Protein locks out prion diseases

19:00 01 October 03

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A chance discovery could lead to the development of a drug that blocks prion diseases such as variant CJD. However, it would only be useful when combined with mass screening to identify infected people who have not yet developed any symptoms.

Adriano Aguzzi's team at the Institute of Neuropathology in Zurich, Switzerland, discovered the effect by accident. The researchers engineered mice to produce a protein that would stick to the scrapie prion, so the team could retrieve the prion protein for testing. The engineered mice turned out to take twice as long as normal to develop the disease.

Because the protein is soluble, it is ideal for use as a drug. Aguzzi now hopes to mass-produce the protein so he can test it on macaque monkeys that have been exposed to BSE.

If it works, Aguzzi told the European Life Science Organisation conference in Dresden last week, his team will test it on people infected with vCJD.

Other drugs are also being developed (New Scientist print edition, 8 March 2003), and some are being tested on people. Last week doctors announced that injecting a substance called pentosan polysulphate into the brain of a teenager in Northern Ireland who has vCJD seems to have slowed the disease's progress.

But fears that thousands of people in the UK are incubating the disease after eating infected beef are receding. There have been only 136 cases so far, and the latest estimate is that only another 40 people will develop vCJD.

Claire Ainsworth, Dresden

Baby study links antibiotics to asthma

15:48 30 September 03

NewScientist.com news service

Babies given antibiotics during the first six months of their lives are far more likely to develop asthma, according to a US study. Why is not clear, but the team claims antibiotics might be partly responsible for the steady rise in asthma cases in western countries.

A handful of studies have blamed antibiotics, but most are suspect because they relied on the memories of parents years after events. Instead, Christine Johnson's team at the Henry Ford Health System in Detroit followed 448 children from birth to age seven, regularly checking on their health.

Nearly the half of the children were given antibiotics in their first six months, a quarter had two courses and a fifth had three or more. At the end of the study, tests revealed that 21 of the children had developed allergic asthma, in which attacks are triggered by environmental factors.

Overall, children given antibiotics in their first half-year were 2.6 times more likely to develop allergic asthma, the team told a meeting of the European Respiratory Society on Tuesday. With broad-spectrum antibiotics, which kill a wide range of bacteria, the risk was far higher: children were 8.9 times more likely to suffer from asthma.

Johnson speculates that the drugs disrupt the developing immune system because they alter the bacterial communities in the gut. This might make it more difficult for a baby's immune system to learn which bacteria are good and which are bad.

The findings fit in with a large body of evidence on the origin of childhood asthma, known as the hygiene hypothesis, says Thomas Kovesi at the Children's Hospital of Eastern Ontario, Ottawa. "The cleaner you make things, the greater the risk of allergy," he says. "The immune system gets bored."

The new study also found that the more courses of antibiotics children were given, the greater the risk. And known risk factors for asthma, such as having a mother with asthma or having fewer than two household pets, seemed to amplify the effect. A child who was given broad-spectrum antibiotics and whose family had no pets faced 11.5 times the risk of allergic asthma.

But even though Johnson's study is better designed than previous ones, not everyone is convinced. Since so many of the children being treated with antibiotics were ill with respiratory tract infections, it might be that the infections, not the antibiotics, triggered the asthma, cautions Wilfried Karmaus at Michigan State University in East Lansing.

Or it may just be that children prone to asthma are more prone to respiratory infections. In his own unpublished study of 600 children from birth to age three, Karmaus also found a link between asthma and antibiotics - but it disappeared when these factors were allowed for.

But Johnson stands by her findings. Although the numbers are relatively small, she claims the effect still holds true when all the children with respiratory tract infections are excluded. Even children treated for non-respiratory illnesses such as kidney infections had a higher risk of developing allergic asthma.

