DukeHealth.org: Duke Health News

Vaccines to Boost Immunity Where It Counts, Not Just Near Shot Site

Sun, 22 Jan 2012 00:00:00 +0000

Researchers at Duke University Medical Center have created synthetic nanoparticles that target lymph nodes and greatly boost vaccine responses, said lead author Ashley St. John, PhD, a researcher at Duke-NUS Graduate Medical School.

The paper was published online in the journal Nature Materials on Jan. 22.

Currently all other adjuvants (substances added to vaccines to help to boost the immune response) are thought to enhance immunity at the skin site where the vaccine is injected rather than going to the lymph nodes, where the most effective immune reactions occur.

The current study used mice to show it is possible to shift the delivery path directly to the lymph nodes.

The researchers based their strategy on their observation that mast cells, which are cells that are found in the skin that fight infections, also communicate directly to the lymph nodes by releasing nanoparticles called granules.

“Our strategy is unique because we have based our bioengineered particles on those naturally produced by mast cells, which effectively solve the same problem we are trying to solve of combating infection,” said St. John, who is in the Duke-NUS Program in Emerging Infectious Diseases.

The synthetic granules consist of a carbohydrate backbone that holds tiny, encapsulated inflammatory mediators such as tumor necrosis factor (TNF). These particles, when injected, mimic the attributes of the granules found in natural cells, and the synthetic particles also target the draining lymph nodes and provide for the timed release of the encapsulated material.

Traditional vaccine adjuvants may help antigens (the small part of a pathogen that is injected during vaccination that the body reacts to) to persist so the body can have an immune reaction and build antibodies so that when a real pathogen, such as the flu virus arrives, it will be conquered. Alternatively, adjuvants may activate cells called dendritic cells, which pick up pathogen parts and must travel from the skin to lymph nodes where immune reactions are initiated.

The Duke team, however, has created a vaccine adjuvant of nanoparticles that are capable of traveling from the point of injection to the lymph nodes where they act on many cell types of the immune system to spur the right reaction for a greatly increased immune response.

The researchers found that they could use this adjuvant in vaccinations of mice with the influenza A virus.

In levels of flu virus exposure that would be lethal in typical mice, the vaccinated mice were able to fight off the disease and had an increased survival rate, thanks to the effective immune response the particles stimulated.

The researchers also showed they could load the same type of particles with a different immune factor, IL-12, that directed a response toward a different set of lymphocytes. This is an important finding since certain types of infections require specialized responses to be overpowered by the body.

St. John said the flexibility of the synthetic particles and their ability to target certain lymph nodes represented a new avenue of personalized medical treatment – personalized vaccines.

Senior author Soman Abraham, PhD, professor of pathology, immunology and molecular genetics and microbiology at Duke in Durham, NC, and emerging infectious diseases at Duke-NUS, is cautiously optimistic that the mast-cell-inspired synthetic particles could make their way into human use soon.

“It should not be long because all the individual cytokines (immune system factors) and additional materials loaded into these particles are already FDA approved for use in humans,” Abraham said. “There is a lot of interest in nanoparticle-based therapy, but we are basing our materials on our observation of mast cells in nature. This is an informed application to deliver the right material to the right place in the body to get the most effective immune reaction.”

Other authors include Herman Staats and Cheryl Chan of Duke Pathology who contributed to the vaccination studies, and Kam Leong, who contributed to the design of the synthetic particles, of the Pratt School of Engineering at Duke.

Funding came from the National Institutes of Health.

New Way to Learn About -- and Potentially Block -- Traits in Harmful Pathogens

Mon, 09 Jan 2012 00:00:00 +0000

Researchers at Duke University Medical Center have developed a new way to identify the genes of harmful microbes, particularly those that have been difficult to study in the laboratory.

This new method uses chemicals to create mutant bacteria, followed by genomic sequencing to identify all mutations. By looking for common genes that were mutated in Chlamydia sharing a particular trait, the investigators were able to rapidly "zero in" on the genes responsible for that trait.

The approach is versatile and inexpensive enough that it could be applied to study a range of microorganisms, said Raphael Valdivia, PhD, an associate professor of molecular genetics and microbiology at Duke.

"We were able to learn about genes that allow Chlamydia to flourish in their hosts without the traditional, lengthy process of domesticating the pathogen to accept recombinant DNA," Valdivia said.

"Our approach marries classical microbiology techniques with 21st century genome-sequencing technologies. If you encounter a new dangerous microorganism and want to determine what genes are important, I think this represents an effective way to learn all we can, as fast as we can."

One of the goals in studying microbial pathogens that harm humans and animals is to locate and disrupt the genes required for infection, Valdivia said.

The microbe in this study, Chlamydia, is usually sexually transmitted, hides in human cells, and is a type of bacteria that must cause disease to be transmitted from one host to another. Chlamydia is the leading sexually transmitted infection and a risk factor for pelvic inflammatory disease and infertility.

Prior to this work, the function of many Chlamydia genes had to be inferred by their similarity to genes from other bacteria. "By isolating mutants that don't grow well inside cells and identifying the underlying mutations, we can learn a lot about how these genes contribute to disease," Valdivia said. "These are the activities we'd like to block."

"For us, this significantly accelerates the analysis of Chlamydia and importantly, should be applicable to many other microbes that have been difficult manipulate with recombinant DNA approaches," he said.

Valdivia suggested that even microbes associated with our normal intestinal flora, which are notoriously difficult to manipulate, are now open to exploration so that we can learn how their genes influence human health, including dietary disorders and inflammatory bowel disease.

The work was published on Jan. 9 in the early edition of the Proceedings of the National Academy of Sciences.

Valdivia also said that the new technique could help to create Chlamydia vaccines that have a combination of mutations that affect the pathogen's virulence. "That way we can cripple some aspects of the bacterium's ability to thrive intact in a host, while still allowing the bacterium to replicate enough to prime the im mune system against it."

The lead author was Bidong D. Nguyen of the Duke Department of Molecular Genetics and Microbiology.

This work was supported by funds from a Chancellor's Science Council Pilot Projects award from Duke University and funds from the NIH.

