May 2005 - World Wide Update

Avian flu trial begins

Fast-track recruitment has begun for a trial to investigate the safety of a vaccine against H5N1 avian influenza, run by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Sites in Rochester, NY, Baltimore and Los Angeles will enrol a total of 450 healthy adults.

The clinical sites are part of the NIAIDsponsored Vaccine and Treatment Evaluation Units (VTEU). “While there have been relatively few cases worldwide of H5N1 avian influenza infection in humans, the public health community is concerned that the virus will develop the capability of efficiently spreading from human to human and thus create a risk for a worldwide pandemic,” says NIAID Director Anthony S Fauci, MD. “NIAID has supported research on H5N1, the strain responsible for this deadly form of avian influenza, since 1997 when the first cases in humans were reported.

The initiation of this vaccine trial marks a key advance in our efforts to prepare to respond to an avian flu pandemic,” he adds. United States-based Sanofi Pasteur manufactured the trial vaccine, which is an inactivated vaccine made from an H5N1 virus isolated in Southeast Asia in 2004. Sanofi Pasteur, formerly Aventis Pasteur, was awarded a contract by NIAID to manufacture the H5N1 vaccine in May last year.

This Phase I trial will test the vaccine's safety and ability to generate an immune response in 450 healthy adults aged 18 to 64. If the vaccine is shown to be safe in adults, there are plans to test it in other populations, such as the elderly and children.

Misfolded proinsulin

Some insulin molecules get produced in misfolded forms — as well as the correct form — inside the cells of the pancreas, new research shows. But that variation occurs far more often in the cells of mice that must overproduce insulin, as people with type 2 diabetes do, than those without, the researchers from the University of Michigan and Pennsylvania State University report.

And, they find, the incorrectly produced forms of insulin can't leave their production site inside the cell nearly as easily as the correct form. The resulting build up of misshapen molecules inside the cell may also be enough to stress its cleanup mechanisms — and may even contribute to the cell's death. The discovery, published early online by the Journal of Biological Chemistry, may help explain why people with all forms of diabetes eventually make less insulin and experience the death of insulin-producing cells in the pancreas.

The destruction of pancreatic beta calls is the hallmark of both type 1 (juvenile) and late-stage type 2 (adult) diabetes. The new U-M research focuses on proinsulin, the molecule made in the endoplasmic reticulum area of the cell that later gets chopped to make insulin. Just seconds after proinsulin is made, the long molecule folds like origami, as six sulphur atoms within the molecule pair up to form three disulfide bonds. The locations of those sulphur atoms, and the bonds, have remained the same throughout the evolution of mammals, likely because of insulin's importance in the body's metabolic system.

For the first time ever, the U-M researchers were able to show that normal rat and human cells produce misfolded, as well as normally folded, proinsulin molecules. They made the discovery by separating proinsulin from cells, and analysing the molecules using a special technique that allowed them to see when the disulfide pairs were mismatched. They also showed far higher levels of misfolded proinsulin in mice with gene mutations that made them prone to diabetes, and in mutants of proinsulin itself. Some of the mutants made no normally-folded insulin at all.

Videocam in a pill

UT Southwestern Medical Center has acquired the new PillCam ESO technology. It allows doctors to quickly and easily assess the presence of esophageal diseases such erosive esophagitis, Barrett's esophagus and esophageal varices.

Approved by the US Food and Drug Administration late last year, the PillCam ESO is a smooth plastic capsule about the size of a large vitamin pill with video cameras on each end, equipped with a battery and internal light source. After the patient lies down, the PillCam ESO is swallowed and glides through the esophagus, taking about 2,600 color pictures (14 per second). The patient gradually sits up to aid its progression down the esophagus, while the photographs are transmitted to a recording device and then viewed on a computer screen.

The single-use capsule is passed naturally in less than 24 hours. “The main use of the PillCam ESO right now is to find pre-cancerous changes in the esophaguses of patients who had had acid reflux for more than five years,” said Dr Charles Ulrich, associate professor of internal medicine. “It also can be used to find varices or dilated veins, and there are a number of other applications under investigation.”

Current traditional diagnosis and evaluation of these conditions usually involves sending a long, flexible tube, called an endoscope, through the patient's mouth and throat into the esophagus. The procedure requires sedation, up to an hour of recovery time, post-procedural transportation and a day off work. By contrast, the PillCam ESO study takes 20 minutes, requires no sedation and provides immediate recovery, said Dr Ulrich, who heads UT Southwestern's endoscopy services. Clinical trials already have shown that its accuracy is comparable to a traditional endoscopy.

Cockroaches and asthma

New results from a nationwide study on factors that affect asthma in inner-city children show that cockroach allergen appears to worsen asthma symptoms more than either dust mite or pet allergens.

