Ouch! Taking a Shot at Plague: Vaccine Offers Hope for Endangered Ferrets in Plague Outbreak

Endangered black-footed ferrets, like children, aren't exactly lining up to be stuck with a vaccine, but in an effort to help control an extensive outbreak of plague in South Dakota, some of the ferrets are getting dosed with a vaccine given by biologists.

This is the first time the vaccine has been used during a major plague epizootic—an animal version of a human epidemic. Sylvatic plague is an infectious bacterial disease usually transmitted from animal to animal by fleas. This exotic disease is usually deadly for black-footed ferrets and their primary prey, prairie dogs. Black-footed ferrets are one of the rarest mammals in North America.

In mid-May, the Centers for Disease Control confirmed sylvatic plague in black-tailed prairie dog colonies in the Conata Basin area of Buffalo Gap National Grasslands in southwestern South Dakota. As of late June, about 9,000 acres of prairie dog habitat — including colonies occupied by vulnerable black-footed ferrets — have been infected by the disease, according to U.S. Forest Service mapping. Black-tailed prairie dogs are also being reconsidered for listing under the Endangered Species Act.

Ferret population surveys in the fall of 2007, before the outbreak, indicated at least 290 ferrets lived in the Conata Basin ferret reintroduction area. Some of the plague-impacted prairie-dog colonies were occupied by ferrets, but researchers do not know yet how many ferrets have died from the outbreak. Scientists report that in the past, such outbreaks have wiped out entire colonies of prairie dogs and the black-footed ferrets that depended on them for food.

To help increase ferret survival during this outbreak, biologists are vaccinating wild ferrets to provide immunity if they become exposed to plague. The plague vaccine was developed for humans by the U.S. Army Medical Research Institute for Infectious Disease and is being tested and modified for animals at the USGS National Wildlife Health Center (NWHC) in Madison, Wisc.

Ferret getting vaccinated at the USGS National Wildlife Health Center (courtesy USGS)

Spraying insecticide in prairie-dog colony (courtesy USFWS)

Black-footed ferret poking its head out of a prairie-dog burrow (courtesy USFWS)

"Although the plague vaccine is still experimental in wildlife, we hope its use during this epizootic will protect as many ferrets as we can capture in the field and boost ferret survival during this critical period," said USGS NWHC Research Chief Dr. Christopher Brand.

Prairie Wildlife biologists working with the federal agencies have captured and vaccinated 40 black-footed ferrets since the outbreak began, said Scott Larson with the U.S. Fish and Wildlife Service, who is coordinating measures to conserve ferrets among the federal agencies.

Dr. Tonie Rocke, the lead researcher at the USGS NWHC testing the vaccine for animals, said the vaccine is administered to prairie dogs and black-footed ferrets through an initial shot and a booster about a month later. She noted that the NWHC is working on a separate oral vaccine for prairie dogs that can be put into bait and delivered in the field without having to handle the animals, a process that is time-consuming.

Another strategy to control plague outbreaks is to apply insecticide that will reduce the flea populations in the prairie dog colonies that are important to black-footed ferrets, but that have not yet experienced plague die-offs.

Dr. Dean Biggins, a research ecologist and black-footed ferret expert at the USGS Fort Collins Science Center in Colorado, is collaborating with the NWHC to investigate the combined efficacy of dusting burrows with insecticide and vaccinating animals in the field. "We've had experience with burrow dusting in other areas, and we know dusting protects both species from plague during these outbreaks," Biggens said.

Field tests, said Biggins, showed that the combination of burrow dusting and experimental vaccine protected black-footed ferrets in Montana during a time of low-level plague mortality in the area.

"What we're trying to do in South Dakota is assess the protectiveness of the vaccine for prairie dogs and ferrets during a full-blown eruption of plague that is causing high mortality in the prairie dog population," Biggins said. About 75 prairie dogs were experimentally vaccinated in 2007 in South Dakota, and vaccination is continuing in 2008.

The U.S. Fish and Wildlife Service, U.S. Geological Survey, Animal and Plant Health Inspection Service, National Park Service, and the U.S. Forest Service are working together to lessen the impacts of this outbreak, as are private organizations such as Prairie Wildlife Research and conservation groups, including World Wildlife Fund, Defenders of Wildlife, and the Prairie Dog Coalition.

The same bacterium that affects ferrets, prairie dogs, and other rodents, is also responsible for human cases of plague. The disease is transmitted from animals to humans by bites of infected fleas, but it can be cured with antibiotics if treatment is prompt. About 5 to 15 people are infected by plague each year, and it is not unusual to have some human fatalities as a result. Last November, a National Park Service biologist contracted plague from a cougar and died.

New Approach Sheds Light on Ways Circadian Disruption Affects Human Health

Growing evidence indicates that exposure to irregular patterns of light and darkness can cause the human circadian system to fall out of synchrony with the 24-hour solar day, negatively affecting human health — but scientists have been unable to effectively study the relationship between circadian disruptions and human maladies.

The Daysimeter, shown above, measures an individual’s daily rest and activity patterns, as well as exposure to circadian light — short-wavelength light, particularly natural light from the blue sky, that stimulates the circadian system. Photo Credit: Rensselaer/Dennis Guyon

A study by researchers in Rensselaer Polytechnic Institute’s Lighting Research Center (LRC) provides a new framework for studying the effects of circadian disruption on breast cancer, obesity, sleep disorders, and other health problems.

Light and dark patterns are the major synchronizer of circadian rhythms — the biological cycles that repeat approximately every 24 hours — to the solar day. Inadequate or irregular light exposure can cause circadian rhythm disruptions that are believed to manifest into a variety of health ailments. However, ecological studies to measure human light exposure are virtually nonexistent, making it difficult to determine if, in fact, light-induced circadian disruption directly affects human health.

LRC researchers have created a small, head-mounted device to measure an individual’s daily rest and activity patterns, as well as exposure to circadian light — short-wavelength light, particularly natural light from the blue sky, that stimulates the circadian system. The device, called the Daysimeter, was sent to 43 female nurses across the country to measure their daily exposure to circadian light, according to Mark Rea, director of the LRC and principal investigator on the project.

The Daysimeter was worn for seven days by both day-shift and rotating shift nurses and then returned to the LRC for analysis. Simultaneously, Rea and his colleagues studied the effect of irregular light exposure to the circadian system of 40 rats, in order to determine if the relationship between circadian disruption and health outcomes could be uncovered using rodent models.

Twenty rats were exposed to a consistently repeating pattern of 12 hours of light followed by 12 hours of dark, to mimic the light exposure experienced by day-shift workers. The remaining rodents were exposed to irregular 12-hour patterns of light and darkness.