Alison Motluk

Drug produces faster healing and fewer scars

10:56 02 October 03

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Initial trials of a drug that reduces scar formation have produced encouraging results. Although the substance still has numerous regulatory hurdles to clear, it is the first of its type to be tested on people. If the drug proves successful, it could routinely be used to prevent scarring after surgery or following serious accidents.

"Scarring is a problem that is much more important to patients than it is to doctors," says Mark Ferguson, an expert on skin healing at the University of Manchester, UK, and chief executive of Renovo, the company set up to develop the drug.

Even a skilful performance in the operating theatre can leave a patient with a disfiguring scar that restricts movement. Facial scarring, in particular, can have a profound effect on self-confidence.

The anti-scarring drug consists of a signalling molecule produced during wound healing called transforming growth factor beta 3 (TGF?3). Ferguson found that wounds in mammalian fetuses, which heal without scarring, contain high levels of TGF?3. After birth, mammals produce less TGF?3 when wounded.

This difference may have been an evolutionary trade-off: before we had antiseptics and antibiotics, preventing infection of wounds was far more important than avoiding scarring. The massive inflammatory response that destroys invading bacteria and swiftly closes wounds also slows healing and creates the tangled masses of tissue that form scars.

Cell migration

TGF?3 acts by speeding up cell migration. Ferguson thinks it encourages fibroblasts and keratinocytes, two of the cell types that generate new skin, move more rapidly into the wound site. This allows the skin to regenerate its usual orderly structure before a scar can form.

At a meeting at the Royal Society in London, UK, last week, Ferguson reported results of the first clinical trials of TGF?3. The experiments involved making two separate wounds in volunteers' arms. One wound was injected with the drug while the other was injected with a placebo. Ferguson says the final product might be given as a cream or injected into the bloodstream.

To date, the drug has been tried on just over 300 volunteers. It does not always prevent scarring, Ferguson says, but it does reduce it. And it also dramatically speeds up healing. Some wounds took around seven days to heal without the drug but only two days with it. Adjusting the size and timing of the dose should produce even better results, he thinks, although it will probably work better in some people than others.

Surprisingly, the results were most impressive in people over 60 years old. Some of the wounds healed so well the researchers could not find them.

Eye surgeons already use a range of drugs to reduce scarring of the eye. Most of these are not suitable for use on the skin, but doctors hope at least one under development will work anywhere in the body (New Scientist print edition, 21 June 2003).

James Randerson

Gene for SARS susceptibility found

14:25 02 October 03

NewScientist.com news service


A gene variant that may make people particularly susceptible to the deadly SARS virus, has been identified by scientists in Taiwan.

The gene variant is prevalent in people of south Chinese origin, so the discovery may help explain why the disease rampaged across southeast Asia emerging in China's southern Guangdong province in November 2002.

The gene produces a protein called HLA-B*4601, which is linked to the immune response and has been linked to a raised risk of suffering more life-threatening reactions to SARS.

"We have discovered that most of the people infected with SARS are from southern China and southeast Asia and that the gene is related to their susceptibility to SARS infection," said Marie Lin, who led the study at Taipei's Mackay Memorial Hospital. The scientists stress that their results needed to be confirmed by other studies.

James Hughes, at the US Centers for Disease Control and Prevention in Atlanta, says possible genetic susceptibility is under investigation. "It is conceivable that people of a certain genetic disposition have a susceptibility to or risk of complications," he told Reuters.

Foreign invaders

The team analysed human leukocyte antigen (HLA) proteins, which are present on the surface of all nucleated cells and are important for the body to distinguish between its own cells and foreign invaders.

Previous studies have linked variations in this HLA system to susceptibility or resistance to malaria, tuberculosis, yellow fever, typhoid and HIV.

Lin and colleagues hoped to discover a gene to use in a future screening programme for health care workers at greater risk of contracting SARS. The team examined the HLA genes in 33 probable SARS cases, 28 fever patients who later proved to have SARS, and 101 health care workers exposed but not infected by the fatal bug at Taiwan's Mackay Memorial Hospital and Taipei Municipal Hoping Hospital.