This research, funded by the National Institute of Environmental Health Sciences (NIEHS) and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the first largescale study to show marked geographic differences in allergen exposure and sensitivity in inner-city children.

Most homes in northeastern US cities had high levels of cockroach allergens, while those in the south and northwest had dust mite allergen levels in ranges known to exacerbate asthma symptoms. The study results were published in the March issue of the Journal of Allergy and Clinical Immunology. “These data confirm that cockroach allergen is the primary contributor to childhood asthma in innercity home environments,” said NIEHS director Kenneth Olden, PhD. “However, general cleaning practices, proven extermination techniques and consistent maintenance methods can bring these allergen levels under control.”

The research discovered that levels of both allergens were influenced by housing type. Cockroach allergen levels were highest in highrise apartments, while dust mite concentrations were greatest in detached homes. While cockroach allergen exposure did produce an increase in asthma symptoms, researchers did not find an increase in asthma symptoms as a result of exposure to dust mite and pet dander.

Genes and lasers

Leading laser scientists at the University of St Andrews, Scotland, have developed a new method of delivering genes to cells using laser light. The new technique, which is cheap, powerful and versatile, could have important implications for future studies in biomedicine and healthcare.

The study is part of a new interdisciplinary initiative funded by SHEFC (Scottish Higher Education Funding Council) and the EPSRC (Engineering and Physical Sciences Research Council) which aims to use light to enhance our understanding of biology and to develop new biomedical devices. Although other research groups have touched on this area, the St Andrews group has greatly simplified the technique by using an extremely uncomplicated and versatile miniature violet laser which is compatible with standard microscopes.

The method is very powerful, and in contrast to other methods the team can select individual cells to be treated at will under the microscope. The new technique involves the violet laser being focused onto cell membranes for a fraction of a second – this causes the membrane to open up, allowing foreign genes to enter. The cell’s internal mechanism causes the membrane of the cell to heal itself thus appearing to suffer no long-lasting damage. After inserting the genes, the team grew the cells, which appeared to remain healthy and multiplied normally.

The presence of the inserted gene in the multiplied cells was then confirmed by observing the red/green fluorescent proteins produced by the ‘new’ gene. Its adaptability means it could have potentially wide medical applications including gene therapy, the delivery of anti-cancer agents and advanced studies of neuro-degenerative diseases. The development is the work of a team of researchers from across the University – with key figures from the School of Physics and Astronomy, the School of Biology and The Bute Medical School.

Heart repair trial

Researchers at Johns Hopkins have begun what is believed to be the first clinical trial in the United States of adult mesenchymal stem cells to repair muscle damaged by heart attack, or myocardial infarct.

The Phase I study is designed to test the safety of injecting adult stem cells at varying doses in patients who have recently suffered a heart attack. “Current approaches to cardiovascular disease can prevent heart attack or alleviate its after-effects, but they have not included repair of damage that leaves sizably dead portions of heart tissue as dangerous scars in the heart,” says study co-investigator and cardiologist Professor Steven Schulman, MD, director of the coronary care unit at The Johns Hopkins Hospital.

Previous research in animals showed that when adult stem cells were injected directly into the heart muscle, heart function was restored to its original condition within two months. Last November, at the American Heart Association Scientific Sessions 2004, the Hopkins team showed, again in animal studies, that more than 75% of dead scar tissue disappeared after therapy, which produced mostly healthy, normal-looking heart tissue and left only a small trace of the heart attack.

The Phase I study is being conducted at Hopkins, with support from Baltimorebased Osiris Therapeutics, which developed the stem cell product. The study will involve 48 adults who have had their first heart attack within 10 days of enrolment in the trial. Upon acceptance in the study, patients will be randomly assigned to one of four groups, each made up of 12 patients who will receive a preset dose of stem cell therapy or placebo.

The study is double blinded, with neither researchers nor patients aware of who received stem cells until the Phase I study ends, six months after the last patient has enrolled.

Grapes kill cancer

Components in grapes, including some newly identified ones, work together to dramatically inhibit an enzyme crucial to the proliferation of cancer cells, say scientists at the University of Illinois at Urbana- Champaign.

The work – done using advanced molecular tools with grape-cell cultures and the target enzyme for new anti-cancer strategies – helps to identify which flavonoids in grapes and red wine are most responsible for anti-cancer qualities.

Flavonoids are a group of organic compounds that include numerous watersoluble plant pigments responsible for colors. They are more abundant in red than in white grapes. The Journal of Agricultural and Food Chemistry published the study, which details a dozen newly discovered constituents in grape-cell culture extracts and how some of them work synergistically against an enzyme known as human DNA topoisomerase II.