For the nurses, circadian entrainment and disruption was measured by comparing exposure light and darkness with each individual’s rest and activity patterns. Wheel running was used to measure rat rest and activity patterns.

A quantitative measure of circadian behavioral entrainment or disruption for day-shift and rotating shift workers was developed based on the circular cross-correlations of activity and light exposure data from both the nurses and the rats. An analysis technique commonly utilized in the field of signal processing, circular cross-correlation involves the concept of time-shifting one signal relative to another to determine relationships between signals that might otherwise be obscured due to timing differences.

“We found that the circadian entrainment and disruption patterns for day-shift and rotating shift nurses were remarkably different from each other, but remarkably similar to the patterns for the two parallel groups of nocturnal rodents,” says Rea. “The marked differences within species, together with the marked similarities across species, in addition to the new method of quantifying circadian entrainment or disruption suggests that health-related problems associated with circadian disruption in humans can be parametrically studied using animal models.”

“This ability to quantitatively define circadian light and dark for humans and for animals will allow a new class of meaningful studies of light as a stimulus for circadian entrainment or disruption to be undertaken, not only in humans, but in nocturnal rodents as well – which, until now, has been impossible,” says Rea. “Additionally, studies of circadian disruption employing animal models for human disease can now be designed and conducted to more accurately reflect their relevance to the actual living conditions in humans.”

Rea carried out his research with LRC researchers Andrew Bierman, Mariana Figueiro, and John Bullough, who are co-authors on the paper. The study is published online in the Journal of Circadian Rhythms and can be viewed in its entirety at: http://www.jcircadianrhythms.com/content/6/1/7.

This project was funded by a grant from the National Institutes of Health’s Genes, Environment, and Health Initiative.

About the Lighting Research Center
The Lighting Research Center (LRC) is part of Rensselaer Polytechnic Institute of Troy, N.Y., and is the leading university-based research center devoted to lighting. The LRC offers the world’s premier graduate education in lighting, including one- and two-year master’s programs and a Ph.D. program. Since 1988 the LRC has built an international reputation as a reliable source for objective information about lighting technologies, applications, and products. The LRC also provides training programs for government agencies, utilities, contractors, lighting designers, and other lighting professionals. Visit www.lrc.rpi.edu.

About Rensselaer
Rensselaer Polytechnic Institute, founded in 1824, is the nation’s oldest technological university. The university offers bachelor’s, master’s, and doctoral degrees in engineering, the sciences, information technology, architecture, management, and the humanities and social sciences. Institute programs serve undergraduates, graduate students, and working professionals around the world. Rensselaer faculty are known for pre-eminence in research conducted in a wide range of fields, with particular emphasis in biotechnology, nanotechnology, information technology, and the media arts and technology. The Institute is well known for its success in the transfer of technology from the laboratory to the marketplace so that new discoveries and inventions benefit human life, protect the environment, and strengthen economic development.

New Paper Addresses Myths, Realities of Government Retiree Health-Care Crisis

While some states are taking adequate steps to address the cost of retiree health-care benefits, others – including New Jersey, New York, California and North Carolina – are facing tens of billions of dollars in so-called "unfunded liabilities." The myths and realities of this potential crisis are laid out in a new issue brief written by Dr. Robert Clark, a professor of economics and of management, innovation and entrepreneurship at North Carolina State University, and released by the Center for State and Local Government Excellence.

The paper, The Crisis in State and Local Government Retiree Health Benefit Plans: Myths and Realities, examines the current financial status of state retiree health plans from around the country. States with the lowest unfunded liabilities include North Dakota, Wyoming, Iowa and Oregon.

The brief finds that:

• Although there are widespread reports of a major fiscal crisis, the reality is that some states face a fiscal crisis while others do not.

• There are substantial differences in the total liabilities of state retiree health plans, depending on the generosity of the plan and the size of the public sector.

• Retirement benefits are not protected by state laws or constitutions, and public sector employers will continue to amend their plans to reduce costs.

For a copy of the full brief, visit the Web at http://tinyurl.com/5rfyw2

The Center for State and Local Government Excellence helps state and local governments become knowledgeable and competitive employers so they can attract and retain a talented and committed workforce. The center identifies best practices and conducts research on competitive employment practices, workforce development, pensions, retiree health security, and financial planning.

Using Magenetic Nanoparticles to Combat Cancer

Scientists at Georgia Tech have developed a potential new treatment against cancer that attaches magnetic nanoparticles to cancer cells, allowing them to be captured and carried out of the body. The treatment, which has been tested in the laboratory and will now be looked at in survival studies, is detailed online in the Journal of the American Chemical Society.

Magnetic Nanoparticles Capture Ovarian Cancer Cells
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"We've been able to use magnetic nanoparticles to capture free-floating cancer cells and then take them out of the body,” said John McDonald, chair of the School of Biology at Georgia Tech and chief research scientist at the Ovarian Cancer Institute. “This technology may be of special importance in the treatment of ovarian cancer where the malignancy is typically spread by free-floating cancer cells released from the primary tumor into the abdominal cavity.”

The idea came to the research team from the work of Ken Scarberry, a Ph.D. student in Tech’s School of Chemistry and Biochemistry. Scarberry originally conceived of the idea as a means of extracting viruses and virally infected cells when his advisor, Chemistry professor John Zhang, had another idea. He asked if the technology could be applied to cancer. Scarberry suggested it might be an effective means of preventing cancer cells from spreading.

They began by testing the therapy on mice. After giving the cancer cells in the mice a fluorescent green tag and staining the magnetic nanoparticles red, they were able to apply a magnet and move the green cancer cells to the abdominal region.
“If the therapy is able to pass further tests that show it can prevent the cancer from spreading from the original tumor,” Scarberry said, “it could be an important tool in cancer treatment.”
This technology holds more promise than solely using antibodies to fight cancer because there seems to be less potential for the body to develop an immune response due to the unique peptide-targeting strategy, and the composition of the magnetic nanoparticles.

"If you modify the nanoparticle and target it directly to the tumor cells using a small peptide, you are less likely to generate an undesirable immune response and more accurately target the cells of interest,” said Research Scientist Erin Dickerson.

In addition to testing magnetic nanoparticles, the research team is collaborating with other groups at Georgia Tech to determine how peptide-directed gold nanoparticles and nanohydrogels might also be used in fighting cancer.