They compared the results with controls including 190 healthy, unrelated Taiwanese people and found that a gene variant coding for HLA-B*4601 was linked to an increased severity of SARS.

Crucially, no cases of SARS were seen in people from the nine indigenous tribes of Taiwan who rarely have the gene variant. All the probable SARS cases were in Taiwanese people of southern Chinese origin. The island's main inhabitants have migrated from China's Guangdong and Fujian provinces over the last few centuries. Only 1.5 per cent of the population are indigenous people.

"Interestingly, HLA-B*4601/B46 is also seldom seen in European populations and very few cases of SARS infection of individuals of European origin were reported," the team write.

Vaccine hope

In a separate development, Canadian researchers taken a step towards developing a vaccine to combat the SARS coronavirus.

A team at McMaster University in Hamilton, Ontario, used DNA sequence data from the virus to construct a specific nuclear protein. They have now engineered this into a common cold adenovirus, which will carry it into humans and hopefully provoke a protective immune response.

The researchers, headed by Jack Gauldie, will begin testing this approach in animals shortly.

The SARS epidemic swept across the globe in spring 2003, killing over 800 people and causing 8400 infections in about 30 different countries. The global all-clear came on 5 July.

Journal reference: BMC Medical Genetics (vol 4, p 9)

Major trial tackles breast cancer prevention

14:58 30 September 03

NewScientist.com news service

A major international trial of a drug to prevent breast cancer was launched in London, UK, on Tuesday. Researchers believe that the drug, called anastrozole, could cut the chance of breast cancer by more than 50 per cent in women with a raised risk of having the disease.

This could potentially save many thousands of lives every year in the UK alone, says Jack Cuzick who is leading the study for Cancer Research UK. Over 30,000 post-menopausal women develop breast cancer every year in the UK.

Preliminary research on the new drug suggests it could be much better at preventing breast cancer than tamoxifen, an earlier cancer "wonder drug". Tamoxifen reduces the risk of breast cancer by about a third. But crucially, anastrozole also has a much lower risk of side-effects, say researchers.

Tamoxifen's ability to prevent breast cancer was demonstrated in the International Breast Cancer Intervention Study -1. Now, IBIS-2 will examine the effectiveness of anastrozole as a preventative measure. Cuzick says: "The new trial has the potential to have an even more dramatic impact on the disease."

"This is a fantastically interesting study," says Alex Markham, chief executive of Cancer Research UK. "Prevention is central to what we do."

Early warning

Early data on anastrozole is already emerging from another major clinical trial, says Cuzick. The ATAC trial is comparing the use of tamoxifen versus anastrozole for treating breast cancer in 9000 postmenopausal women from 21 countries.

The trial is running five years ahead of the newly launched IBIS-II trial and so should give an "early warning" of unexpected side effects.

Tamoxifen reduced the incidence of tumours developing in the opposite breast in women who already had cancer by about 40 per cent. Anastrozole seemed to reduce these "contralateral tumours" by about 70 per cent, which prompted scientists to examine it more closely.

Hormone sensitive

The five-year IBIS-2 trial is looking at preventing the "hormone sensitive" breast cancers that account for two-thirds of all cases of the disease.

These cancers can be prevented by blocking the action of oestrogen. Tamoxifen stops the action of oestrogen on cells in the breast while maintaining the positive effects of the hormone on the bones. But anastrozole inhibits an enzyme called aromatase which is needed to make oestrogen and could cut breast cancer risk by 70 per cent.

IBIS-2 has enrolled 6000 healthy post-menopausal women who have at least twice the normal risk of developing breast cancer, about five to 10 per cent of all women. This increased risk could be because, for example, they have a mother or sister who developed the disease before 50. They will be given either anastrozole or a placebo.

A second part of the study will compare anastrozole's effects with those of tamoxifen in 4000 women who have an extremely early form of breast cancer called ductal carcinoma in situ (DCIS).