Electron micrograph of Chlamydia mutant bacteria inside of a cell. These particular mutant bacteria, colored red, are defective in secreting high levels of virulence proteins, seen here as the accumulating dark granules in between two bacterial membranes. Photo credit: Bidong Nguyen, Duke Molecular Genetics and Microbiology

Headphone Music Eases Anxiety During Prostate Biopsies

Mon, 09 Jan 2012 00:00:00 +0000

Tuning in to tune out may be just what's needed for men undergoing a prostate biopsy, according to researchers at the Duke Cancer Institute.

The Duke team found that noise-cancelling headphones playing a classical melody may reduce the pain and anxiety of the often uncomfortable procedure.

The finding, published this month in the journal Urology, points to a simple and inexpensive way to help an estimated 700,000 U.S. men who undergo a prostate biopsy a year. The procedure is essentially the only way to diagnose prostate cancer, which strikes one in six men during their lifetimes.

"It's a matter of shifting attention, so the music provides a distraction from the procedure," said Matvey Tsivian, MD, a Duke urologic oncology fellow and lead author.

For the study, which was conceived by medical students and had no outside funding, the Duke team enrolled 88 patients and randomly assigned them to three groups. The first had no headphones; the second wore the noise-cancelling headphones but heard no music; and the third wore the headphones and listened to Bach concertos.

Blood pressure was taken before and after a trans-rectal biopsy, which is an intrusive procedure involving an ultrasound probe and a spring-loaded needle that has a loud trigger. The noise alone causes many men to flinch even if they report no pain, and 20 percent of men experience high stress and anxiety about the procedure.

Among study participants in both groups with no musical intervention, diastolic blood pressure remained elevated after the procedure, compared to before. But the men who wore the headphones and listened to Bach had no such spike in blood pressure. Diastolic blood pressure often rises as a function of stress and anxiety.

Study participants who had the music also reported less pain, as measured by questionnaires. The researchers said they did not determine whether the choice of music might have had an impact.

"We couldn't study all the permutations and variables, but it's evident that this kind of approach works," said Thomas Polascik, MD, director of Urologic Oncology at the Duke Cancer Institute and senior author of the study. "This is something that could be broadly employed. It's easy and inexpensive -- a set of headphones and music. That's it."

In addition to Tsivian and Polascik, study authors included Peter Qi; Masaki Kimura; Valerie Chen; Stephanie Chen; and Tong J Gan.

Cancer Drugs Help the Hardest Cases of Pompe Disease

Thu, 05 Jan 2012 00:00:00 +0000

Kids with Pompe disease fail because of a missing enzyme, GAA, that leads to dangerous sugar build-up, which affects muscles and movement.

An enzyme replacement treatment pioneered at Duke University has saved many lives, but some children with Pompe disease produce an immune reaction that blocks the benefits of the life-saving enzyme treatment.

To date, there has been no success in eliminating or suppressing this immune response.

Now research led by Duke University Medical Center, with collaborators at other centers, has resulted in successful enzyme replacement therapy for children who were predicted to have or who had the immune reaction blocking the effects of the enzyme therapy. In the past, children with this immune response died despite treatment.

In an article appearing in Genetics in Medicine, the researchers showed that a very low-dose combination of medicines typically used to treat cancer was successful in eliminating or preventing the immune response.

The drugs were rituximab, methotrexate and gammaglobulins -- a mix of chemotherapeutic drugs and drugs to support the immune system. These drugs were the right mix for children who had Pompe, and who most likely weren’t going to benefit from the enzyme treatment because of their anti-GAA immune response.

“The goal is to get the new combination therapy to the child who is at risk of rejecting the enzyme, before or at the time the enzyme (recombinant human GAA (rhGAA), known as Myozyme) is infused,” said senior author Priya Kishnani, MD, professor of pediatrics and medical genetics at Duke.

“If you can get this combination to people early, before they are infused with the enzyme, they will likely have a very good response to the enzyme treatment. Once the body has been exposed to the enzyme treatment, the babies at risk are likely to mount an immune response that blocks the effectiveness of the infused enzyme.”

The group at Duke earlier showed the role of the immune response in children with Pompe disease. Once this response occurred, children who were previously doing well failed to benefit from treatment and died.

The researchers in the current study, spread out in centers at Children’s Hospitals & Clinics of Minnesota, Medical College of Wisconsin/Children’s Hospital of Wisconsin, Sorka Medical Center in Israel, and the Evelina Children’s Hospital in London, worked together to treat the at-risk babies with the chemotherapy medicines at the time enzyme treatment started or shortly thereafter.

The team at Duke used genetic sequencing to identify the children at risk of enzyme-treatment failure. The experience of the Duke group allowed for identification of these cases early.

Senior author Kishnani said the stakes of failure are very high. “Until now, children with Pompe who make antibodies to the enzyme treatment die or are placed on invasive ventilation by age 27 months,” she said. “It is very difficult for families, because some children who initially showed a benefit and were able to walk then started failing once the immune response occurred. It is heartbreaking to watch, not only for family members, but also for the team that cares for the children.”

The study examined four children -- two who had Pompe and had never been treated and two who were treated, but were failing.

“We have made a difference in the lives of four patients at medical centers around the world,” Kishnani said. “All of them have achieved new motor abilities, in distinct contrast with the relentless downhill course of patients who were unable to tolerate the enzyme therapy and would otherwise have died.” Some of these children have now been doing well for a number of years, Kishnani said.

Other authors include Deeksha Bali and Sarah P. Young of Division of Medical Genetics, Duke Department of Pediatrics; Laura E. Case of the Duke Division of Physical Therapy, Department of Community and Family Medicine; Yoav H. Messinger of Pediatric Hematology/Oncology, and Nancy J. Mendelsohn and Rebecca Olson of Medical Genetics, at Children's Hospitals & Clinics of Minnesota; William Rhead, Amy White, Cara Wells and David Dimmock of the Division of Genetics, Departments of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin; Eli Hershkovitz of Pediatric Endocrinology & Metabolism Unit, Soroka Medical Center, Beer Sheva, Israel,; Michael Champion of the Department of Inherited Metabolic Disease, Evelina Children's Hospital, London, United Kingdom; Simon A. Jones of Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University, Manchester, UK; and Amy S. Rosenberg of the Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland.