Largest review of office-based plastic surgery confirms safety in accredited facilities

Mortality rate less than 1 percent in over 1.1 million procedures

ARLINGTON HEIGHTS, Ill. –A study examining plastic surgery procedures performed in accredited outpatient facilities found that office-based surgery is as safe as surgery performed in hospitals. The study published in July's Plastic and Reconstructive Surgery® (PRS), the official medical journal of the American Society of Plastic Surgeons (ASPS), reviewed more than 1.1 million procedures and found the mortality rate to be significantly less than one percent or 0.002 percent.

"The study shows that plastic surgery in accredited facilities is safe and deaths are rare," said ASPS Member Surgeon Geoffrey Keyes, MD, study co-author. "However, people should consider plastic surgery with the same seriousness as medically necessary surgery. Most importantly, patients should have their procedure performed by an ASPS Member Surgeon in an accredited facility."

The study reviewed data collected from January 2001 through June 2006 by The American Association for Accreditation of Ambulatory Surgery Facilities (AAAASF), which mandates biannual reporting of all complications and fatalities. The data was obtained from facilities accredited by the AAAASF, which requires that surgeons be board-certified and have credentials at a hospital to perform any procedure being contemplated at an office-based facility. The ASPS requires all of its Member Surgeons to operate only in accredited or licensed facilities.

The study found deaths occurring at office-based surgery facilities are rare. More than 1.1 million operative procedures in AAAASF-accredited office-based outpatient surgery centers were studied from 2001-2006. Deaths were infrequent, occurring 2.02 in 100,000 procedures or 0.002 percent, which is comparable to the overall risk of such procedures performed in hospital surgery facilities. The vast majority of deaths were due to pulmonary embolism (a blood clot that travels to the lungs, blocking major blood vessels). Pulmonary embolism is an uncommon cause of death associated with any type of surgery whether elective or medically necessary.

These new findings contribute to a growing safety record for office-based surgery procedures. A 2004 PRS journal study examined 400,000 operative procedures in AAAASF-accredited office-based outpatient surgery centers from 2001-2002 and found that death occurred in 1 in 59,000 procedures or 0.0017 percent.

"While all surgery carries risks, the bottom line is that this study illustrates patients can and should feel safe when they go to an ASPS Member Surgeon who performs their procedures in an accredited facility," said ASPS President Richard D'Amico, MD. "Amazingly, only 14 states mandate accreditation of facilities, so it's up to the patient to be knowledgeable. A patient's safety and life is everything."

Nearly 11.8 million cosmetic surgery procedures were performed in 2007, up 59 percent since 2000, according to ASPS statistics. Fifty-nine percent of cosmetic surgery procedures were performed in an office-based facility, 21 percent in a free-standing ambulatory surgical facility, and 20 percent in a hospital.

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The American Society of Plastic Surgeons is the largest organization of board-certified plastic surgeons in the world. Representing more than 6,700 physician members, the Society is recognized as a leading authority and information source on cosmetic and reconstructive plastic surgery. ASPS comprises more than 90 percent of all board-certified plastic surgeons in the United States. Founded in 1931, the Society represents physicians certified by The American Board of Plastic Surgery or The Royal College of Physicians and Surgeons of Canada.

Booster vaccination may help with possible future avian influenza pandemic

New evidence suggests that a booster vaccination against H5N1 avian influenza given years after initial vaccination with a different strain may prove useful in controlling a potential future pandemic. The study is published in the August 1 issue of The Journal of Infectious Diseases, now available online.

H5N1 continues to pose a major health risk to birds and humans. As of mid-June, more than 60 percent of the more than 380 human cases have been fatal, and hundreds of millions of birds have died or been culled to prevent the spread of the disease. Should the virus evolve making human-to-human transmission more likely, a destructive global influenza pandemic could result.

The cornerstone of planning for such a possible pandemic is the development and distribution of effective vaccines. Several vaccines have been developed, but as the virus continues to mutate into genetically distinct lineages, or clades, the problem arises as to whether vaccines based on an older clade will be effective against newer versions. The new study is the first to report that giving one dose of a newer-clade vaccine to those who were vaccinated previously with older versions is more effective than giving only doses of the newer vaccine to unvaccinated subjects.

The study, conducted by Nega Ali Goji, MD, and colleagues from New York, Maryland, and Alabama, gave a single booster dose of a vaccine based on a clade 1 H5N1 virus circulating in Vietnam in 2004 to subjects who eight years earlier had received two doses of a vaccine based on the original, clade 0 virus that appeared in Hong Kong in 1997. Sixty-four percent had a positive immune response, which compares favorably to the results of a previous study using two doses of the clade 1 Vietnam virus, in which only 43 percent of those vaccinated had a positive immune response.

The results not only support the booster technique, but also show that even though the virus had mutated since the initial vaccination, using it to boost an earlier vaccine is more effective than simply vaccinating subjects with the most current vaccine. These findings are important given the fact that influenza viruses are mutating constantly.

"These results suggest that one strategy for pandemic control could involve prevaccination of some segments of the population prior to the emergence of a pandemic so that effective protection could be achieved with a single dose schedule if and when a pandemic emerges," the authors wrote. "If the finding that priming can result in enhanced responses to single-dose vaccination schedules were confirmed, then pre-pandemic vaccination programs could be considered, especially in populations of first responders, health care workers, or the military. Such populations might then be able to be effectively and rapidly vaccinated with a single dose of a vaccine specific for an emerging pandemic if it were to occur."

In an accompanying editorial, Gregory A. Poland, MD, of the Mayo Clinic College of Medicine, noted that some are already looking to begin such prevaccination primers against H5N1 influenza. For example, Japan is planning to immunize health care workers starting in 2009, and the U.S. Department of Defense is offering a vaccine to those in high risk specialties.

Dr. Poland pointed out that new studies are needed to investigate different types of vaccine administration, deal with vaccinations that prevent death but not infection and illness, search for more broadly cross-protective influenza vaccines, and collect data on the vaccination of those who are not healthy adults. Although, he said, "determining who should receive these vaccines, when, and in what order and under what circumstances deserves widespread debate," he agrees that the findings of the study are novel, as they "suggest that such a prime-boost strategy using vaccines derived from different H5 clades, separated by years, may be worthwhile, immunologically feasible, and safe."

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Fast Facts

1) Experts are concerned about a possible pandemic of H5N1 influenza. As of mid-June, 60 percent of the more than 380 human cases have been fatal, and half a billion birds have died or been culled to prevent the spread of the disease. Should the virus evolve making human-to-human transmission more likely, a destructive global influenza pandemic could result.

2) Giving a "booster" vaccine using a recent strain of virus to those previously vaccinated with an older strain was more effective than only vaccinating with the recent strain. Especially relevant is the fact that the primer and booster vaccines were derived from different strains of the virus and still were effective.

Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 8,000 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.

Psychological and social issues associated with tooth loss

Expert shares ways to cope with the impact of losing teeth

ORLANDO (July 16, 2008)—Are feelings of depression overwhelming you? Is your self-esteem an issue? Having problems advancing in life or your career? Maybe you feel nervous or self conscious in social settings? Do you avoid social settings all together? Check your smile; tooth loss could be the culprit and you're not alone. Nearly 20 million teeth are extracted each year leaving scores of people to deal with the psychological affects of a less than perfect smile. However, during the Academy of General Dentistry's (AGD) 56th Annual Meeting & Exhibits in Orlando, Fla., July 16-20, H. Asuman Kiyak, PhD, will address the psychological issues affecting people who must deal with the loss of a tooth, as well as explain how this loss can affect the quality of life.

In Dr. Kiyak's course, "Enhancing the Oral Health and Quality of Life for Partially Edentulous or Fully Edentulous Patients: The Importance of Communication," she will reveal the post traumatic effects a patient endures after the loss of a tooth and will also pinpoint ways a doctor can communicate with a patient to help them cope with and understand their options for restoring their smile.

"The major impact of tooth loss is on the appearance and social relations component of quality of life because people cannot change their appearance with missing teeth," says Dr. Kiyak.

In fact, recent results from a survey distributed to nearly 20,000 AGD members revealed that more than 86 percent of general dentists reported social embarrassment is one of the greatest problems associated with tooth loss and more than half of these patients avoid social interaction because of it.

Yet, Dr. Kiyak noted that there are ways that patients can learn how to cope with the loss of a tooth. Dr. Kiyak encourages patients to:

• Weigh their options with the pros and cons for replacement teeth or even endodontic treatment to save a "hopeless" tooth.

• Review videos or still photos of others who have lost teeth and their current teeth status with removable or implant-supported dentures.

• Read testimonials of others who have undergone single, multiple, total tooth loss and replacement of these teeth with removable or implant-supported dentures, how they have coped with each stage and how they are functioning orally, systemically and psychologically with these dentures.

"A smile serves as an individual's most powerful tool," says AGD spokesperson Laura Murcko, DMD. "A great smile can make a great lasting impression, boost a person's self-esteem and confidence as well as improve their overall health."

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Dr. Kiyak will be one of more than 100 speakers that will present the latest developments in oral health and technology during the AGD's Annual Meeting & Exhibits. Dr. Kiyak's course will be held on Thursday, July 17 from 1:00 p.m. to 4:00 p.m. EDT.

About the AGD

The AGD is a professional association of more than 35,000 general dentists dedicated to staying up-to-date in the profession through continuing education. Founded in 1952, the AGD has grown to become the world's second largest dental association, which is the only association that exclusively represents the needs and interests of general dentists.

More than 786,000 persons are employed directly in the field of dentistry. A general dentist is the primary care provider for patients of all ages and is responsible for the diagnosis, treatment, management, and overall coordination of the general dentist through financial support of scientific, educational services related to a patient's oral health.

For more information about the AGD, please visit www.agd.org.

Dentists will be available for interviews about this topic, and/or other oral health topics, prior to and during the Annual Meeting which takes place July 16-July 20, 2008. Please contact Joshauna Walker at 312.440.4974 or media@agd.org.

New research from Rhode Island Hospital may help predict outcomes for stomach cancer patients

Study identifies possible markers for cancer prognosis

PROVIDENCE, R.I. – Researchers at Rhode Island Hospital have identified two potential molecular markers that may predict outcomes for patients with stomach cancer, one of the most common and fatal cancers worldwide.

According to the study, published in the July 1 issue of Clinical Cancer Research, patients who had poor outcomes following surgery for stomach cancer also had extremely low amounts of two proteins, known as gastrokine 1 and 2 (GKN1 and GKN2), which are produced by normal stomach cells.

The study's findings confirm previous research showing that once stomach cells become cancerous, they manufacture very low amounts of GKN1 and GKN2. However, this is the first known study to link these low protein levels with outcomes following stomach cancer surgery. Researchers say this discovery could eventually help physicians better determine and individualize therapy for stomach cancer, including which patients should be offered chemotherapy and other treatments in addition to surgery.

"Unfortunately, stomach cancer is difficult to cure unless it's discovered early, but because the early stage of the disease has very few symptoms, the cancer is usually advanced by the time it's diagnosed," says lead author Steven Moss, MD, a gastroenterologist with Rhode Island Hospital and an associate professor of medicine at The Warren Alpert Medical School of Brown University.

"That's what makes our findings so significant, because if the potential markers identified in our study can help predict a patient's prognosis, we can decide right away which course of action to take and hopefully help patients live longer and more comfortably," he adds.

According to the National Cancer Institute, approximately 760,000 cases of stomach cancer are diagnosed worldwide each year. Microscopically, stomach cancers can be subdivided into those which appear "diffuse" (a more aggressive form of cancer that can occur throughout the stomach and is more likely to spread) or "intestinal" (resembling the cells normally found only in the small or large intestines). Stomach cancers of both types are often triggered by a chronic infection brought on by Helicobacter pylori (H. pylori), a common bacterium that causes stomach inflammation and ulcers. Surgery is the most common treatment for stomach cancer and can include partial or full removal of the stomach. The five-year relative survival rate of patients with stomach cancer is 24 percent.

Moss, an expert on H.pylori, and colleagues initially set out to learn more about what the bacterium does to normal stomach cells. They focused on GKN1 and GKN2 because these proteins are also suppressed by stomach infections caused by H. pylori.

After looking at tissue samples from more than 150 stomach cancer patients who underwent surgery, the researchers discovered a near total suppression of GKN1 and GKN2 in the majority of patients. This was particularly evident in those patients with the diffuse variant of stomach cancer. More than three-quarters of these patients had extremely low levels of GKN1 and 85 percent had nearly nonexistent levels of GKN2.

Furthermore, in those patients with the intestinal variant of stomach cancer, very low levels of GKN 1 or GKN 2 at the time of surgery were associated with a significantly worse outcome. The median survival was about two years in these patients compared to a survival of more than 10 years for patients with normal levels of GKN1 or GKN2.

Researchers do not yet know the exact function of GKN1 and GKN2. They say further studies are needed to demonstrate the mechanisms responsible for the loss of GKN1 and GKN2 in this patient popoulation as well as the clinical biomarker potential of these two proteins.

