together, blocking viral replication.

Lab tests at VIRxSYS, a US-based company, showed viral replication is at least 100 times lower in treated cells. In July last year the company started treating patients by filtering immune cells from their blood, exposing the cells to very low doses of the modified virus, and then putting them back into the body.

Like existing antiretroviral drugs, the approach will not completely eliminate HIV from the body. However, because the antisense RNA fragment is very long, HIV should never be able to mutate enough to become resistant to it, Boro Dropulic, chief scientific officer of VIRxSYS, told the RNAi 2004 meeting in Boston in May.

It is the first time that this has been attempted with modified HIV. Dropulic says the results so far are encouraging, but Richard Sutton of Baylor College of Medicine in Houston is sceptical, saying the many problems inherent in gene therapy for HIV have led others to give up on the approach. “A lot of people, including large pharma, have seen the writing on the wall,” he says. 

New cancer therapy

Researchers at VIB, the Flanders Interuniversity Institute for Biotechnology, are using nanobodies to target cancer tumours as an alternative to chemotherapy.

Most of the current medicines for treating tumours – the so-called chemotherapeutics – are seldom specific. Because a chemotherapy treatment is not only toxic to cancer cells also to the body’s normal cells, patients often experience severe side effects.

However, for several years now, the leading strategy in the treatment of cancer has been based on the production of antibodies, which are protective substances produced in the organism to defend against intruding foreign bodies, protecting people against infections arising from bacteria and viruses. Antibodies can also react with tumour-specific substances that appear only on the cancer cell membrane. These ingenious antibodies seek out and bind very specifically to the cancer cells. As a result, the tumour is removed in a highly targeted, specific manner.

The antibodies, although a step in the right direction, are nonetheless large proteins that have difficulty penetrating tumours. In addition, their complex structure makes large-scale production very difficult and expensive.

In order to cope with these problems, the VIB researchers are using camel antibodies. Extremely small compared to conventional antibodies, this unique class of antibodies has been renamed ‘nanobodies’. Having all the advantages of conventional antibodies, nanobodies also have several more important characteristics: they are small and they keep their tumour-specific character. At the same time, they are very stable, soluble proteins that are much easier and less expensive to produce than conventional antibodies. Hence, researchers have recently begun to evaluate nanobodies as anti-cancer medicines. The first results look promising.

To translate these results into a possible application for humans, VIB is collaborating with Ablynx, a company established by VIB and GIMV in 2001 with the aim of marketing the nanobody technology. To date, Ablynx has already developed nanobodies against 16 different therapeutic targets that represent a wide range of diseases in humans. Two of these nanobodies are in the pre-clinical phase and, according to plan, will be ready for clinical tests next year.

These recent results are a new step toward the development of medicines based on nanobodies.

Gene for CdLS found

An international team of researchers has discovered the gene for Cornelia de Lange Syndrome (CdLS), a disabling, multi-system genetic disease that affects an estimated one in 40,000 children. The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease.

CdLS can be devastating, causing affected youngsters to have growth problems, missing or deformed limbs, gastro-intestinal disorders, seizures, cardiac problems, neurological, learning and behavioural difficulties and oro-dental issues.

The breakthrough, by a team led by Professor Tom Strachan at Newcastle University’s Institute for Human Genetics, came after 15 years of research. The researchers reported in the May 16th Nature Genetics that the gene had been located to chromosome five.
The findings have been confirmed by a simultaneous study carried out in the United States at the Children’s Hospital of Philadelphia.

Alan Peaford, Chairman of the parent support group, The Cornelia de Lange Syndrome Foundation, said: “This is fantastic news. Over the years we have had a number of false starts when we thought the gene had been found. Now, something like 50 per cent of the samples being tested in Newcastle and Philadelphia show involvement of this gene. Work must now go on to develop the testing so we can identify the problem in a much wider sample.