Dr. Kishnani received research funding and honoraria from Genzyme, and is a member of Pompe and Gaucher Disease Registry Advisory Boards for Genzyme. Dr. Case also received research support from Genzyme, and PTC Therapeutics, Leal Foundation, families of SMA, and grant support from the National Skeletal Muscle Research Center, and is also a consultant for the Genzyme registry advisory boards. Several other authors received research funding or honoraria from or consult for Genzyme.

New Approach to Prostate Cancer Care Draws Patients with Riskiest Disease

Wed, 04 Jan 2012 00:00:00 +0000

In choosing where they get treatment, prostate cancer patients tend to opt for a major cancer center if they have severe disease, but stick closer to home for less complicated cases, even when offered a model of care that taps numerous experts.

The findings by Duke Cancer Institute researchers, published in the January issue of the Journal of Urology, are the first large analysis of the so-called multidisciplinary care strategy that gives prostate cancer patients access to a surgeon, a medical oncologist, and a radiation oncologist -- all in a single visit.

The care team then decides as a group what's best for the patient, easing the bias for any one specialty.

Such multidisciplinary care has been common in Europe and is often used in the United States for breast and lung cancers, but it can be expensive and difficult to structure outside of large, sophisticated hospitals.

The approach may be increasingly useful as prostate cancer patients now face a complex array of treatment options, including different surgical methods, radiation therapies, and active surveillance.

"Optimum management of prostate cancer continues to be controversial and not well defined," said lead author Suzanne B. Stewart, MD, a urology resident in the Duke Prostate Center. "With so many options, it can leave patients with uncertainty and distress."

Stewart said the Duke team set out to determine whether the multidisciplinary approach could be a viable model of care for hospitals and community doctors, providing prostate cancer patients more standardized, less fragmented information. Figuring out how patients are drawn to the multidisciplinary model, and who then stays for treatment, is an important step in expanding the services beyond big cancer centers.

The Duke physicians studied two groups from 2005 to 2009, including 701 patients who sought an evaluation at Duke's multidisciplinary prostate cancer clinic, and 1,318 who accessed care in the hospital's traditional urology prostate cancer center or genitourinary oncology clinics.

In the multidisciplinary clinic, which is generally offered once a week, the men seeking evaluations tended to be younger, white, more affluent, and live further away than Duke's typical prostate cancer patients. Sixty-one percent of the men sought the clinic on their own, rather than through a doctor who referred them because they had a difficult case.

But those patients often didn't stick around to undergo treatment. About 42 percent of the multidisciplinary clinic patients took the expert advice and then opted for treatment closer to home, especially if they had low-risk disease. As a result, those who actually got multidisciplinary care were sicker, and were demographically similar to typical Duke prostate cancer patients -- younger, black, lower income, and living nearby.

Stewart said that finding raises questions about access to multidisciplinary care for many prostate cancer patients. Poorer men who lived more than 100 miles from the clinic were less inclined to travel for the evaluation and treatment in the model program, particularly if they weren't referred by a physician.

Judd W. Moul, MD, senior author of the study, said spreading the multidisciplinary approach beyond major hospitals and cancer centers remains a costly proposition that could be an impediment to removing barriers to care.

"From the patient perspective, it's a wonderful opportunity to get an in-depth education about the disease, but it's difficult for many health systems to do something like this, considering the time commitment of multiple cancer specialists needed at the same time for the clinic," Moul said. "In light of multitude new treatments that have been approved in the last two years for advanced prostate cancer, it is critical to embrace the multi-D concept so that patients can become acclimated to the total care team earlier in their disease course."

W. Robert Lee, MD, MEd, a radiation oncologist and co-author of the study, agreed that new treatment choices have complicated the decision process for patients. "Prostate cancer is a disease with many options for treatment," Lee said. "It is our hope that this format allows patients to make wise decisions on what treatment is best for them."

The Duke team is now exploring whether patients fare better in multidisciplinary clinics than in regular care. For many of the physicians who have participated in the multidisciplinary approach, the treatment model has already proved useful.

"What I've learned from practicing in our multidisciplinary environment has helped me make better decisions for my patients," said Daniel J. George, MD, director of genitourinary medical oncology.

In addition to Stewart, Moul, Lee and George, study authors included: Lionel L. Bañez; Cary N. Robertson; Stephen J. Freedland; Thomas J. Polascik; Donghua Xie; Bridget F. Koontz; Zeljko Vujaskovic; Andrew J. Armstrong; Phillip G. Febbo.

Funding for the study was provided by the Committee for Urologic Research, Education and Development at Duke University. The study authors reported no conflicts of interest.

Short Hospitalizations for Heart Attacks May Increase Readmissions in U.S.

Tue, 03 Jan 2012 00:00:00 +0000

Patients treated for acute heart attacks in the United States are readmitted within 30 days more often than in other countries, a finding explained in part by significantly shorter initial hospitalizations, according to an international study led by researchers at Duke University Medical Center.

The study, published in the Jan. 4, 2012, issue of the Journal of the American Medical Association, found that 60 percent of severe heart attack patients enrolled in the United States were discharged in three days or less, yet 14.5 percent of the U.S. patients required another stay within a month.

By comparison, 54 percent of study participants in other countries spent at least six days in the hospital, leading to a 9.9 percent 30-day readmission rate.

The findings provide data for U.S. policy makers, hospital officials, and doctors who are working to determine the appropriate length of stay for patients with severe heart attacks and the best way to coordinate their care after they've been released.

Given recent trends to use readmission rates for heart attacks as a measure of hospital quality, the data add new insights on the predictors of readmission.

"Readmission should be avoided if at all possible, everyone agrees on that," said Manesh R. Patel, MD, assistant professor of cardiology at Duke and senior author of the study. "It may be that the total number of days a patient spends in the hospital in the first 30 days may reflect the amount of care required. In places other than the United States, you may initially stay longer and get much of that care coordinated at the beginning."