Blood clotting

Trials of tamoxifen for breast cancer prevention have shown it can treble the risk of rare endometrial cancer and doubles the risk of blood clotting events. "The role of tamoxifen for prevention remains unclear," says Cuzick. "The benefit does appear to outweigh the risk, but not enormously."

Anastrozole cuts the risks of side effects considerably. For example, the risk of endometrial cancer is 80 per cent lower with anastrozole than tamoxifen.

However, the new drug may cause a loss of bone density that increase the risk of fractures by 50 per cent. To tackle this, the IBIS-2 team will be assessing the women regularly and giving them bone-boosting drugs called bisphosphonates if necessary.

Shaoni Bhattacharya

Evaluation of D-Dimer in the Diagnosis of Suspected Deep-Vein Thrombosis

Philip S. Wells, M.D., David R. Anderson, M.D., Marc Rodger, M.D., Melissa Forgie, M.D., Clive Kearon, M.D., Ph.D., Jonathan Dreyer, M.D., George Kovacs, M.D., Michael Mitchell, M.D., Bernard Lewandowski, M.D., and Michael J. Kovacs, M.D.

ABSTRACT

Background: Several diagnostic strategies using ultrasound imaging, measurement of D-dimer, and assessment of clinical probability of disease have proved safe in patients with suspected deep-vein thrombosis, but they have not been compared in randomized trials.

Methods: Outpatients presenting with suspected lower-extremity deep-vein thrombosis were potentially eligible. Using a clinical model, physicians evaluated the patients and categorized them as likely or unlikely to have deep-vein thrombosis. The patients were then randomly assigned to undergo ultrasound imaging alone (control group) or to undergo D-dimer testing (D-dimer group) followed by ultrasound imaging unless the D-dimer test was negative and the patient was considered clinically unlikely to have deep-vein thrombosis, in which case ultrasound imaging was not performed.

Results: Five hundred thirty patients were randomly assigned to the control group, and 566 to the D-dimer group. The overall prevalence of deep-vein thrombosis or pulmonary embolism was 15.7 percent. Among patients for whom deep-vein thrombosis had been ruled out by the initial diagnostic strategy, there were two confirmed venous thromboembolic events in the D-dimer group (0.4 percent; 95 percent confidence interval, 0.05 to 1.5 percent) and six events in the control group (1.4 percent; 95 percent confidence interval, 0.5 to 2.9 percent; P=0.16) during three months of follow-up. The use of D-dimer testing resulted in a significant reduction in the use of ultrasonography, from a mean of 1.34 tests per patient in the control group to 0.78 in the D-dimer group (P=0.008). Two hundred eighteen patients (39 percent) in the D-dimer group did not require ultrasound imaging.

Conclusions: Deep-vein thrombosis can be ruled out in a patient who is judged clinically unlikely to have deep-vein thrombosis and who has a negative D-dimer test. Ultrasound testing can be safely omitted in such patients.

Source Information

From the Departments of Medicine, Radiology, and Emergency Medicine, Ottawa Hospital, University of Ottawa, Ottawa, Ont. (P.S.W., M.R., M.F., B.L.); Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, N.S. (D.R.A., G.K., M.M.); London Health Sciences Centre, University of Western Ontario, London, Ont. (J.D.); and Henderson Hospital, McMaster University, Hamilton, Ont. (C.K.) — all in Canada.

Address reprint requests to Dr. Wells at Ottawa Hospital Civic Campus, Suite F647, 1053 Carling Ave., Ottawa, ON K1Y 4E9, Canada, or at pwells@ohri.ca.

Determinants of Ventilator Withdrawal in Critically Ill Patients Have Changed

By Anthony J. Brown, MD

NEW YORK (Reuters Health) Sept 18 - In the past, the decision to stop mechanical ventilation in a critically ill patient was primarily based on objective data, such as illness severity and organ dysfunction. New study findings suggest that this has changed and that physicians now base the decision on what they believe the patient wants and on their likely outcome.