The study included tissue samples from 155 patients with stomach cancer (81 men and 74 women) who underwent surgery at Rhode Island Hospital and The Miriam Hospital, both in Providence, R.I. The average age at surgery was 72 years. All four stages of cancer were represented in the study, including 37 patients with Stage I, 44 patients with Stage II, 34 patients with Stage III, and 40 patients with Stage IV. More than 61 patients were being treated for the intestinal variant of stomach cancer while 90 patients had the diffuse variant.

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The study was funded by research grants from the National Institutes of Health.

Study co-authors were Murray Resnick, Edmond Sabo, John Gao, Patricia A. Meitner, and Rose Tavares from Rhode Island Hospital and Alpert Medical School; John Rommel and Anna Rubin from Alpert Medical School; Jin-Woo Lee from Inha University Hospital, South Korea; and Bruce R. Westley and Felicity E.B. May from the Northern Institute for Cancer Research at University of Newscastle upon Tyne, United Kingdom.

Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of The Warren Alpert Medical School of Brown University. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks among the country's leading independent hospitals that receive funding from the National Institutes of Health, with research awards of nearly $27 million annually. Many of its physicians are recognized as leaders in their respective fields of cancer, cardiology, diabetes, orthopedics, neurology and minimally invasive surgery. The hospital's pediatrics division, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery. Rhode Island Hospital is a founding member of the Lifespan health system.

Genetic cause of innate resistance to HIV/AIDS

MUHC and CHUM researchers demonstrate how 2 specific genes are involved in an innate resistance to HIV infection

Montreal, 16 July 2008 - Some people may be naturally resistant to infection with HIV, the virus that causes AIDS. The results of a study conducted by Dr. Nicole Bernard of the Research Institute of the McGill University Health Centre (MUHC) bring us closer to a genetic explanation. Her study findings were published on July 16 in the journal AIDS.

The simultaneous expression of certain versions of two specific genes called KIR3DL1 and HLA-B*57 is thought to be at the root of some cases of this innate resistance to HIV infection. Depending on which versions of these two genes the patient has, he or she will resist HIV infection or develop AIDS at a slower rate.

These results were obtained by comparing the genetic profiles of people undergoing primary HIV infection ( in their first year of infection) to those repeatedly exposed to HIV but non-infected. The group of exposed but non-infected patients came from a cohort studied by Dr. Julie Bruneau of the Centre hospitalier de l'Université de Montréal. The cohort of primary HIV infected patients is studied by Dr. Jean-Pierre Routy, from the MUHC. Analyses show that the "good" versions of both genes were present in 12.2% of exposed but non-infected subjects versus only 2.7% in patients in primary HIV infection.

As of yet, no study has clearly described the mechanism of this protection. The KIR3DL1 gene codes for a receptor on the surface of the immune system's natural killer (NK) cells, which when activated destroy infected cells in the body. The HLA-B*57 gene codes for a protein normally found on the surface of all body cells that binds the KIR3DL1 and dampens NK cell activity. The most likely hypothesis is that HIV prevents the HLA-B*57-encoded protein from being expressed on the surface of the infected cells, making it unavailable to bind KIR3DL1. As a consequence, the NK cells retain their activity and destroy the virus-infected cells.

As this mechanism can occur very soon after the virus has started to infect the body cells, people carrying those versions of the 2 genes may be able to destroy more efficiently the infected cells following exposure to HIV, thus lowering their chances of developing AIDS.

"More research is needed to determine the exact mechanism behind the protection we have observed, but these findings have revealed a promising avenue," according to Dr. Bernard.

This study opens the way for new ideas in the fight against HIV infection. "In the future, our findings could be used to somehow 'boost' the innate immune system and thus fight the virus as soon as it enters the body," said Dr. Bernard.

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Dr. Nicole Bernard is a researcher in the Infection and Immunity Axis of the Research Institute of the McGill University Health Centre (RI MUHC) and a member of the McGill AIDS Centre. She is also an Associate Professor of Medicine at the Faculty of Medicine of McGill University.

Dr. Julie Bruneau is a practitioner at the Service de médecine des toxicomanies of the Centre hospitalier de l'Université de Montréal (CHUM) and Assistant Scientific Director of Clinical Research of the Centre de recherche du CHUM. She is also Associate professor at the department of family medicine, Université de Montréal

Dr Jean-Pierre Routy is an investigator in the Infection and Immunity Axis of the RI MUHC, and an Associate Professor of haematology at the Faculty of Medicine of McGill University.

This study was funded by the Canadian Institutes for Health Research (CIHR) and the Fonds de la recherche en santé du Québec (FRSQ).

The McGill University Health Centre

The McGill University Health Centre (MUHC) is a comprehensive academic health institution with an international reputation for excellence in clinical programs, research and teaching. Its partner hospitals are the Montreal Children's Hospital, the Montreal General Hospital, the Royal Victoria Hospital, the Montreal Neurological Hospital, the Montreal Chest Institute and the Lachine Hospital. The goal of the MUHC is to provide patient care based on the most advanced knowledge in the health care field and to contribute to the development of new knowledge. www.muhc.ca

The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.

The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santé du Québec.

For further details visit: www.muhc.ca/research.

About CHUM

The Centre hospitalier de l'Université de Montréal (CHUM) provides specialized and ultra-specialized services to a regional and supra-regional clientele. Within its more immediate coverage area, the CHUM also provides general and specialized hospital care and services. The CHUM uses an integrated network model to carry out its five-part mandate of care, teaching, research, the assessment of technologies and health care methodologies, and the promotion of health care. Through its determined efforts to continuously improve quality of care and patient safety, the CHUM has again received accreditation from the Canadian Council on Health Services Accreditation, for the 2007-2010 period. Hôtel-Dieu, Hôpital Notre-Dame, and Hôpital Saint-Luc make up the CHUM, with approximately 10,000 employees, 900 physicians, 270 researchers, 6,000 students and trainees and 700 volunteers providing services to over a million patients each year. www.chumontreal.qc.ca.

For more information please contact:

Isabelle Kling
Communications Coordinator (research)
MUHC Public Relations and Communications
(514) 843 1560
isabelle.kling@muhc.mcgill.ca

Nathalie Forgue
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CHUM
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Pager : 514 801-5762

Genetic variation increases HIV risk in Africans

A genetic variation which evolved to protect people of African descent against malaria has now been shown to increase their susceptibility to HIV infection by up to 40 per cent, according to new research. Conversely, the same variation also appears to prolong survival of those infected with HIV by approximately two years.

The discovery marks the first genetic risk factor for HIV found only in people of African descent, and sheds light on the differences in genetic makeup that play a crucial role in susceptibility to HIV and AIDS.