Patel and colleagues examined the admission and discharge data of 5,745 heart attack patients from 17 countries enrolled in a study called the Assessment of Pexelizumab in Acute Myocardial Infarction. Patients all suffered a severe form of heart attack referred to as a STEMI, or ST segment elevation myocardial infarction, in which the coronary artery is completely blocked by a clot.

Among these patients, having blockages in numerous arteries and living in the United States were the two main factors predicting whether they'd be readmitted to the hospital.

Patients with multiple blockages had almost twice the risk of readmission compared to those without, and patients in the United States had 68 percent increased risk of readmission compared to study participants from other countries.

Readmission rates in the United States were by far the highest among the countries studied. Patient populations were largely similar across nationalities, although U.S. participants were slightly younger and had a higher prevalence of previous coronary artery disease.

When the data were adjusted to account for the length of stay, the difference between U.S. readmission rates and those in other countries was greatly diminished, suggesting that the shorter length of stay in U.S. hospitals impacts readmissions.

"This speaks to how health care is provided in the United States," Patel said. "In the United States, care is episodic, not always coordinated, and it's not clear in many cases whether the patient is seen again by the same doctor or care team within the first seven days after discharge. When they are discharged quickly, they are at risk for being readmitted because the system may not be in place to effectively manage them when issues arise."

The study authors noted that 30-day hospital readmission rates for patients with heart attacks have been used by the U.S. Centers for Medicare & Medicaid Services as a quality measure since 2009. The issue is complicated by rising health care costs and pressure to keep the length of expensive hospitals stays to a minimum.

"We don't know if simply making the stay longer would help -- we don't know that at all," Patel said. "We just know that when the stay is shorter, the correlation is associated with more readmissions."

Robb D. Kociol, MD, lead author of the study and now advanced fellow in heart failure and transplant at Tufts Medical Center in Boston, said the retrospective study provides fodder for additional research that could eventually determine the best way to care for people with severe heart attacks.

"One of the limitations with our study is there are probably other cultural differences in terms of health insurance coverage or primary care providers that we don't capture here," Kociol said. "If anything, this suggests we need to look more at the differences internationally to optimize outcomes."

In addition to Patel and Kociol, Duke-affiliated authors include: Renato D. Lopes; Robert Clare; Laine Thomas; Rajendra H. Mehta; Karen S. Pieper; and Christopher B. Granger. Other authors include Padma Kaul and Paul W. Armstrong from the University of Alberta, Edmonton, Canada; Judith S. Hochman from New York University; and W. Douglas Weaver from the Henry Ford Heart and Vascular Institute in Detroit, Mich.

Support for the study came from the Duke Clinical Research Institute; the American Heart Association; and David and Stevie Spina. Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals jointly funded the Assessment of Pexelizumab in Acute Myocardial Infarction trial.

Study authors reported no conflicts of interest.

Duke Celebrates Distinguished Fellows Who Have Advanced Science

Thu, 22 Dec 2011 00:00:00 +0000

Five scientists from Duke University Medical Center and three from Duke University have been chosen for the distinct honor of fellow of the American Association for the Advancement of Science (AAAS).

Election as an AAAS fellow is granted because of scientifically or socially distinguished efforts to advance science or its applications. Notably, three new fellows are from the Department of Molecular Genetics and Microbiology, and three are department chairs.

"All of these individuals are world-class scientists, who have made discoveries that drive their fields forward,” said Nancy Andrews, MD, dean of the Duke University School of Medicine. “With this honor, they join a very distinguished group of scientific leaders. We are very fortunate to have so many people of this caliber on our faculty."

“These are all outstanding scientists whom we are proud to have as colleagues,” said Sally Kornbluth, PhD, vice dean for basic science at Duke University School of Medicine. “They are also terrific citizens and leaders who make important contributions to the life of the Duke community.”

This year’s new AAAS fellows from the Duke University Medical Center are:

Richard Brennan, PhD, chair of the Duke Department of Biochemistry, for distinguished contributions in the area of structural biology and his work deciphering mechanisms of gene expression and multi-drug resistance.

Bryan Cullen, PhD, professor of molecular genetics and microbiology, for distinguished contributions to the field of virology, particularly for studies on human immunodeficiency virus and the role of microRNAs in viral pathogenesis.

Mariano Garcia-Blanco, MD, PhD, professor of medicine and professor of molecular genetics and microbiology, for distinguished contributions in RNA biology, and particularly for unraveling the importance of RNA-protein interactions that regulate messenger RNA splicing and control pathogenic RNA viruses.

Sue Jinks-Robertson, PhD, professor of molecular genetics and microbiology, for distinguished contributions to the fields of genetics and molecular biology, particularly for advancing the understanding of basic mechanisms of mutagenesis and homologous recombination of chromosomes.

Donald McDonnell, PhD, Glaxo-Wellcome Professor of Molecular and Cellular Biology and chair of the Duke Department of Pharmacology and Cancer Biology, for research that has provided fundamental insights into the molecular mechanisms underlying the pharmacological activities of nuclear receptor ligands in physiology and disease.

From Duke University, the new AAAS fellows are:

Ingrid Daubechies, PhD, James B. Duke Professor of Mathematics, for her seminal work in wavelets, as well as significant contributions in the area of signal processing, quantum mechanics, discrete geometry, and applied mathematics.

Xinnian Dong, PhD, professor of biology, for her research on the interactions of plants and microbes, and for her outstanding service to the American Society of Plant Biologists and the journal Plant Cell.

Dan Kiehart, PhD, chair of the Department of Biology, for his contributions to developmental biology through detailed study of the embryonic development of fruitflies.

In a ceremony in February 2012, 539 members will receive this honor. The AAAS is the world’s largest general scientific society and publisher of the journal Science, among other journals.

Gene Discovery Explains How Fruitflies Retreat from Heat

Fri, 16 Dec 2011 00:00:00 +0000

A discovery in fruit flies may be able to tell us more about how animals, including humans, sense potentially dangerous discomforts.