"Studies from a couple of decades ago have suggested that patient age and organ dysfunction were major factors influencing withdrawal of life support," lead author Dr. Deborah Cook, from McMaster University in Hamilton, Canada, told Reuters Health. Also, such support typically "wasn't withdrawn until after many weeks in the ICU."

In the new study, which was published in the September 18th issue of The New England Journal of Medicine (NEJM), "we wanted to see whether or not things had changed since these studies were reported," Dr. Cook noted.

Instead of increased age and illness severity, "we found that more patient-centered factors were the main determinants of ventilator withdrawal," Dr. Cook stated. Specifically, "if the physician believed the patient didn't want life support or if they thought their chance of survival in the ICU was less than 10% then withdrawal was more likely,"

Other predictors of ventilator withdrawal included the physician's perception that future cognitive function would be severely impaired and the use of vasopressors or inotropes.

The findings are based on a study of 851 critically ill patients who were receiving mechanical ventilation in ICUs in Canada, the US, Sweden, or Australia.

Of the various determinants identified, the physician's perception of the patient's desire for life support was the strongest. When the physician believed that the patient wanted no life support, ventilator withdrawal was 4.2 times more likely.

In contrast with the older studies, patients typically spent just a few days on mechanical ventilation, the findings show.

The new findings may indicate that physicians are communicating better with critically ill patients, Dr. Cook observed. Physicians seem to be "paying more attention to conversations with the patient and their family rather than looking at some scoring system that tallies up injury severity," she added.

N Engl J Med 2003;349:1123-1132.

Expression of Human Herpesvirus 8 in Primary Pulmonary Hypertension

Carlyne D. Cool, M.D., Pradeep R. Rai, M.D., Michael E. Yeager, Ph.D., Daniel Hernandez-Saavedra, Ph.D., Amanda E. Serls, B.A., Todd M. Bull, M.D., Mark W. Geraci, M.D., Kevin K. Brown, M.D., John M. Routes, M.D., Rubin M. Tuder, M.D., and Norbert F. Voelkel, M.D.

ABSTRACT

Background: Severe pulmonary hypertension constitutes a group of diseases characterized by complex, lumen-occluding vascular lesions that develop in genetically susceptible persons. The only viral infection associated with severe pulmonary hypertension has been that due to human immunodeficiency virus type 1, but neither the viral genome nor viral antigens have been demonstrated in pathologic lesions.

Methods: We examined lung-tissue samples from 16 patients with sporadic primary pulmonary hypertension and 14 patients with secondary pulmonary hypertension for evidence of infection with human herpesvirus 8 (HHV-8). HHV-8 infection was ascertained immunohistochemically with use of an antibody directed against latency-associated nuclear antigen 1 (LANA-1), and a polymerase-chain-reaction (PCR) assay was performed on lung DNA to detect the viral cyclin gene of HHV-8. Sequence analysis was also performed.

Results: In lung tissue from 10 of 16 patients with primary pulmonary hypertension (62 percent), cells within the plexiform lesions as well as cells outside the lesions were positive for LANA-1 on immunohistochemical analysis. Tissue from the same 10 patients contained viral cyclin on PCR analysis. No LANA-1 was detected in lung tissue from patients with secondary pulmonary hypertension, although one such patient had PCR evidence of viral cyclin. Plexiform lesions from patients with primary pulmonary hypertension had a histologic and immunohistochemical resemblance to cutaneous Kaposi's sarcoma lesions.

Conclusions: The spectrum of trigger factors and molecular mechanisms leading to severe pulmonary hypertension and the formation of plexiform lesions is apparently wide, including both genetic and epigenetic factors. Our data suggest that infection with the vasculotropic virus HHV-8 may have a pathogenetic role in primary pulmonary hypertension.