The research, published today in Cell Host & Microbe, was co-authored by Professor Robin Weiss, UCL Infection and Immunity, who worked with colleagues in the US to analyse data from a 25-year study of thousands of Americans of different ethnic backgrounds.

The gene that the research focused on encodes a binding protein found on the surface of cells, called Duffy Antigen Receptor for Chemokines (DARC). The variation of this gene, which is common in people of African descent, means that they do not express DARC on red blood cells. DARC influences the levels of inflammatory and anti-HIV blood factors called chemokines.

Discussing the findings, Professor Weiss said: "The big message here is that something that protected against malaria in the past is now leaving the host more susceptible to HIV.

"In sub-Saharan Africa, the vast majority of people do not express DARC on their red blood cells and previous research has shown that this variation seems to have evolved to protect against a particular form of malaria. However, this protective effect actually leaves those with the variation more susceptible to HIV."

Lead author of the study, Professor Sunil K. Ahuja, from The University of Texas Health Science Center at San Antonio, added: "It turns out that having this variation is a double-edged sword. The finding is another valuable piece in the puzzle of HIV-AIDS genetics."

HIV affects 25 million people in sub-Saharan Africa today, an HIV burden greater than any other region of the world. Around 90 per cent of people in Africa carry the genetic variation, meaning that it may be responsible for an estimated 11 per cent of the HIV burden there. The authors observe that sexual behaviour and other social factors do not fully explain the large discrepancy in HIV prevalence in populations around the world, which is why genetic factors are a vital field of study.

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Notes for Editors

1. Journalists seeking more information, or to interview Professor Robin Weiss, can contact Ruth Metcalfe in the UCL Media Relations Office on tel: +44 (0)20 7679 9739, mobile: +44 (0)7990 675 947, out of hours: +44 (0)7917 271 364, e-mail: r.metcalfe@ucl.ac.uk

2. The paper 'Duffy Antigen Receptor for Chemokines (DARC) Mediates Trans-infection of HIV-1 from Red Blood Cells to Target cells and Affects HIV-AIDS Susceptibility' is published in the journal Cell Host & Microbe, published by Cell Press. This is not an open-access journal but copies of the paper can be obtained from Ruth Metcalfe, UCL Media Relations, using the above contact details.

3. The authors of this paper are from: South Texas Veterans Health Care System, Texas, US; The University of Texas Health Science Center in San Antonio, US; UCL; Uniformed Services University, Maryland, US; Wilford Hall United States Air Force Medical Center, US and the San Antonio Military Medical Center.

4. In the UK, this work was supported by a grant to Professor Weiss from the Medical Research Council.

About UCL

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. In the government's most recent Research Assessment Exercise, 59 UCL departments achieved top ratings of 5* and 5, indicating research quality of international excellence.

UCL is in the top ten world universities in the 2007 THES-QS World University Rankings, and the fourth-ranked UK university in the 2007 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. www.ucl.ac.uk

After ER visit, many patients in a fog, U-M study finds

3/4 don't understand either what's wrong, what was done, or what they should do after leaving emergency room

ANN ARBOR, Mich. — Every year, more than 115 million patients enter emergency rooms at hospitals around the nation. And more than three-quarters of them leave with an impression of what happened – or what should happen next – that doesn't match what their emergency care team would want.

That's the finding of a new study led by University of Michigan Health System researchers, and published early online in the Annals of Emergency Medicine. The results suggest that emergency room teams need to do a better job of making sure patients go home with clear information and instructions – and that patients and their loved ones shouldn't leave until they fully comprehend their situation.

The researchers carried out detailed interviews with 140 English-speaking patients who visited one of two emergency departments, and were released to go home. They compared those interviews with the patients' medical records, and found a serious mismatch between what doctors and nurses found or advised, and what patients comprehended.

What's worse, patients were pretty sure of what they "knew" 80 percent of the time – even if what they knew wasn't quite right.

"It is critical that emergency patients understand their diagnosis, their care, and perhaps most important, their discharge instructions," says lead author Kirsten Engel, M.D., a former U-M emergency medicine fellow and Robert Wood Johnson Clinical Scholar who is now at Northwestern University. "It is disturbing that so many patients do not understand their post-emergency department care, and that they do not even recognize where the gaps in understanding are. Patients who fail to follow discharge instructions may have a greater likelihood of complications after leaving the emergency department."

The study's senior author agrees. "As a physician, I would like to think I could look someone in the eye and ask: 'Do you have any questions?,' and those who were confused or overwhelmed would ask for more help," says Peter Ubel, M.D., a professor of internal medicine at the U-M Medical School. "This study shows that many patients walk away from important clinical encounters confident that they know what happened and why, but with little reason to be so confident."

The researchers measured the extent to which patients' reports agreed with their doctors' records in four areas: diagnosis, emergency care that was given, post-ER care needs and what kinds of symptoms or signs would require the patient to return to the ER or seek immediate care.

Only 22 percent of patients' reports were in complete harmony with what their care teams reported on all four counts.

Fifty-eight percent of patients understood at least two of the four areas, but 20 percent were off on three or four areas of their care and follow-up needs.

After asking patients about their diagnosis, care and post-ER instructions, the team also asked them if they were not sure about any of the four areas. Interestingly, patients whose understanding perfectly matched their doctors' records were just as likely to report being unsure as patients whose understanding was lacking.

"Doctors need to not only ask patients if they have questions, but ask them to explain, in their own words, what they think is wrong with their health and what they can do about it," says Ubel. "And patients need to ask their doctors more questions, and even need to explain, to their doctors, what they think is going on."

The biggest area of misunderstanding or lack of comprehension was post-emergency care – that is, what steps the patient needs to take to be seen by their regular doctor or a specialist, how soon to see a doctor, or what medicines or self-care steps they need to take, how to take them, and when.

Ubel, Engel and their colleagues found that 34 percent of the deficiencies in patient comprehension reflected a less-than-complete understanding of what their ER team recommended they do after they left the ER. Meanwhile, 22 percent of the deficiencies in the study had to do with patients' understanding of what symptoms or changes in their condition should spur them to return to the ER.

Recently, the U-M Health System introduced a program that aims directly at this problem: the Emergency Medicine Consult/Referral Service, run by the Department of Emergency Medicine and the Physician and Consumer Communications division of Public Relations & Marketing Communications.

It is staffed by referral coordinators who follow up with ER patients by phone within 24 hours of their ER visit, to help schedule appointments with U-M physicians for specialty care if the patients' insurance allows it or make sure they know that they need to schedule an appointment elsewhere.

More than 12,000 follow-up appointments have been scheduled for recent U-M ER patients since the program began in February 2007, and 81 percent of those patients have arrived for their scheduled appointments, up from 59 percent before the program began. Appointment cancellations are also down.

