New insights in diagnosing diabetes may help the millions who are undiagnosed (5/30/2008)
June 3, 2008
In light of the 6.2 million Americans who don’t realize they have diabetes, a panel of experts examined the current criteria for screening and diagnosing the disease and found a significant need for improvement. Their conclusions and recommendations can be found in a new report accepted for publication in the Journal of Clinical Endocrinology & Metabolism (JCEM).
“Approximately 30 percent of people with diabetes in the United States are undiagnosed,” said Christopher Saudek, M.D., of Johns Hopkins School of Medicine in Baltimore, Md., and lead author of the report. “There are serious deficiencies in the current criteria for diagnosing diabetes and these shortcomings are contributing to avoidable morbidity and mortality”.
One reason so many people with diabetes are undiagnosed is because commonly prescribed diagnostic tests require that a patient be fasting, said Saudek. This means that people who have eaten on the day of a doctor visit will not be diagnosed unless they have quite advanced diabetes.
As an alternative to the fasting plasma glucose or oral glucose tolerance tests, the panel suggested incorporating another measurement of glucose, hemoglobin A1c (HbA1c), into criteria for screening and diagnosing diabetes.
Hemoglobin is the oxygen-carrying protein located in red blood cells. HbA1c is a form of hemoglobin that reflects the average blood glucose level over the previous several months, and has been used for a long time to indicate blood sugar levels in patients with diabetes. But it has never been officially accepted as a way for doctors to screen for or diagnose diabetes.
Current recommendations of the American Diabetes Association were made a decade ago and they rejected the use of HbA1c as a diagnostic tool largely because it was considered at the time to be inadequately standardized and insensitive. Given more recent evidence, the panel believes it is time to revisit using HbA1c and include it as necessary criteria in screening and diagnosing diabetes.
The measurement of HbA1c does not require fasting, while current accepted tests require the patient to fast for at least eight hours. Furthermore, HbA1c more accurately reflects longer-term glucose concentration in the blood; other tests can easily be affected by short-term lifestyle changes, such as a few days of dieting or exercise. And finally, HbA1c laboratory methods are now well standardized and reliable.
The panel recommends that screening standards be established that prompt further testing and closer follow-up. Standards could include HbA1c tests, for example HbA1c greater than 6 percent would qualify as being in need of follow-up; HbA1c greater than or equal to 6.5 percent confirmed by a glucose-dependent test should establish the diagnosis of diabetes.
Other members of the panel include William Herman of the University of Michigan in Ann Arbor, Mich.; David Sacks of Harvard Medical School in Boston, Mass.; Richard Bergenstal of the International Diabetes Center in Minneapolis, Minn.; David Edelman of Duke University in Durham, N.C.; and Mayer Davidson of Charles R. Drew University in Los Angeles, Calif.
The article “A New Look at Screening and Diagnosing Diabetes Mellitus,” will appear in the July issue of JCEM, a publication of The Endocrine Society.
Note: This story has been adapted from a news release issued by The Endocrine Society
New HIV browser gives researchers access to valuable data from vaccine trials (5/30/2008)
June 3, 2008
A new HIV data browser developed by the University of California, Santa Cruz, and the nonprofit organization Global Solutions for Infectious Diseases (GSID) will give researchers access to a wealth of data collected during clinical trials of an AIDS vaccine. Although the vaccine did not succeed in preventing infections, the clinical trial generated a huge amount of valuable data for researchers studying how the virus evolves and causes new infections.
Modeled on the UCSC Genome Browser, the GSID HIV Data Browser is the brainchild of Phillip Berman, professor and chair of biomolecular engineering in UCSC’s Baskin School of Engineering. Berman helped oversee the clinical trials, which ended in 2003, when he was senior vice president for research and development at VaxGen, the company that developed the vaccine and conducted Phase III clinical trials in North America, Europe, and Thailand.
“After the trials concluded, I spent a couple of years trying to think what was the most important thing I could do for HIV research,” Berman said. “I concluded it was using new technology to preserve the data from these clinical trials and present it in a form useful to the scientific community.”
In 2004, Berman cofounded GSID, based in South San Francisco and dedicated to combining knowledge and expertise from the biotechnology industry and the public health sector to address infectious disease problems in the developing world. He joined the UCSC faculty in 2006.
“Despite the fact that the vaccine trial didn’t work, a huge amount of useful information was obtained,” Berman said. The “North American” trial included about 60 different clinical sites in North America and one site in the Netherlands. Of particular value to researchers are the genetic sequences of the viruses that infected participants during the trial.