The enzyme is necessary for the spread of cancer and commonly used in cancer research to screen plant chemicals. “The findings add to the argument for eating whole foods,” said Elvira Gonzalez de Mejia, a professor in the department of food science and human nutrition. “It's very clear that the synergy is critical. When a cell becomes malignant that enzyme is expressed 300 times more than in a normal cell.

If we can find a compound or mixture of compounds that can reduce the activity of that enzyme, the cancerous cells will die.” The synergistic activity involves specific phytochemicals from the proanthocyanidin and anthocyanin classes of the varied flavonoid family. They worked more effectively against the enzyme than do the previously identified flavonoids quercetin and resveratrol. Alone, the individual components had less effect on the enzyme. Using vegetative samples of the plants, rather than the fruit itself, the Illinois team was able quickly to produce the whole range of grape flavonoids in greater quantity.

The researchers then extracted individual flavonoids intact. Their analytic work involved the use of reversed phase highperformance liquid chromatography and LC-electrospray ionization (ESI)/mass spectrometry to profile the most bioactive components.

Insurance pays for email

Medical insurance companies in California are reimbursing physicians for their email interactions with patients, saying that such exchanges nip potential problems in the bud without the expense of an office visit.

Paul Auwaerter, an internal medicine specialist at Johns Hopkins, feels that from the doctor's perspective, certain things lend themselves to email and others don't. He believes that consultations by email are appropriate for management of conditions about which the patient is knowledgeable, such as hypertension or diabetes.

Email replies may also be suitable for quick questions about common maladies such as colds or sinus infections. However, he felt that anything more sophisticated than that this would require a telephone conversation at a minimum.

Artificial heart study

Jarvik Heart, a developer of advanced technology for the treatment of heart failure, has received conditional approval to begin a pivotal trial of the Jarvik 2000 FlowMaker for bridge-totransplant use.

The study will enroll up to 160 patients at 25 medical centres throughout the United States. The primary endpoint of the study will be successful bridging to heart transplant or survival for six months supported by the device. Secondary endpoints will include measures of quality of life, neuro-cognitive function and rates of serious adverse events. Jarvik recently completed enrollment in its pilot study of the Jarvik 2000, which included 63 patients at eight leading medical centres.

Many of those patients are surviving up to five years following implant of the mechanical heart and subsequent transplant. In the pilot study there have been no failures of the implanted device, and although not evaluated for statistical significance, the data suggest lower device infection rates than reported in the literature for the two currently FDA-approved heart assist devices, and rates of thromboembolism and stroke that are approximately the same as published for the approved devices.

The Jarvik 2000 weighs only 90 grammes, compared to 1200g for HeartMate and 1800g for Novacor. It is silent whereas HeartMate and Novacor produce constant noise audible to the patient and others nearby. And because the Jarvik 2000 is a true booster pump, the patient's natural heart continues to work in tandem with it. Therefore the device requires less power and achieves long battery life.

These and other characteristics have been "human engineered" to provide the patient a high quality of life. The Jarvik 2000 FlowMaker has also been used as a permanent implant in Europe. The first patient to receive the device for lifetime use is in good health nearly five years following his surgery and is the longest surviving patient in the world continuously supported by any type of artificial heart.

New waterbalance disorder

Two infant boys whose bodies were overloaded with excess fluid have led University of California San Francisco paediatricians to the discovery of a new genetic disease.

The new disorder, called Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD), is described in the 24 March issue of The New England Journal of Medicine. This discovery gives insights into treating these patients and potentially many others, as it sheds new light on the mechanisms that the body uses to maintain fluid homeostasis – the correct balance of fluids needed for health and life.

The team of paediatricians at University of California, San Francisco found that each infant has a different mutation in a specific gene, AVPR2, that encodes the V2 receptor (V2R) for vasopressin, a hormone that instructs the kidneys to retain water. Neither patient was producing measurable levels of vasopressin, yet the V2 receptor on cells in the collecting duct of the kidneys remained activated as if it was binding to the hormone. Both mutations activate the receptor by changing a single amino acid, arginine, located on the gene at position 137.

This location, R137, already is known to scientists who study fluid homeostasis. A third, different mutation had been previously shown to block the V2 receptor, causing a condition opposite to NSIAD called diabetes insipidus. In that condition, instead of retaining fluids, the kidneys excrete water excessively, leading to severe dehydration.

"To our knowledge, this is the only reported example in which mutations affecting the same amino acid cause two different genetic diseases," the UCSF researchers write. While only two infants so far have been identified with NSIAD, the condition may not be rare, according to Stephen Rosenthal, MD, professor of paediatric endocrinology and co-lead author of the study with endocrinology fellow Brian Feldman, MD, PhD. “Water retention is a common problem, and with new tools we can examine our longheld assumptions about its cause,” Rosenthal said.