Researchers at Duke University Medical Center uncovered naturally occurring variations of a gene named TRPA1 that is important for the function of pain-sensing neurons throughout the animal kingdom.

The gene makes an ion channel, which floods sensory neurons with calcium ions when the fly is near a heat source, causing fruit fly larvae to respond with a corkscrew-style rolling motion away from the heat source.

View a video of an escaping larva.

The team, led by co-authors Lixian Zhong, PhD, and Andrew Bellemer PhD, of Duke Department of Anesthesiology, found a 37-amino-acid section of nearly four identical protein molecules that controls the responses of the proteins to temperature. The larvae start their nociception (pain perception) escape roll at just over 100 degrees Fahrenheit (39 degrees Celsius).

Senior author Dan Tracey, PhD, associate professor of anesthesiology, cell biology and neurobiology, said these discoveries could have a bearing on injured people with temperature sensitivity in damaged tissues or people with allodynia, who perceive even modest changes in temperature as painful.

Even spontaneous pain that occurs in pathological pain states might be explained if the human versions of these channels were to open inappropriately at the normal body temperature, Tracey said.

The work was published in the inaugural issue of Cell Reports on Thursday, Dec. 15.

Interestingly, the authors found that the version of TRPA1 that is necessary for detecting the painful temperatures was not a direct temperature sensor. Tracey said this discovery suggests that TRPA1 channels may play an important role in sensing other kinds of pain besides temperature.

The four proteins vary in only two small sections. The scientists were able to find a 37-amino acid section in two of the variants that was important for sensing hot temperature.

Interestingly, many noxious chemicals that trigger painful sensations, including wasabi and tear gas, also activate the TRPA1 channel in humans and fruit flies. The variants identified by the Duke team all respond to these noxious chemicals but vary in their responses to temperature. Finding similar variants in humans may give important insights into pain-sensing.

"Typically heat responses of nociception channels are tested with artificially made mutants, but our study involved four natural gene variants, two of which were related to the avoidance behavior we could observe under the microscope," said Tracey, who directs the Molecular Pain Signaling Laboratory at Duke.

"Because evolution created these variants, we had more confidence that the amino-acid section we found was particularly important. We had clues there were unknown versions of this gene, so we were pleased to find the relevant part of the proteins that allows for heat-sensing and nociception."

Other authors include Ken Honjo and Richard Y. Hwang of Duke Anesthesiology, Jessica Robertson of the Duke Department of Cell Biology, and Haidun Yan and Geoffrey Pitt of the Duke Department of Medicine. Dr. Pitt is also with the Duke Department of Neurobiology and directs the Duke Ion Channel Research Unit.

This work was supported by a grant from the National Institutes of Neurological Disorders and Stroke, the Ruth K. Broad Biomedical Research Foundation, the National Institute of General Medicine Postdoctoral Training Grant, a National Science Foundation Graduate Research Fellowship and a James B. Duke Fellowship.

Lyman Elected to Serve on Board of Directors of ASCO

Thu, 08 Dec 2011 00:00:00 +0000

Gary H. Lyman, MD, MPH, a professor of medicine at Duke University Medical Center, has been elected to the board of directors of the American Society of Clinical Oncology, which is the leading professional organization representing more than 30,000 oncologists and others who care for people with cancer.

Lyman will begin his four-year appointment in June 2012. As a member of the board, he will help set policies, oversee finances, and influence the direction of the organization.

“I am honored to be asked by the ASCO membership to serve in this capacity,” Lyman said. “I am committed to the society and its membership, as well as the patients that we serve, to work together to improve care, promote research, and encourage policies that will eventually lead us to cure and prevent this disease.”

An expert in breast cancer, Dr. Lyman is director of the Comparative Effectiveness and Outcomes Research Program, a senior fellow at the Duke Center for Clinical Health Policy Research, and a member of the Duke Cancer Institute and Duke Center for Personalized Medicine.

He serves as an adviser on new oncologic agents to the U.S. Food and Drug Administration, and also serves as editor-in-chief of the journal Cancer Investigation. An ASCO member since 1977, Dr. Lyman serves on the editorial boards of the Journal of Clinical Oncology and the Journal of Oncology Practice.

Lyman’s research interests include personalized management of early-stage breast cancer and supportive care of patients receiving chemotherapy, most notably those at risk for febrile neutropenia and venous thromboembolism.

Among his grants, Lyman is co-principal investigator on a National Cancer Institute study of comparative effectiveness of cancer pharmacogenomics and the validation of new genomic tools for guiding more personalized cancer treatments.

Additionally, Lyman leads efforts in evidence synthesis, clinical practice guidelines, and health policy, conducting systematic reviews and meta-analyses of major clinical issues in support of clinical practice guidelines. He also conducts analyses of large population studies that examine clinical outcomes associated with current cancer patient management in a real world-setting, with a particular focus on cancer management in older cancer patients.

Lyman, who has published more than 350 peer-reviewed articles, has been at Duke since 2007. Previously, he held positions at the Moffitt Cancer Center and Research Institute, the University of South Florida, and the University of Rochester.

Premature Babies Harbor Fewer, But More Dangerous Microbe Types

Thu, 08 Dec 2011 00:00:00 +0000

One of the most comprehensive studies to date of the microbes that are found in extremely low-birthweight infants found that hard-to-treat Candida fungus is often present, as well as some harmful bacteria and parasites.

Researchers at the Duke University Medical Center and Nicholas School of the Environment looked at the microbes in 11 premature infants and found much less diversity than in full-term infants.

“The babies’ guts were taken over by microbes we know are dangerous if they get into the blood,” said senior author Patrick Seed, MD, PhD, assistant professor of pediatrics at Duke. “Even after the babies were no longer on antibiotics, healthier bacteria didn’t appear in the babies very quickly. This may be one reason why premature babies are so vulnerable to infections.”

All of the premature children were placed on antibiotic treatments after birth, which would wipe out some types of bacteria and yeast, but once they were off the antibiotics and taking food, the researchers expected to see more diversity of bacteria in the babies’ developing digestive systems than they found.

The findings were published in PLoS One open-access journal on December 8, 2011.