“The trial represented the only up-to-date broad survey of virus sequences from new infections that had ever been carried out,” Berman said. “Every time there was a new infection in the vaccine or placebo group, the virus was sequenced. The sequence information provides the best picture we have about what the immune system sees when there is a new infection.”
This is important, Berman said, because other major repositories of HIV sequence data are not annotated for the time after infection, the clinical status of the patient, or the histories of the specimens sequenced. That limits their usefulness for studying such a rapidly evolving virus.
HIV is highly mutable and evolves in response to attacks by the immune system. As a result, HIV isolated from a patient years after the initial infection is genetically different from the virus that caused the infection in the first place. A vaccine should target the most infectious form of the virus, Berman said. Yet all the vaccines tested so far have been based on viruses isolated from patients with longstanding infections.
“A current hypothesis in HIV vaccine research is that the antigenic structures of HIV viruses that mediate new infections differ from those recovered from people long after infection,” Berman explained. “The specimens in this set represent the largest group from new infections that has ever been collected.”
Besides viral genome-sequence data, the database links to a repository of preserved specimens (blood samples and cells) that researchers can access from GSID and the National Insitutes of Health (NIH) for further study.
“This is the first time that an HIV sequence database has been linked to a specimen repository and a database of clinical information,” Berman said. “These clinical specimens are longitudinal, collected from the same person during a two-year follow-up period. This will allow investigators to study the evolution of the virus and the evolution of the immune response and clinical outcomes.”
At UCSC, Berman teamed up with the Genome Browser group to develop a browser for the sensitive clinical data collected during the vaccine trial. Jim Kent, associate research scientist for the UCSC Genome Browser and principal investigator on the project, said it was the first time his group had worked with data from participants in a clinical trial.
“This data must be handled differently and great care taken with confidentiality,” Kent said. “We learned from this project how to build the infrastructure to cope with that. This will be useful for other medical projects, such as cancer genomics, in the future.”
Fan Hsu, director of proteomics for the UCSC Genome Browser, said the emphasis on security was very different from past projects. “Before, everything we have worked on is totally open, totally public. With the GSID project, only authorized users can access the data, so we needed to set up special controls,” Hsu said.
How to display the very large number of HIV sequences on the browser was another challenge. “Our original genome browser has only one reference genome. For this HIV database, we have about 350 infected people and more than 1,000 sequences,” he said.
Hsu and software developer Galt Barber adapted the genome browser software to accommodate the large number of HIV sequences and the data security along with interactive selection criteria for viewing the data. As the project evolved, Hsu also coordinated the transfer of the software to GSID. The UCSC team, which also included Erich Weiler, Robert Kuhn, and Ann Zweig, worked nights and weekends to bring the new browser online.
The resulting GSID HIV Data Browser is a customized version of the UCSC Genome Browser. It provides researchers with searchable demographic and clinical data from volunteers who became HIV infected during the VaxGen clinical trial. The browser allows users to align viral sequences with one another and with reference or consensus sequences.
“This is something where the university can make a difference, because the private sector is not so interested in vaccines; they’re not so profitable,” Kent said. “There is very little economic incentive to develop an AIDS vaccine, but there is a tremendous humanitarian incentive.”
Kent hopes that just as the UCSC Genome Browser has continued to build the collaborative nature of the genomics research community, this HIV data browser will help motivate the AIDS research community to work together and pool their data.
Vaccine development efforts have been repeatedly frustrated. An HIV vaccine candidate developed by the pharmaceutical company Merck recently failed in clinical trials cosponsored by NIH. “The recent failure of the Merck HIV vaccine has thrown the field into turmoil,” Berman said. “All the best ideas for an HIV vaccine in the past 20 years have failed. The information in this database is now more critical than anyone could have imagined. It tells us what’s being transmitted.”
The next phase of the HIV browser project involves releasing the sequence data from infected participants in the Phase III clinical trial that VaxGen conducted in Thailand.
“In the future, the database will be expanded to allow associations between virus sequences, clinical data, immune response data, and host genetics,” Berman said. “We hope to eventually include data from other HIV vaccine trials sponsored by the NIH, private companies, and other HIV vaccine research organizations.”
GSID is making these data and serological samples available to the HIV research community through an agreement with VaxGen and with funding provided by the Bill and Melinda Gates Foundation.