“It was important to have found the CdLS gene so we can confirm the diagnosis; understand it and improve existing therapies, as well as design new medical therapies; understand the role the gene plays in development; offer reassurance, through genetic testing, that other family members are not affected; provide accurate information and counselling resources for future pregnancies and improve awareness of the syndrome in the medical/scientific research community.”

Ebola outbreak in Sudan

The deadly Ebola haemorrhagic fever has been reported in Southern Sudan. As of 10 June, the health authorities of Yambio County have reported a total of 30 cases, including seven deaths from Ebola (case fatality, 23 per cent) in Yambio, Western Equatoria, south Sudan.

At the time of writing, 157 contacts were being followed up.

According to the World Health Organisation, intensive social mobilisation activities were being carried out. A workshop involving 94 teachers from the area was organised to disseminate messages about the disease and necessary prevention measures. Trained staff were placed in the hospital to provide information and counseling to patients and their relatives. Health education materials have been distributed in schools and other community centres.

Ebola haemorrhagic fever (EHF) is a febrile haemorrhagic illness which causes death in 50-90 per cent of all clinically ill cases. It is often characterised by the sudden onset of fever, intense weakness, muscle pain, headache and sore throat. This is often followed by vomiting, diarrhoea, a rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Laboratory findings show low counts of white blood cells and platelets as well as elevated liver enzymes.

The Ebola virus is transmitted by direct contact with the blood, secretions, organs or other bodily fluids of infected persons. Burial ceremonies where mourners have direct contact with the body of the deceased person can play a significant role in the transmission of Ebola. Healthcare workers have frequently been infected while treating Ebola patients through close contact without the use of correct infection control precautions and adequate barrier nursing procedures. 

Low sperm count IVF warning

Researchers warn that men with low sperm counts may pass on genetic defects to children conceived using fertility treatment.

BBC online reports that scientists from the University of Porto in Portugal compared sperm DNA from men with normal and low sperm counts and found the lower the sperm count, the more genetic defects were observed. The findings were published in The Lancet.

The researchers said these faults could increase the risk of the developing embryo being affected by certain genetic conditions.
The researchers examined specific imprinting genes which, if they do not behave in whichever way they should, can cause faults in other genes in sperm DNA from 123 men with low or normal sperm counts.

They found that in all 27 men who had normal sperm counts, the imprinting genes behaved in the correct way. But faults were observed in just under a quarter of the 96 men with low sperm count.

Professor Mario Sousa said the study showed that men with low sperm counts carried a significant risk of transmitting imprinting errors to children conceived through IVF. 

Nanobacteria a new life form?

After four years’ work a team of doctors, based at the Mayo Clinic in Rochester, Minnesota, has come up with some of the best evidence yet that nanobacteria do exist.

For years there has been debate over the issue. Some claim they are a new life-form responsible for a wide range of diseases, including the calcification of the arteries that afflicts us all as we age. Others say they are simply too small to be living creatures.

Cautiously titled Evidence of nanobacterial-like structures in human calcified arteries and cardiac valves, the paper by John Lieske and his team describes how they isolated minuscule- cell-like structures from diseased human arteries. These particles self-replicated in culture and could be identified with an antibody and a DNA stain.

“The evidence is suggestive,” is all Lieske claims in a report in New Scientist.

However, critics are not convinced. “I just don’t think this is real,” says Jack Maniloff of the University of Rochester in New York. “It is the cold fusion of microbiology.”

John Cisar of the National Institutes of Health is also skeptical. “There are always people who are trying to keep this alive. It’s like it is on life-support.”

The first claims about nanobacteria came from geologists studying tiny cell-like structures in rock slices. But in 1998 the debate took a different twist when Olavi Kajander and Neva Ciftcioglu of the University of Kuopio in Finland claimed to have found nanobacteria, surrounded by a calcium-rich mineral called apatite, in human kidney stones.