Five infants had blood infections while three had necrotizing enterocolitis, an infection-related death of bowel tissue, said Seed, who is also with the Jean and George Brumley Jr. Neonatal-Perinatal Research Institute and the Duke Center for Microbial Pathogenesis.

Seed said that while the study babies were colonized mainly by organisms that were found in stool specimens, in some cases they also had infections with Staphylococcus epidermidis, a form of staph infection, that was abundant in many of the babies’ digestive tracts.

The bacteria and yeast in the premature babies’ digestive tracts are known causes of devastating infections in these babies. The gut seems to be a reservoir for some organisms that form infections, Seed said. Previous to this work, “we only knew the tip of the iceberg,” he said.

The researchers used genomic (DNA) typing of the bacteria, fungi, and parasites to determine which types were present.

It’s not clear if the newborns are picking up these early infections from their mother’s milk, blood, or in other ways, or if the pathogens are from the environment surrounding the infants.

“It’s important to know where these pathogens come from so that doctors can possibly manipulate the babies’ environment or their digestive systems,” Seed said. He noted that other studies had shown value for giving babies probiotic substances to tip the internal balance toward more favorable bacteria, necessary for immunity and better health.

Seed stressed that certain bacteria and other microbes are helpful for growing babies and their immune systems, so it is important not to do any damage by creating an antiseptic environment.

“It’s a question of balance,” Seed said. “As vulnerable as these babies are, we still wouldn’t want to wipe out all of the bacteria, even all of the potentially harmful bacteria.”

Other authors include Mariam LaTuga, Michael Cotton, Ronald Goldberg and James Wynn of Duke Department of Pediatrics; and Christopher Ellis and Robert Jackson of Duke’s Nicholas School of the Environment (Jackson is also with the Biology Department and the Center on Global Change at Duke University).

This research was supported by a pilot grant from the Duke Institute for Genome Sciences & Policy, the Duke Department of Pediatrics -- Division of Perinatal-Neonatal Medicine, the Jean and George Brumley, Jr. Neonatal-Perinatal Research Network and the Center on Global Change, as well as support from the Gerber and Hartwell Foundations.

New Insights Come From Tracing Cells that Scar Lungs

Thu, 01 Dec 2011 00:00:00 +0000

Tracking individual cells within the lung as they move around and multiply has given Duke University researchers new insights into the causes of idiopathic pulmonary fibrosis (IPF), a disease which can only be treated now by lung transplantation.

IPF fills the delicate gas exchange region of the lung with scar tissue, progressively restricting breathing. The Duke University Medical Center researchers have discovered that some commonly held ideas about the origins of the scar-forming (fibrotic) cells are oversimplified, if not wrong.

"We are the first to show that pericytes, a population of cells previously described to play a role in the development of fibrosis in other organs, are present in fibrotic lung tissue," said Christina Barkauskas, MD, a pulmonary fellow in the Duke Division of Pulmonary, Allergy, and Critical Care Medicine.

The team found that pericytes move from blood vessels into fibrotic regions, and were in the damaged lungs of both humans and mice. In mice, they also showed that the epithelial cells, which make up the lacy sacs called alveoli, could divide and repair the damage in the gas-exchange location, but these cells were not the source of scarring.

Idiopathic pulmonary fibrosis affects about 100,000 people in the United States each year and leads to death within three years of diagnosis.

The study was published the week of Nov. 28 in PNAS Plus online edition.

"We don't know yet whether the pericytes make the scar matrix itself or just release signals that stimulate the scarring process, but either way, they are a potential target for new therapies," said Brigid Hogan, PhD, senior author and chair of the Duke Department of Cell Biology.

The researchers used genetic lineage tracing to study the origin of cells that gathered in fibrotic areas. They gave several different cell types an indelible fluorescent tag and then followed the cells over time.

The cells kept the tag even if they multiplied, migrated within the lung, or differentiated into another cell type.

Paul Noble, MD, co-author and chief of the Pulmonary Division at Duke, said that identifying the source of the lethal expansion of the scarring (fibroblast) cells is a critical missing link in understanding disease progression.

Previous studies had suggested that the epithelial cells in the alveoli are a source of fibroblast accumulation after lung injury, he said.

"This study used the newest tracing approaches to conclusively demonstrate, however, that the alveolar epithelium isn't a significant source for fibroblast accumulation following lung injury in mice," Noble said. "The studies suggest that there may be several sources for the scar-forming cell accumulation in fibrosis, including pericytes, which hadn't been implicated in lung fibrosis until now."

Noble said that the study data provide new insights into the sources of scar-forming cells and would help to target the correct cell population that causes disease progression.

Now the researchers are focusing on what these cells may make that could promote a healing process. "One idea is that perhaps in IPF these epithelial cells have lost the ability to repair damage to the lung, so that scarring continues inexorably and cannot be restrained -- perhaps we could find a way to assist the repair process," Hogan said. "Promoting the healing process might be another therapeutic approach."

Other authors include Jason R. Rock and Yan Xue of the Duke Department of Cell Biology; Michael J. Cronce and Jiurong Liang of the Duke Division of Pulmonary, Allergy and Critical Care Medicine; and Jeffrey R. Harris of the Duke Division of Cellular Therapy. Jason Rock is now with the University of California -- San Francisco.

Duke Wins Three Gates Grants for AIDS Research

Wed, 30 Nov 2011 00:00:00 +0000

The Bill & Melinda Gates Foundation has awarded three grants to the Duke University Medical Center for HIV projects in the Collaboration for AIDS Vaccine Discovery (CAVD) program. The total amount of all three grants is about $37.2 million.

A five-year, $24.6 million grant from the Gates Foundation will allow David Montefiori, PhD, professor of surgery and director of the Laboratory for AIDS Vaccine Research and Development in the Department of Surgery and his collaborators to continue their efforts. Their first CAVD grant began with a five-year, $31.5 million award from the Gates Foundation in 2006.

The original grant allowed them to establish the Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC). The new grant will allow the consortium to operate on a lower budget, because several discovery projects were completed during the first five years.