For information on accessing the GSID HIV Data Browser and background on the clinical trials, visit the GSID web site.
Note: This story has been adapted from a news release issued by UC Santa Cruz
Coronary Calcium Distribution Tied to Heart Attack Risk (5/29/2008)
May 30, 2008
A new calcium scoring method may better predict a person’s risk of heart attack, according to a new multicenter study published in the June issue of the journal Radiology. Calcium coverage scoring takes into account not only the amount of calcified plaque build-up in the coronary arteries, but also its distribution.
“Now we know that the location of the calcium in the arteries is particularly important in estimating a patient’s potential risk,” said the study’s lead author Elizabeth Brown, Sc.D., research assistant professor in the Department of Biostatistics at the University of Washington in Seattle.
Heart disease is the leading cause of death in the U.S. Each year, 700,000 Americans die of heart disease, according to the Centers for Disease Control and Prevention. The most common form of heart disease in the U.S. is coronary artery disease, which is caused by a build-up of calcific plaque in the coronary arteries leading to the heart. The current standard of coronary calcium measurement gauges only the amount of calcium present in the arteries, not its spatial distribution.
“Currently, physicians only see the result in terms of an overall score designed to measure the amount of calcified plaque,” Dr. Brown said. “This new approach will provide physicians with a measure of the proportion of the arteries affected.”
The Multi-Ethnic Study of Atherosclerosis (MESA) began in July 2000. The prospective study included 6,814 men and women between the ages of 45 and 84. The researchers compared CT image data for 3,252 participants with calcific plaque to data collected from 3,416 patients without calcific plaque. (Due to lack of sufficient CT image data, 146 additional MESA participants were excluded from this analysis.) A calcium coverage score was developed to estimate the percentage of coronary arteries affected by plaque.
The patients were then followed up for a median period of 41 months to determine if there was a relationship between the distribution of calcium shown in the CT images and the likelihood heart attack or other cardiac event.
The results showed that diabetes, hypertension and dyslipidemia (abnormal concentrations of lipids [fats] or lipoproteins in the blood) were highly associated with calcium coverage score. The study also found that the calcium coverage score-which takes into account the location of the calcium-was a better predictor of future cardiac events than currently used measures that gauge only the amount of calcium present. On average, compared to patients without diabetes, patients with diabetes had 44 percent more of their coronary arteries affected by plaque. A twofold increase in calcium coverage score indicated a 34 percent increase in risk of heart attack or other serious cardiac event and a 52 percent increase in the risk of any cardiac event.
“Calcium coverage scoring has the potential to improve our estimate of a patient’s risk for adverse clinical outcomes, such as heart attacks or death,” Dr. Brown said.
“Coronary Calcium Coverage Score: Determination, Correlates, and Predictive Accuracy in the Multi-Ethnic Study of Atherosclerosis.” Collaborating with Dr. Brown were Richard A. Kronmal, Ph.D. (University of Washington), David A. Bluemke, M.D., Ph.D. (Johns Hopkins University, Baltimore), Alan D. Guerci, M.D. (Heart Center, St. Francis Hospital, Roslyn, N.Y.), J. Jeffrey Carr, M.D. (Wake Forest University Health Sciences, Winston-Salem, N.C.), Jonathan Goldin, Ph.D. (UCLA School of Medicine, Los Angeles) and Robert Detrano, M.D. (University of California, Irvine). Journal attribution requested.
Note: This story has been adapted from a news release issued by the Radiological Society of North America
Battling bird flu by the numbers (5/29/2008)
May 30, 2008
Los Alamos mathematical model gauges epidemic potential of emerging diseases
A pair of Los Alamos National Laboratory researchers have developed a mathematical tool that could help health experts and crisis managers determine in real time whether an emerging infectious disease such as avian influenza H5N1 is poised to spread globally.
In a paper published recently in the Public Library of Science, researchers Luís Bettencourt and Ruy Ribeiro of Los Alamos’ Theoretical Division describe a novel approach to reading subtle changes in epidemiological data to gain insight into whether something like the H5N1 strain of avian influenza-commonly known these days as the “Bird Flu”-has gained the ability to touch off a deadly global pandemic.
“What we wanted to create was a mathematically rigorous way to account for changes in transmissibility,” said Bettencourt. “We now have a tool that will tell us in the very short term what is happening based on anomaly detection. What this method won’t tell you is what’s going to happen five years from now.”