Objections were raised immediately. Many of the supposed nanobacteria were less than 100 nanometres across, smaller than many viruses, which cannot replicate independently. Mani-loff’s work suggests that to contain the DNA and proteins needed to function, a cell must be at least 140 nanometres across. Kajander and Ciftcioglu, however, insisted that they observed the nanoparticles self-replicating in a culture medium and claimed to have identified a unique DNA se-quence.

Lieske’s paper went through seven cycles of revision before it was accepted by the American Journal of Physiology: Heart and Circu-latory Physiology in May. “The review process, as painful as it was, forced us to look at the counter-arguments inside out, upside down and back to front, then repeat our experiments,” says Virginia Miller, a member of Lieske’s team.

The self-replicating particles suggest RNA is being produced in the particles. However, no one has yet been able to isolate DNA from these particles which would be a crucial piece of evidence in the face of the critics.

Miller was quoted by New Scientist as saying the Mayo team had managed to isolate RNA and DNA, but was not yet ready to talk about the results. “We are a conservative group, and that has stood us in good stead.”

WHO agrees global strategy on diet

The World Health Orga-nisation (WHO) Global Strategy on Diet, Physical Activity and Health was recently endorsed by Member States at their annual Health Assembly in Geneva. The strategy addresses two of the major risk factors responsible for the heavy and growing burden of non-communicable diseases (NCDs), which now account for some 60 per cent of global deaths and almost half (47 per cent) of the global burden of disease. NCDs include cardiovascular disease, Type 2 diabetes, cancers and obesity-related conditions.

“This is a landmark achievement in global public health policy. It provides our Member States with a powerful instrument, which will enable them to develop effective and integrated national strategies to reduce the human and socio-economic costs of non-communicable diseases,” said Dr Lee Jong-wook, Director-General, WHO. “The burden of death, illness and disability caused by non-communicable diseases is now greatest in developing countries where those affected are, on average, younger than in the developed world.”

WHO has developed the strategy over the past two years through a wide-ranging series of consultations with all concerned stakeholders, including Member States, other UN agencies, civil society and non-governmental organisations, and the private sector. The strategy specifies roles for these stakeholders in reducing NCDs.

The strategy emphasises the need to limit the consumption of saturated fats and trans fatty acids, salt and sugars, as well as to increase consumption of fruit and vegetables and levels of physical activity. It also addresses the role of prevention in health services; food and agriculture policies; fiscal policies; surveillance systems; regulatory policies; consumer education and communication including marketing, health claims and nutrition labelling; and school policies as they affect food and physical activity choices.

Dr Catherine Le Galès-Camus, WHO Assistant-Director General, Non-communicable Diseases and Mental Health said: “The strategy recommends a prevention-oriented approach that emphasises the need for countries to develop coherent, multi-sectoral national strategies with a long-term, sustainable perspective, to make the healthy choices the preferred alternatives at both the individual and community level.”

New treatment reduces stroke risk

New evidence confirming that surgery to open narrowed neck vessels can dramatically reduce stroke risk means more people should be getting the treatment - and points out the need for screenings to diagnose the condition - say researchers from Wake Forest University Baptist Medical Center, US.

“We now know definitively that we can reduce stroke risk by half with surgery to ‘clean out’ narrowed arteries leading to the brain - even in patients who have no symptoms,” said neurologist James Toole, MD. “We should offer this option to more patients, as well as begin screening seemingly healthy individuals for stroke risk.”

Toole’s comments are in response to a recent report in The Lancet on the “Asymptomatic Carotid Surgery Trial,” a study based in England of more than 3,000 patients. The results - that surgery to remove fatty deposits from narrowed vessels in the neck can significantly reduce stroke risk - were nearly identical to the findings of a study that Toole co-ordinated in the United States and Canada.

The idea that surgery can be beneficial for people without symptoms was not easy for physicians and researchers to believe when it was first reported in 1995, said Toole. “People were so astonished by this they thought the data was flawed. That led to the European study.”