"The goal of the CAVIMC is to facilitate the discovery and timely licensure of a safe, effective and practical HIV vaccine for the world," Montefiori said. "We aim to accomplish this by using valid laboratory criteria and good clinical laboratory practices (GCLP) to monitor antibody responses in the systemic and mucosal compartments in preclinical and clinical phases of vaccine testing. We also aim to identify correlates of protective immunity and to generate new scientific findings that will help bridge the gap between preclinical vaccine discovery and human clinical trials."

Montefiori noted that the outcome of the recent Thai trial called RV144 has generated optimism that a broadly effective HIV vaccine is finally within reach. The CAVIMC consortium will take the lessons learned from this trial and translate them into a stronger laboratory program for HIV vaccine discovery and licensure.

Barton Haynes, MD, a national leader in AIDS/HIV research and director of the Center for HIV/AIDS Vaccine Immunology (CHAVI), as well as director of the Duke Human Vaccine Institute (DHVI), has won a new award to study the best way to create effective immunogens that mimic the proteins on the HIV outer envelope that will help to stimulate the right antibodies to neutralize the virus at the time of transmission. The grant will provide $11.7 million over three years.

The research team will focus on evaluating antibodies as candidates for correlates of protection that we are learning about from the RV144 trial in Thailand, said Haynes, who is Frederic M. Hanes Professor of Medicine and Immunology.

Haynes led a multinational, in-depth correlates-of-protection analysis of the RV144 Thai efficacy trial results, which showed that a combination of vaccines lowered the rate of HIV infection 31 percent compared to placebo in the population, but that the protective effect was short-lived. The immune correlates analysis identified two types of antibodies that correlated with infection risk.

Haynes' new grant will study the mechanisms of effects of these two RV144-induced antibody types. In this research, he will work closely with the Montefiori team.

Michael Frank, MD, a professor of pediatrics and immunology, is new to the CAVD and won a grant for more than $892,000 over three years.

His work involves the study of complement proteins, which play a role in host defense and are part of the innate immune system; that is, these proteins are present even before a person receives a vaccine and is immunized. The complement proteins coat viral envelope antigens with peptides that facilitate ingestion by cells called phagocytes that act to destroy a microbe, Frank said. Complement coating of antigens also facilitates the immune response.

"We made the observation that intact HIV envelope antigen binds complement poorly or not at all, and postulate that this contributes to the poor response to viral antigen," said Frank. "We believe that failure to bind complement contributes to the poor antibody response in HIV vaccine recipients immunized to prevent HIV infection. We also find that the intact HIV envelope antigen has a very short half-life in vivo that further contributes to the poor response to the vaccine."

The group plans to modify the HIV antigen so that it is able to bind the appropriate complement proteins, and they also intend to stabilize the protein so that it is not broken down rapidly and thus can contribute to a normal, effective immune response.

Surgery Improves Endocarditis-Induced Heart Failure Survival Rates

Tue, 22 Nov 2011 00:00:00 +0000

Surgery significantly improves short- and long-term outcomes in patients with heart failure caused by a bacterial infection known as endocarditis, according to Duke University Medical Center researchers.

“About 60 percent of patients with heart failure in endocarditis undergo surgery during initial hospitalization,” says Duke cardiologist Andrew Wang, MD, senior author of the study which appears today in the Journal of the American Medical Association.

He believes that percentage should be higher. American College of Cardiology guidelines strongly recommend surgery for this condition.

“Patients with heart failure as a complication of endocarditis do not do well and require very aggressive treatment,” says Wang. “Our study shows patients who were treated with surgery do better during initial hospitalization and at one year. We were surprised to see that also holds true for patients with milder forms of heart failure who may only receive medical therapy. Patients with milder degrees of heart failure did better with surgery when compared to those who did not undergo surgery.”

Endocarditis is an infection that occurs when bacteria or fungi adhere to and destroy the tissues in the lining of the heart and heart valves. As a result, the valves stop working properly. They begin to leak, which causes blood to flow in the wrong direction. That leads to heart failure, meaning the heart can no longer pump enough blood to the rest of the body.

About one-third of endocarditis patients develop heart failure that can be severe and often fatal. Previous studies show endocarditis is associated with a mortality rate of 15 percent to 20 percent in the hospital, and 40 percent within one year of diagnosis. In the United States alone, about 15,000 cases of endocarditis are reported each year.

While endocarditis risk is higher in already malfunctioning valves, it also occurs when bacteria enters the bloodstream of otherwise healthy hearts. “We’re seeing it as a complication of medical procedures more frequently,” Wang says.

The study data were collected from the International Collaboration on Endocarditis-Prospective Cohort Study, which enrolled more than 4,000 patients from 61 centers in 28 countries between June 2000 and December 2006.

Of the 1,359 patients with heart failure, 839 (61.7 percent) had valve surgery during their initial hospitalization. Heart failure patients who had surgery had a significantly lower, unadjusted in-hospitality mortality rate (20.6 percent) compared to those who did not undergo surgery (44.7 percent).

The one-year mortality rate was 29.1 percent for patients who were treated with surgery compared to 58.4 percent for patients treated with medical therapy alone.

“This study gives us a much better understanding of one of the most feared complications of endocarditis, which is heart failure,” says Wang. “We now know that the prognosis and outcome can be poor unless patients are followed closely and treated aggressively by a multidisciplinary team of cardiologists, infectious disease specialists, and cardiothoracic surgeons.”

Study Questions Whether Asia and Tropics Are Source of Seasonal Flu

Mon, 14 Nov 2011 00:00:00 +0000

A commonly held theory says that flu virus persists in Southeast and Eastern Asia, making this region the source of seasonal flu epidemics in other parts of the world.

However, researchers at Duke-NUS Graduate Medical School in Singapore have found that influenza A virus doesn't persist in those tropical regions as the only global source of annual epidemics. The international team of scientists involved in the work found that any one of the urban centers they studied could act as a source for an epidemic in any other locality.

"We found that these regions are just one node in a network of urban centers connected by air travel, through which flu virus circulates and causes a series of local epidemics that overlap in time," said Gavin Smith, PhD, senior author and associate professor in the Program in Emerging Infectious Diseases at Duke-NUS.