Bettencourt and Ribeiro began their work nearly three years ago, at a time when the world was wondering whether avian influenza H5N1, with its relatively high human mortality rate, could become a frightening new pandemic. Health experts believe that right now the virus primarily infects humans who come in contact with infected poultry.
But some health experts fear the virus could evolve to a form that would become transmissible from human to human, the basis of a pandemic like the 1918 Spanish Flu that killed an estimated 50 million people.
The Los Alamos researchers set out to create a “smart methodology” to look at changes in disease transmissibility that did not require mounds of epidemiological surveillance data for accuracy. The ability to look at small disease populations in real time could allow responders and health experts to implement quarantine policies and provide medical resources to key areas early on in an emerging pandemic and possibly stem the spread.
Bettencourt and Ribeiro developed an extension of standard epidemiological models that describes the probability of disease spread among a given population. The model then takes into account actual disease surveillance data gathered by health experts like the World Health Organization and looks for anomalies in the expected transmission rate versus the actual one. Based on this, the model provides health experts actual transmission probabilities for the disease. Unlike other statistical models that require huge amounts of data for accuracy, the Los Alamos tool works on very small populations such as a handful of infected people in a remote village.
After developing their Bayesian estimation of epidemic potential, Bettencourt went back and looked at actual epidemiological surveillance data collected during Bird Flu outbreaks in certain parts of the world. Their model accurately portrayed actual transmission scenarios, lending confidence to its methodology.
In addition to its utility in understanding the transmissibility of emerging diseases, the new method is also advantageous because it allows public health experts to study outbreaks of more common ailments such as seasonal influenza early on. This can assist medical professionals in making better estimates of potential morbidity and mortality, along with assessments of intervention strategies and resource allocations that can help a population better cope with a developing seasonal outbreak.
“We are closing the loop on science-based prediction of transmission consequences in real time,” said Ribeiro. “A program of this type is something that needs to be implemented at a worldwide level to provide an integrated way to respond a priori to an emerging disease threat.”
Note: This story has been adapted from a news release issued by the Los Alamos National Laboratory
Hormone may hold key to helping elderly men live longer (5/29/2008)
May 30, 2008
Elderly men with higher activity of the hormone IGF-1-or insulin-growth factor 1-appear to have greater life expectancy and reduced cardiovascular risk, according to a new study accepted for publication in the Journal of Clinical Endocrinology & Metabolism (JCEM).
IGF-1 is a hormone similar in molecular structure to insulin. It is released from the liver and plays an important role in childhood growth and continues to have anabolic effects in adults.
In this study, researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years. A serum sample was taken from each subject at the beginning of the study and researchers were contacted about the status of the participants over a period of eight years.
Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.
These new findings come as a result of a new form of testing for IGF-bioactivity. Researchers in this study used a new method, a bioassay, to measure the function of IGF-1 in the blood. Compared to commonly used methods to measure IGF-1, the IGF-1 bioassay gives more information about the actual function (bioactivity) of circulating IGF-1 in the body.
“The bioassay allowed us to more clearly see the association between high circulating IGF-1 bioactivity and extended survival,” said Michael Brugts, MD, of the Erasmus Medical Center in Rotterdam, The Netherlands and lead author of the study. “Interestingly, we could not find such a relationship when IGF-1 in blood was measured with the more commonly used methods.”
Immunoassays, commonly used previously to determine IGF-1 circulation levels, remove certain proteins that interfere with accurate measurements. Recent studies however have found that these proteins are important modulators of IGF-1 bioactivity. The bioassay used in this study does not disregard or remove this protein, thus enabling researchers to have a more accurate understanding of IGF-1 function.
Determination of IGF-1 function using the bioassay opens the possibility to gather new insights about the functions of IGF-1 in the body, said Brugts.
Other researchers working on the study include A.W. Van den Beld, L.J. Hofland, K. van der Wansem, P.M. van Koetsveld, S.W.J. Lamberts, and J.A.M.J.L. Janssen of Erasmus Medical Center in Rotterdam, The Netherlands and J. Frystyk of Aarhus University Hospital in Aarhus, Denmark.
The article “Low Circulating IGF-1 Bioactivity in Elderly Men is Associated with Increased Mortality,” will appear in the June issue of JCEM, a publication of The Endocrine Society.