Before the program began, 24 percent of U-M ER patients who needed a follow-up appointment never scheduled one. And many patients and clinicians who did try to arrange follow-up care went through a frustrating and confusing process that is repeated every day in hospitals around the country. The new call center offers a standardized, centralized way to make sure patients get scheduled to see the provider they need soon after their ER visit.

The new study involved patients from ages 18 to 83 years, 59 percent of whom were women. Nineteen percent of patients were African-American, and 68 percent were white, with the remaining percentage being other races or without a race recorded on their record. Thirty-five percent had a high school education or less. Patients were given a brief cognition test before being interviewed, to make sure their thinking and understanding abilities were normal. In some cases, caretakers were also interviewed.

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In addition to Engel and Ubel, who directs the Program for Behavioral and Decision Sciences in Medicine, the new study's authors include Michele Heisler, M.D., MPA, Dylan Smith, Ph.D., Claire Robinson, MPH, and Jane Forman, M.D. The study was funded by the Robert Wood Johnson Foundation and the U-M Clinical Scholars Program.

Reference: Annals of Emergency Medicine, doi:10.1016/j.annemergmed.2008.05.016

In two complementary studies

Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer. So far, the scientists have been able to calculate the age of the tumor and characterize its growth pattern. The scientists believe cell lineage studies of cancer can eventually lead us to the root of cancer.

Weizmann Institute Scientists’ New Technique Gets to the Root of Cancer

In two complementary studies, Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer.

The quest to understand a cell’s path of descent, called a cell lineage tree, is shared by many branches of biology and medicine as gleaning such knowledge is key to answering many fundamental questions, such as whether neurons in our brain can regenerate, or whether new eggs are created in adult females.

So far, only tree lineages of tiny organisms, such as worms, which possess only a thousand cells, or 'branches,' have been determined. Now, Prof. Ehud Shapiro of the Institute’s Biological Chemistry, and Computer Science and Applied Mathematics Departments, together with Doctoral students Dan Frumkin and Adam Wasserstrom have developed a novel way to reconstruct, in principle, trees for larger organisms, including humans.

The human body is made of about 100 trillion cells, all of which are descendants of a single cell – the fertilized egg (zygote). Cells that have undergone a small number of cell divisions are relatively close descendants (akin to branches representing children and grandchildren etc., on a family tree), while some cells may have undergone hundreds or even thousands of divisions ('distant cell generations'). Knowing the number of cell divisions since the zygote, known as the depth of cells, would enable scientists to address questions about the behavior of the body under physiological and pathological conditions.

Until now, estimates of cell depth were based on theoretical calculations and assumptions, but Shapiro provides a practical way of determining cell depth precisely. The concept behind their new method is simple: Previous research indicated that each time a cell divides, harmless mutations are introduced, and that 'cell relatives' of distant generations tend to acquire more mutations, drifting away from the original DNA sequence of the zygote. Inspired by this, the team developed a non-invasive, accurate and systematic way, involving DNA amplification and computer simulations, to quantitatively estimate cell depth on the basis of the number of mutations in microsatellites (repetitive DNA sequences), and has applied it to several cell lineages in mice.

According to the team’s estimates, as reported in PLoS Computational Biology, the average depth of B cells – a type of immune cell – is related to mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent fewer divisions, supporting the notion that they are relatively quiescent.

Shapiro and Frumkin, in collaboration with Prof. Gideon Rechavi from the Sheba Medical Center and others then decided to apply this method to reconstruct, for the first time, the family tree of a cancer cell. 'Despite several decades of scientific research, basic properties of the growth and spread of tumor cells remain controversial. This is surprising, since cancer is primarily a disturbance of cell growth and survival, and an aberrant growth pattern is perhaps the only property that is shared by all cancers. However, because the initiation and much of the subsequent development of tumors occurs prior to diagnosis, studying the growth and spread of tumors seems to require retrospective techniques and these have not been forthcoming,' explains Shapiro.

Therefore, by reconstructing a cancer cell lineage tree and performing an analysis of mutations accumulated in the cells, scientists would be able to trace back and reveal several aspects of the tumor’s developmental history. Shapiro: 'We intend to apply this method to study key questions in human cancers, including when and where does a tumor initiate? The progression from pre-malignant to malignant states. At what stage does metastasis occur? Can the depth of tumor cells serve as a prognostic marker for cancer severity? And does chemotherapy target a subset of cells characterized by distinct lineage features (e.g. greater depth)?'

So far, their findings, featuring on the cover of the July 15th issue of Cancer Research, show that cancer cells (extracted from tissue sections of a mouse lymphoma by laser micro-dissection) had almost double the number of branched generations (i.e., had divided almost twice as many times) compared to adjacent normal lung cells in the same amount of time. They were also able to calculate the age of the tumor and characterize its growth pattern. Further analysis was sufficient to corroborate the long-standing hypothesis on the single-cell origin of cancer.

The scientists believe cell lineage studies of cancer can greatly enhance our understanding of, and eventually lead us to the root of cancer.

Prof. Ehud Shapiro's research is supported by the Clore Center for Biological Physics; the Arie and Ida Crown Memorial Charitable Fund; the Cymerman - Jakubskind Prize; the Fusfeld Research Fund; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; the Henry Gutwirth Fund for Research; Ms. Sally Leafman Appelbaum, Scottsdale, AZ; the Carolito Stiftung, Switzerland; the Louis Chor Memorial Trust Fund; and the estate of Fannie Sherr, New York, NY.
Prof. Shapiro is the incumbent of the Harry Weinrebe Chair of Computer Science and Biology

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il, and are also available at http://www.eurekalert.org.

Researchers discover link between organ transplantation and increased cancer risk

Researchers have determined a novel mechanism through which organ transplantation often leads to cancer, and their findings suggest that targeted therapies may reduce or prevent that risk.

In the July 15, 2008, issue of Cancer Research, researchers at Harvard Medical School found in animal and laboratory experiments that the anti-rejection, immunosuppressive drug cyclosporine ramps up expression of vascular endothelial growth factor (VEGF), which signals the growth of new blood vessels that can feed tumors.

They also found that simultaneously administering an anti-VEGF therapy with cyclosporine in mice repressed this tumor growth. Several inhibitors of VEGF are already in use in human cancer therapy.

The findings could offer some good news for the 15 to 20 percent of transplant patients who develop cancer within a decade of receiving new organs, according to the study's senior investigator, Soumitro Pal, Ph.D., an assistant professor at Harvard Medical School's Transplantation Research Center at Children's Hospital in Boston.