The study was published the week of Nov. 14, 2011 in the online Proceedings of the National Academy of Sciences Early Edition.

The research team chose to study influenza A because it is much more prevalent than both influenza B and C. Influenza is a significant cause of human illness and death worldwide -- the World Health Organization estimates that 250,000 to 500,000 influenza A related deaths occur per year worldwide, and about 49,000 deaths occur in the United States.

The team obtained RNA sequences of virus samples from 2003 to 2006 in Australia, Europe, Japan, New York, New Zealand, and Southeast Asia, as well as some more recently sequenced viruses from Hong Kong.

The analysis used time and space parameters to reveal high rates of viral migration among the urban centers tested. Although the virus population that migrated between Southeast Asia and Hong Kong persisted through time, the pattern of infections also depended on virus input from temperate regions that have distinct seasons.

None of the seven temperate and tropical regions they examined was the source of all of the new flu strains in a given year. The migration pattern was more complex: viral strains moved from one region to several others in a year, and flu outbreaks were traced back to more than one source.

The scientists showed that multiple lineages of a virus could seed annual flu epidemics, and that each region could function as a potential source population.

Current strategies for controlling flu virus through vaccination are based on biannual selection of vaccine candidates for the Northern and Southern hemispheres, and these plans require an understanding of circulating viruses.

"While current vaccine-strain selection strategies are generally effective, the results of our study could potentially be used to improve this process by incorporating knowledge of virus migration and connections between regions," said lead author Justin Bahl, PhD, assistant professor in the Duke-NUS Program in Emerging Infectious Diseases.

Many examples of the global movement of viruses facilitated by air travel exist, including the SARS epidemic and the H1N1 pandemic in 2009. Because air travel by large groups of people has been common for some time, today there is not any increased risk from air travel, Smith said. "Larger regions with greater connectedness may potentially contribute more to the global diversity of influenza viruses circulating."

The researchers plan to build on this study by generating new data from areas where there is currently little or no genetic information available. This work forms part of a larger effort to understand the patterns and mechanisms of transmission of respiratory viruses in humans, using influenza as a model system, Bahl said.

Other authors were from Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Department of Community Medicine and School of Public Health, Li Ka Shing Faculty of Medicine, and Hong Kong University-Pasteur Research Centre, University of Hong Kong, Pokfulam, in the Hong Kong Special Administrative Region; Laboratory of Virus Evolution, Program in Emerging Infectious Diseases, Duke–National University of Singapore Graduate Medical School; Fogarty International Center, National Institutes of Health, Bethesda, Md.; University of Texas Medical Branch, Galveston; J. Craig Venter Institute, Rockville, Md.; Center for Vaccine Research, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine; Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London; Institute of Evolutionary Biology, University of Edinburgh; and the Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University.

The study was supported by contracts for the Influenza Genome Sequencing Project of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; the Area of Excellence Scheme of the University Grants Committee of the Hong Kong Special Administrative Region Government; the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security and the Fogarty International Center, National Institutes of Health; a career development award under National Institute of Allergy and Infectious Diseases Contract and the Duke–National University of Singapore Signature Research Program funded by the Agency for Science, Technology and Research, Singapore; and the Ministry of Health, Singapore.

Hysterectomy Increases Risk for Earlier Menopause In Younger Women

Mon, 14 Nov 2011 00:00:00 +0000

In a finding that confirms what many obstetricians and gynecologists suspected, Duke University researchers report that younger women who undergo hysterectomies face a nearly two-fold increased risk for developing menopause early.

The study, published in the December issue of the journal Obstetrics & Gynecology, is the largest analysis to track over time the actual hormonal impact of woman who had hysterectomies and compare them to women whose uteruses remained intact.

"Hysterectomy is a common treatment for many conditions, including fibroids and excessive bleeding," said Patricia G. Moorman, PhD, MSPH, an associate professor in the Department of Community and Family Medicine at Duke University and lead author of the study. "Most women are very satisfied with the results of a hysterectomy. But this is a potential risk of the surgery that should be considered along with the benefit."

Up to 600,000 women in the United States undergo hysterectomy each year, but the long-term consequences of the procedure have not been well documented. Studies have been small or relied on the recollections of women about the onset of menopause.

The Duke team enrolled nearly 900 women ages 30 to 47 at two hospitals in Durham, N.C. -- Duke University Hospital and Durham Regional Hospital -- and followed up with blood tests and questionnaires for five years. Half the women, 465, were healthy controls who had no surgery, while 406 women underwent hysterectomies that spared at least one ovary.

Preserving the ovaries while removing the uterus is a strategy designed to allow a woman's hormone production to continue, which has health benefits. Moorman said doctors have long known that early menopause -- either from surgery or from other factors that halt egg production -- can increase a woman's risk of osteoporosis, heart disease, and other ailments.

Yet despite preserving the ovaries, the Duke team found that 14.8 percent of women in the study who had hysterectomies experienced menopause over the course of the study, compared to 8 percent of women who had no surgery.

The risk for menopause was highest among women who had one ovary removed along with their uterus, but it remained elevated even when both ovaries stayed in place. The Duke team's analysis estimated that menopause occurred approximately two years earlier in the women who underwent hysterectomy.

Moorman said it's unknown what triggers the ovaries of some women to shut down after a hysterectomy.

"Some have hypothesized that surgery disrupts the blood flow to the ovaries, so the surgery leads to early ovarian failure," she said. "Others have speculated it's not the surgery, but the underlying condition preceding the surgery that causes it. Right now, it's unresolved."

Regardless of the cause, Moorman said the Duke finding provides women and their doctors with concrete information about a potential risk.

"This could potentially change practice because women who are considering hysterectomy for fibroids or other problems may want to explore other treatment options for their condition if they know they may go through menopause earlier," Moorman said.

In addition to Moorman, study authors include Evan R. Myers; Joellen M. Schildkraut; Edwin S. Iversen; Frances Wang; and Nicolette Warren.

The study was funded with grants from the National Institute on Aging and the National Center for Research Resources. The authors reported no financial conflicts of interest.