Note: This story has been adapted from a news release issued by the The Endocrine Society
Miracle leaves that may help protect against liver damage (5/28/2008)
May 30, 2008
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| Close-up of fruit of Common Sea-Buckthorn (Hippophae rhamnoides) |
Indigineous to the mountainous regions of China and Russia, sea buckthorn has been shown to be rich in vitamin C, vitamin E, flavonoids and essential fatty acids. The leaves are also used to make a tea.
In a clinically controlled study, scientists looked at whether the leaves had any protective effects by testing a group of rats, some of whom were given the leaf extract before being administered with a liver damage agent, carbon tetrachloride (CCI4).
Six groups were looked at in all - group 1 was given a daily dose of saline for 5 days; group 2 received saline for 4 days and on the 5th day was given CCI4; group 3 was given a daily dose of silymarin for 5 days followed by a single dose of CCI4; groups 4, 5 and 6 were given 50, 100 and 200mg of sea buckthorn leaf extract respectively for five days followed by a single dose of CCI4 on the 5th day.
The results showed that the leaf extract appeared to confer a protective mechanism on the liver - the rats given CCI4 minus the leaf extract had sustained significant liver damage compared to the control group that did not receive CCI4. In comparison, liver damage was severely restricted in the rats given leaf extract at 100mg and 200mg and CCI4.
Note: This story has been adapted from a news release issued by the Society of Chemical Industry
Let there be light (5/28/2008)
May 30, 2008
Photodynamic therapy breakthrough in cancer treatment
Researchers from the Peninsula Medical School in Cornwall, UK, have modified a photodynamic therapy (PDT) treatment that combines a topically applied cream with visible light to destroy cancer cells while leaving surrounding tissue unharmed.
The cream is applied directly to skin cancers and pre-cancers, which then naturally produces a photosensitive drug. A special red light is then shone on the tumour a few hours later, to activate this light sensitive compound. This results in cellular damage and the destruction of the tumour.
This technique results in reduced scarring and little or no damage to the surrounding healthy cells.
By adding the iron chelator CP94 to the cream, the research team have found that the effects of PDT are greatly improved and achieve greater reductions in tumour depth in tumours currently too thick to be treated easily by the non-enhanced form of this treatment.
This is the first time in the world that PDT trials of this modified PDT treatment have been carried out involving humans. Trials involving patients have taken place at clinics at the Royal Cornwall Hospitals NHS Trust in Truro.
PDT is achieving success in the treatment of actinic keratoses (lesions that can develop after years of exposure to UV light); Bowen’s disease (the growth of abnormal calls that can turn into skin cancer, and that is partly due to long-term exposure to the sun); and basal cell carcinoma (the most common form of skin cancer).
The work of the Peninsula Medical School in this area of research is funded in part by the Duchy Health Charity in Cornwall.
Dr. Alison Curnow from the Peninsula Medical School in Cornwall, commented: “PDT is very effective non-surgical treatment for certain types of dermatological cancers and precancers. It normally destroys the tumour without scarring or damage to surrounding healthy cells.”
She added: “Through years of research we have been able to develop a modified PDT treatment enabling for the first time for thicker nodular basal cell carcinomas to be treated effectively with a single PDT treatment. This is important, as this is a very common form of skin cancer.”
The work of Dr. Curnow and her team are part of a developing research theme for the Peninsula Medical School, which is Environment and Human Health. Operated mainly from the Peninsula Medical School in Cornwall, but with collaboration from colleagues within the institution across the South West of England, this research theme seeks to identify and study the links between our health and well-being and the environment.
Care Study
Graham O’Neill, 54, is technical marketing director at Imerys Minerals in Cornwall and lives near Mevagissey.
Graham was raised in the West Indies, and although his mother was very careful about protecting him from the sun, his exposure to the sun’s rays at an early age led to the discovery of melanomas on his skin in 1983.
“Back then the treatments were quite severe,” said Graham. “It involved liquid nitrogen, scraping out the melanoma and cauterizing it. Not only was this very painful, but it also left scarring.”
He now receives treatment with PDT, which is much better for him. He said: “The treatment is extremely good. From a personal point of view it is much less unpleasant and seems to be more effective. It also treats quite a big area in one go, which means fewer treatments in the long run. The other issue with melanomas is that they keep coming back. With PDT I have found that they do not return as frequently and, when they do, they are far less severe.”
On balance Graham is delighted with the treatments, which he has been receiving at Treliske Hospital, Royal Cornwall Hospitals NHS Trust in Truro. He said: “Compared with the old way of doing things, PDT is a fantastic therapy and one which I would recommend to other patients. It is very exciting that the Peninsula Medical School is taking such a worldwide lead in research in this area.”