Both studies looked at the value of surgery, known as carotid endarterectomy, in people who had no symptoms but whose carotid arteries were narrowed by at least 60 per cent, a condition called carotid artery stenosis. The surgery is typically only offered to patients who have symptoms of an impending stroke.

Charles Tegeler MD, Professor of Neurology at Wake Forest Baptist, said: “The research results, which confirm a benefit of surgery to prevent stroke in people who had no symptoms, despite having severely narrowed arteries, highlight two important issues for stroke prevention. First, we need to screen more adults for narrowed carotid arteries. Second, patients with severe carotid narrowing should at least be considered for the surgery as a stroke-prevention treatment.”

Toole recommends that men undergo a baseline screening of their carotid arteries between the ages of 50 and 60, depending on their overall health. The simple test, which was pioneered by Wake Forest, uses ultrasound technology to gauge artery health. Toole believes that both men and women with diabetes, hypertension or a family history of stroke - all which increase the risk of stroke - should be screened in their 40s. The surgery can be performed under local or regional anaesthesia.

Biology of obesity

Obesity has reached epidemic proportions in America and is a major health problem in the Gulf. This is due to a number of factors including increased technology and the rise in consumption of prepared and preserved foods. Obesity is one of the most serious risk factors for some of the leading causes of death, such as heart disease.

Two studies presented at Digestive Disease Week in New Orleans, United States, in May show significant progress has been made in finding the underlying characteristics of obesity.

Digestive Disease Week (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

One study looked at exaggerated gastric accommodation. For patients suffering from morbid obesity, new research suggests that exaggerated gastric accommodation to meals may be to blame for the continued struggle against weight loss, according to researchers from the Union Hospital of Tongji Medical College in China.

The results of the study showed that obese patients eat more during meals than people at a healthy weight before experiencing a feeling of fullness, due to an increased minimal distending pressure and an exaggerated gastric accommodation.

“We believe this could help explain some of the biological challenges for the morbidly obese to losing weight through conventional methods such as calorie counting,” said Xiaohua Hou, MD, lead author of the study. “Weight loss approaches in this population need to be addressed differently to achieve successful results and surgery may often be a necessity to correct the problem.”

A second study looked at gene expression profiles associated with obesity. Researchers from the Center for Liver Diseases at Inova Fairfax Hospital and George Mason University noted significant differentiation of gene expression in obese patients undergoing bariatric surgery.

Gene expression data comparing obese patients to lean controls revealed a number of genes with more than a two-fold increased altered expression. In particular, obese patients showed significant up-regulation of genes related to energy expenditure pathways as compared to controls.

“In patients with morbid obesity, differential expression of genes related to energy expenditure in the fat tissue is important to note, as this may explain a host of related factors contributing to obesity for this patient population,” said Zobair Younossi, MD, MPH, lead investigator of the study. “The exact contribution of these genes to the development of obesity is currently being studied to offer additional insight on the underlying mechanisms of the disease.” 

Prostate cancer calculator

A study recently completed by researchers at the Josephine Ford Cancer Center has resulted in the most comprehensive long-term prostate cancer survival model available to date. An interactive version of the survival model is available online at www.prostatecalculator.org

Patients and doctors who visit the site can obtain a personalised 10-year sur-vival estimate based on age, race, a few clinical measures, and the kind of treatment being pursued. Once data have been entered, a simple mouse-click pro-vides the prognosis.

Researchers identifeid a cohort of 1,611 patients with clinically localised prostate cancer as well as 4,538 age, race, and co-morbidity matched con-trols. Based on demographic and clinical variables, propensity risk scoring was used to develop survival probability estimates for both patients and controls. Because the calculator, and the companion look-up tables published in the April issue of the Journal of Urology, provide a comparison with men with similar characteristics but who do not have prostate cancer, users receive a realistic estimate of the impact of prostate cancer on long-term sur-vival.

The www.prostatecalculator.org web site was produced by the Artificial Neural Networks in Prostate Cancer Project, Denver, Colorado, US.