“There may be mutations in other components of the V2 receptor signalling cascade that result in inappropriate antidiuresis.”

Stem cells in nose

Reseachers at Griffith in Brisbane, Australia, have successfully grown adult stem cells harvested from the olfactory mucosa, the organ of smell in the human nose. They demonstrated the cells can give rise not only to nerve cells but also to heart, liver, kidney, and muscle cells.

The research team has spent the past four years developing the research that will have potential clinical application in stem cell transplantation therapies and in understanding the biology of diseases. Professor Alan Mackay- Sim, deputy director of the university’s Institute for Cell and Molecular Therapies said the discoveries highlighted significant advantages of these adult stem cells over embryonic stem cells.

“Our experiments have shown adult stem cells isolated from the olfactory mucosa have the ability to develop into many different cell types if they are given the right chemical or cellular environment,” Professor Mackay-Sim said. “These adult olfactory stem cells appear to have the same ability as embryonic stem cells in giving rise to many different cell types but have the advantage that they can be obtained from all individuals, even older people who might be most in need of stem cell therapies.

Stem cells obtained from and transplanted into the same person would not be rejected by the immune system,” he added. Another advantage of adult olfactory stem cells is they are readily obtained from the nose and relatively easy to grow and multiply in the lab. For the past three years Professor Mackay-Sim’s research team has been investigating the potential of olfactory stem cells in treating Parkinson’s disease and is currently using stem cells from Parkinson’s sufferers to gain insights into the causes of the disease.

Optic nerve regeneration

For the first time, scientists have regenerated a damaged optic nerve -– from the eye to the brain. This achievement, which occurred in laboratory mice, holds great promise for victims of diseases that destroy the optic nerve, and for sufferers of central nervous system injuries.

“For us, this is a dream becoming reality," says Dr Dong Feng Chen, lead author of the study, assistant scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School.

"This is the closest science has come to regenerating so many nerve fibres over a long distance to reach their targets and to repair a nerve previously considered irreparably damaged.” In addition to the thousands of Americans blinded by glaucoma and injuries that destroy the optic nerve, and hundreds of thousands disabled by spinal cord injuries, “we were hearing stories of soldiers in the Middle East whose lives were saved by body armour, but who were returning with severe damage to limbs and eyes,” he says.

“At the same time, we learned of the untimely death of Christopher Reeves. It was, therefore, a priority for us to redouble our efforts to find ways to restore damaged nerves.” Chen and her research team have dedicated themselves to learning the reasons why CNS tissue stops regenerating and to finding ways to reverse that process, using the optic nerve as their research model.

The optic nerve, which connects the eye to the brain, consists of millions of nerve cells, which, when uninjured, transmit visual information from the retina to the brain for interpretation.

Airborne SARS

Two new studies present evidence that the virus causing severe acute respiratory syndrome (SARS) may spread through the air, not just through direct contact with contaminated water droplets as previous research had shown.

SARS coronavirus was detected in the air in a patient's room during the 2003 outbreak in Toronto, according to a new study published in The Journal of Infectious Diseases. Another study, from Hong Kong, shows patients in hospital bays near a SARS patient had a much higher infection rate than patients in distant bays, consistent with the possibility of airborne SARS transmission, according to an article in Clinical Infectious Diseases. The Toronto research was conducted by Timothy F Booth, PhD and colleagues during the SARS outbreak there in March 2003.

Their results mark the first experimental confirmation of the presence of the SARS virus in the air of an infected patient's hospital room. The authors cautioned that their results do not document any cases of airborne transmission of the SARS virus from one person to another, only the dissemination of the virus from an infected patient to the air, via breathing or coughing. During the outbreak in Toronto hospitals, health care workers became infected with the virus despite observance of strict infection control precautions.

The investigators wondered whether environmental contamination of hospital air or surfaces could explain the ongoing risk of SARS coronavirus transmission to health care workers. To answer this question, they collected patient information and environmental samples from the SARS units of four Toronto hospitals. SARS coronavirus was detected in the air in one of the four rooms tested. The researchers also detected virus in four of 85 surface samples taken from frequently touched surfaces, highlighting the importance of strict adherence to infection control precautions to prevent SARS coronavirus transmission in the health care setting.

In the Hong Kong study, which focused on the 2003 SARS outbreak at the Prince of Wales Hospital, 41% of patients admitted to the ward in which the first SARS patient was staying became infected. Proximity to the bed of the first case seemed to be strongly linked with incidence of infection-twothirds of patients in the same bay and half of patients in an adjacent bay were infected with SARS, while only 18% of patients in distant bays were infected.