Note: This story has been adapted from a news release issued by the The Peninsula College of Medicine and Dentistry
New Links in Tobacco Carcinogen Chemical Pathway (5/28/2008)
May 30, 2008
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| pah-reactive-oxygen.jpg |
Two types of cancer-causing agents in cigarettes-a nicotine-derived chemical and polycyclic aromatic hydrocarbons (PAHs) are the main culprits in lung cancer. Exposure to tobaccosmoke - both mainstream and second-hand - is a leading cause of cancer death in the United States.
Previous studies have shown how PAHs damage DNA, with the emphasis on how PAHs bind directly to DNA itself, leading to the mutations in critical genes that cause disease. Now, researchers at the University of Pennsylvania’s School of Medicine’s Center of Excellence in Environmental Toxicology (CEET) have shown that PAHs, via oxidative stress, can also led to mutations in critical genes important in lung cancer. The findings were published online last week in the Proceedings of the National Academy of Sciences.
“This is the first demonstration of this link,” says co-author Ian Blair, PhD, Professor and Vice Chair of the Department of Pharmacology. “This is a second, but indirect, way in which PAHs can cause cancer. We also know that PAHs can also cause cancer directly.”
Several genetic studies have also shown that the enzymes responsible for generating the oxidative stress from PAHs are overexpressed in lung cancer tumor tissue and esophageal cancers, explains Trevor Penning, PhD, CEET’s director and the study’s senior author. “Our study also shows that those same enzymes, called AKRs, are responsible for the oxidative stress from PAHs in the human lung cells we used in our experiments.”
Oxidative stress is the accumulation of destructive molecules called free radicals that can lead to cell death. Free radicals damage cell membranes, proteins, or genetic material by “oxidizing” them, the same way oxygen causes iron to rust.
The AKR enzymes transform PAHs to produce oxygen free radicals. These oxygen radicals bind to DNA, and if this damage is not repaired it leads to mutations that are carried through to the next generation of cells.
Penning also mentions another genetic ramification due to this association. A recent microarray study of all 30,000 human genes asked what genes were most over-expressed in non-small cell lung carcinoma. Of the eight genes that were most abundantly overexpressed, two were AKR enzymes.
“Because this study relates AKR overexpression to oxidative damage of DNA with lung cancer, it makes you wonder if the 10 percent of smokers that are most prone to lung cancer, have either dysregulated AKR expression or genetic differences in their AKRs that predispose them to disease,” says Penning. Since oxidative stress is also linked to tumor promotion, it is possible that his link may also explain other stages of the disease process.
“These findings go beyond the first step of DNA damage and may provide a reason why disease progresses,” says Penning.
Penn coauthors are Jong-Heum Park , Kirk A. Tacka, and Amy M. Quinn, and Dipti Mangal and Ronald G. Harvey from the University of Chicago. This work was funded by the National Institutes of Environmental Health Sciences and the National Cancer Institute.
Note: This story has been adapted from a news release issued by the University of Pennsylvania
Protein Provides Innate Defense Against HIV (5/28/2008)
May 30, 2008
By identifying a protein that restricts the release of HIV-1 virus from human cells, scientists believe they may be closer to identifying new approaches to treatment. The research is published in the advance online edition of Nature Medicine.
Scientists have known that most human cells contain a factor that regulates the release of virus particles, but until now they have been uncertain about the factor’s identity. Now a research team from Emory University School of Medicine, Vanderbilt University School of Medicine, and Mayo Medical School has identified CAML (calcium-modulating cyclophilin ligand) as the cellular protein that inhibits the release of HIV particles.
CAML works by inhibiting a very late step in the virus lifecycle, leading to the retention of HIV particles on the membrane of the cell. The virus has developed a means of counteracting CAML, through the action of the viral Vpu protein. When Vpu is absent, HIV particles don’t detach from the plasma membrane and instead accumulate by a protein tether at the cell surface.
When the research team depleted CAML in human cells in the laboratory, they found that Vpu was no longer required for the efficient exit of HIV-1 particles from the cell. When they expressed CAML in cell types that normally allow particles to exit freely, the particles remained attached to the cell surface. “This research is important because it identifies CAML as an innate defense mechanism against HIV,” says senior author Paul Spearman, professor of pediatrics (infectious diseases) at Emory University School of Medicine. “We are continuing to work on the mechanism that Vpu uses to counteract CAML and on defining exactly how CAML leads to virus particle retention on the infected cell membrane. We hope this will lead us to new treatments.”