"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence," he said.

VEGF expression is markedly increased in patients post-transplantation, and this can aid in the development of a blood supply to a transplanted organ, helping it survive and thrive. "But once the organ has stabilized, it may be possible to lower the level of VEGF expression to prevent tumor growth," he said. "We would need to figure out how to balance benefit and risk to keep cancer at bay."

Tumors that develop after transplantation may have three potential sources: they may have pre-existed or could have been a recurrence of previous cancer – and in both of these cases, a patient's pre-transplant immune system might have kept these cancers in check – or cancer-causing viruses could have come from the donor organ. Physicians have long observed that immunosuppressive agents, such as the class of calcineurin inhibitors that includes cyclosporine, appear to promote cancer development, often in organs that are not transplanted, but the cause of this was unclear. The Harvard team tested the ability of cyclosporine to promote growth of pre-existing tumors in mice implanted with human renal (kidney) cancer cells. Mice treated with the agent formed tumors faster than untreated mice, but anti-VEGF therapy substantially reduced that excessive growth.

Digging deeper into the biological pathway of VEGF activation, the scientists found that cyclosporine activates two of the three forms of the common protein catalyst, protein kinase C, which leads to increased expression of VEGF.

"We think PKC-mediated VEGF transcriptional activation is a key component in the progression of cyclosporine-induced post-transplantation cancer," Pal said. "It is likely not the whole story, but this gives us a clue that we might be able to use existing or novel therapies to reduce cancer risk in transplanted patients."

Gene variant found in those with African ancestry increases odds of HIV infection

A variant of a gene found only in people of African ancestry increases the odds of becoming infected with the human immunodeficiency virus (HIV-1) by 40 percent, according to a long-term study of African Americans reported in the [date] issue of the journal Cell Host & Microbe, a publication of Cell Press. However, once people are infected, the same variant seems to protect against progression of the disease, allowing those who carry it to live about two years longer.

" It's well-known that individuals vary in their susceptibility to HIV and that after infection occurs, the disease progresses at variable rates," said Sunil Ahuja of South Texas Veterans Health Care System and University of Texas Health Science Center at San Antonio. "The mystery of variable infection and progression was originally thought to be mainly the result of viral characteristics, but in recent years it has become evident that there is a strong host genetic component."

The new discovery is one of few genetic risk factors for HIV found only in people of African descent, the researchers added. If the new findings can be extrapolated to Africa, where about 90 percent of all people carry the variant, it may be responsible for 11 percent of the HIV burden there, they estimate.

The gene in question encodes a protein found mainly at the surface of red blood cells, which is called Duffy Antigen Receptor for Chemokines (DARC). The DARC variant found commonly in people of African ancestry leaves them without this particular red blood cell receptor. That so-called "DARC-negative" condition has been well studied because it also confers protection against infection by a malaria parasite known as Plasmodium vivax. (P. vivax is unfortunately not the parasite responsible for millions of malaria deaths each year in Africa today. The researchers speculate that this DARC gene variant may have risen to such high frequency as protection against some other, more lethal strain of malaria that existed at some time in the past.)

" The big message of this paper is that something that protected people against malaria in the past is now leaving them more susceptible to HIV," said Robin Weiss of University College London. "After thousands of years of adaptation, this Duffy variant rose to high frequency because it helped protect against malaria," added Matthew Dolan of the Wilford Hall United States Air Force Medical Center and San Antonio Military Medical Center. "Now, with another global pandemic on the scene, this same variant renders people more susceptible to HIV. It shows the complex interplay between historically important diseases and susceptibility in contemporary times."

Earlier studies had suggested that HIV can bind to red blood cells via DARC. In accord with its name, DARC also binds a wide array of inflammatory molecules known as chemokines, including one called CCL5, which is highly effective in suppressing replication of HIV-1.

Those hints led the researchers to wonder just what the impact of DARC on HIV-AIDS might be. In cell culture, they found further evidence that HIV binds to DARC on red cells. "We started looking at red cells together with HIV and, sure enough, the virus attached," Weiss said. "The DARC molecule on red cells in cell culture then transferred the virus to lymphocytes to get infected." CD4+ T lymphocytes are white blood cells that are a primary target of HIV infection.

When chemokines that also bind DARC were added to the mix, less HIV-1 bound to the red cells, confirming that the virus and chemokines were in competition for the DARC receptor. "Duffy acts somewhat like a sponge," Ahuja said. "It binds all these chemokine molecules and that binding also extends to HIV, setting up a triumvirate of interactions between DARC, chemokines and virus."

The researchers next looked to a large cohort of people in the U.S. Air Force, including more than 1,200 who are HIV positive, who have been followed for nearly 22 years. This group is ideal for evaluating the role of such a gene because this cohort is ethnically balanced and without many of the factors, including differences in economic status and access to health care, that would generally confound any genetic effect, Dolan explained.

Those studies showed that the prevalence of the "DARC-negative" variant in African Americans was greater amongst those with HIV than in those without. Although the DARC-negative genotype was associated with an increased risk of acquiring HIV infection, within the context of established infection a contrary result was observed: people with that variant had a slower disease course, they report.

" The parts of a car that get it into gear are separate from those that get it moving once in gear," Ahuja said. "A similar analogy applies to HIV; the factors that influence its transmission are not necessarily the same as those that influence disease progression."

Although it isn't yet entirely clear how exactly DARC mediates opposing effects during HIV acquisition and disease, the researchers suspect those with the DARC receptor are initially protected because they also have more HIV suppressive chemokines in their system. Once infected, however, the balance turns in favor of those without DARC as increased chemokine levels may promote inflammation in those with DARC. Also, once the virus reaches higher levels, it is more likely to displace chemokines bound to DARC on red cells, further exacerbating inflammation. And during established infection, HIV bound to DARC on red cells is poised for delivery to CD4+ T cells, the researchers said.

The findings help answer an earlier conundrum: the researchers had previously shown that people with a particular variant of the chemokine CCL5 have a faster rate of HIV progression. But, that pattern only held in European Americans, not in African Americans. They now show that the disease-accelerating effect of the CCL5 variant is evident only in DARC-expressing and not in DARC-negative HIV-positive individuals. In other words, the unmeasured effects of DARC amongst African Americans in the earlier study "masked" the influence of CCL5, exemplifying the importance of accounting for such complex gene-gene interactions in genetic studies.

" The results underscore that genetic variants that influence transmission and disease progression can differ in their frequency among different populations, with possible impacts on the heterogeneity of HIV disease burden--not just at the level of individuals but also populations," they concluded. They may also have implications for evaluating the efficacy of HIV vaccines.