The research was funded by the National Institutes of Health. First author of the paper was Vasundhara Varthakavi, PhD, in the Department of Pediatrics at Vanderbilt University School of Medicine. Other authors included Ellen Heimann-Nichols, Rita M. Smith and Yuehui Sun from Vanderbilt School of Medicine, Richard J. Bram from Mayo Medical School, and Showkat Ali, Jeremy Rose and Lingmei Ding from Emory School of Medicine.
Reference: “Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV- release overcome by Vpu.
Note: This story has been adapted from a news release issued by Emory University
Combining exercise with hormone could prevent weight gain (5/28/2008)
May 30, 2008
Once heralded as a promising obesity treatment, the hormone leptin lost its fat-fighting luster when scientists discovered overweight patients were resistant to its effects. But pairing leptin with just a minor amount of exercise seems to revive the hormone’s ability to fight fat again, University of Florida researchers recently discovered.
The combination of leptin and a modest dose of wheel running prevented obese rats on a belt-busting, high-fat diet from gaining weight, even though neither tactic worked alone, say UF researchers, writing in the journal Diabetes.
“They don’t run enough to use sufficient energy to prevent weight gain,” said Philip Scarpace, a professor of pharmacology and therapeutics in the UF College of Medicine and the senior author of the study. “What the act of running appears to do is allow the leptin to work again. It’s a demonstration that this simple act can reverse leptin resistance.”
More than 34 percent of American adults - about 72 million people - are obese or overweight, according to the Centers for Disease Control and Prevention. Scientists had hoped to wield leptin, a hormone that sends the body chemical signals to stop eating and use stored energy, as a weight-loss weapon. Studies in lean animals were promising, but overweight animals and people don’t respond the same way, likely because their bodies already overproduce leptin, causing them to develop resistance to the hormone, Scarpace said.
“Obese animals and humans don’t respond to leptin at all,” he said. “Our lab is interested in elucidating why this is the case. We know that often single-entity treatments are not successful. The concept was maybe a dual-entity treatment would work.”
To test this, the researchers decided to pair leptin with exercise, comparing the effects on both normal-weight and obese rats kept on high-fat diets, which simulate the type of fast-food-filled fare many Americans eat.
The rats were further separated into three groups to test three approaches. One group received leptin, another group got an exercise wheel and the third group got both leptin and a wheel. In the normal-weight rats, leptin and exercise both worked to prevent weight gain. The normal-weight rats ran significantly more than their bulkier peers, logging in about two and a half miles a day on their wheels, and kept off weight proportionally to how much they ran. The rats were allowed to run as much as they chose.
In the obese rats, which ran six to eight times less, neither running nor leptin alone kept the weight from accruing. Giving the rats leptin actually caused them to gain more weight than eating a high-fat diet alone, the study shows.
“This is a startling finding. Leptin is expected to reduce body weight, not promote weight and fat gain,” Scarpace said.
But the obese rats that ran and took leptin kept the extra weight off, Scarpace said. More research is needed to understand exactly why this combination works, but the scientists speculate that the low level of running triggered a metabolic change in the rats that cleared the way for the leptin signal to get through.
“They should have been gaining weight,” Scarpace said. “They don’t run enough to make any difference.”
Christopher Morrison, an assistant professor at the Pennington Biomedical Research Center at Louisiana State University who wrote a commentary about the UF study in Diabetes, said he thinks the discovery has potential to help combat obesity in humans.
“That’s the hope and the reason for doing this type of work,” he said. “The study raises many questions. If we can improve leptin sensitivity and enhance the ability of the signal to get through, maybe it will lead to weight loss.”
UF researchers are now aiming to team with doctors and test the leptin and exercise combination in humans. They also are working on additional studies to better understand leptin’s effects and its signaling pathway. Scientists still can’t pinpoint exactly why overweight people develop resistance to leptin and what role the hormone really plays in obesity.
“Leptin may be the cause of obesity rather than a cure,” Scarpace said. “Unless you run.”
Collaborating with Scarpace on the study were Alexandra Shapiro, Michael Matheny, Yi Zhang, Nihal Tümer, Kit-Yan Cheng, Enda Rodrigues and Sergei Zolutukhin.
Note: This story has been adapted from a news release issued by the University of Florida
