DukeHealth.org: Duke Health News

Sequencing Works in Clinical Setting to Help -- Finally -- Get a Diagnosis

Tue, 08 May 2012 00:00:00 +0000

Advanced high-speed gene-sequencing has been used in the clinical setting to find diagnoses for seven children out of a dozen who were experiencing developmental delays and congenital abnormalities for mysterious reasons.

"I thought if we could obtain even a couple of relatively secure diagnoses out of the 12 patients, that would prove the value of deploying sequencing approaches systematically in patients with unknown but apparently genetic conditions," said David Goldstein, PhD, director of the Duke Center for Human Genome Variation and professor of molecular genetics and microbiology.

"Few sequencing studies have approached the problem as we did, taking a very heterogeneous group of patients," Goldstein said. "Getting a likely diagnosis about half of the time is quite stunning and strongly motivates next-generation sequencing for all patients that fail to get a genetic diagnosis through traditional testing."

The research team used next-generation sequencing, a new technology that can rapidly read a person's entire genome or just their exome, the sections of DNA that make the proteins, which direct physiological activities. The cost of such sequencing is becoming lower, making it feasible to do the study in a clinical setting.

The work was published online on May 8, in the Journal of Medical Genetics.

"There are up to 50,000 live births in America each year with the children having features of developmental delays, intellectual disabilities or congenital abnormalities similar to those we studied," said Vandana Shashi, MD, co-author and associate professor of pediatrics in the Duke Center for Human Genetics. "Many of these children remain without diagnoses and we could systematically try to help identify a cause."

Shashi said families involved with the study often expressed relief just to have a diagnosis, even when a condition remained difficult or impossible to treat.

"Just knowing what was causing the problem took away the mystery, which gives families some comfort," Shashi said.

Goldstein said that simply studying more patients with sequencing tools would facilitate discovery by searching for similarities among patients that have mutations in the same or similar genes.

With time, this would also reveal more diagnoses, said lead author Anna Need, PhD, who works in the Duke Center for Human Genome Variation.

"Despite the fact that we ended up with a short list of gene variants for each person we studied and ran other tests, we had no real evidence of a related disease because there haven't been other reported conditions or people with mutations in those genes," Need said. "Some of the people we had no results for yet may get answers as their variants become associated with diseases through other sequencing."

The results of this study also are important for genetic counseling, Goldstein said.

For example, some of the likely diagnoses are due to new mutations that happened in the children, known as de novo mutations. In these cases, the parents would be less likely to pass it on through a subsequent pregnancy, for example.

Another lesson of the study was that some of these individuals may have multiple genetic conditions. Shashi noted one child received a diagnosis for only one of several conditions she had.

"We may not find all of the genetic causes, but over time the success of this type of testing and the information we learn will only grow," Need said. "Out of the genes we found, two have been found to be associated with disease through recent studies by other researchers."

Goldstein said it is imperative to set up large genetic databases in tertiary medical centers, which have the doctors and scientists who can evaluate patients who might benefit from next-generation sequencing. They would also have the team to do the genomic sequencing, and then, to follow up with biological tests that show the function of the gene.

Goldstein said that hospitals with the right systems in place can note a patient's clinical features and then examine a patient's cells or do a relatively general protein localization assay in cells to get an idea about gene function.

"This is a generalized follow-up system for any of the candidate genes, and the work can be done at a tertiary hospital center for virtually any candidate gene, but not by the diagnostic companies, which don't do any functional testing," Goldstein said. "That's why I see a role for this effort being grounded in an academic research environment."

Other authors include Yuki Hitomi and Kevin Shianna of the Duke Center for Human Genome Variation; Kelly Schoch of the Duke Department of Pediatrics, section of Medical Genetics; and Miriam H. Meisler of the Department of Human Genetics, University of Michigan.

Southeast Program to Fight Diabetes Awarded Nearly $10 Million by Health and Human Services

Tue, 08 May 2012 00:00:00 +0000

A plan to reduce death and disability from type 2 diabetes among at-risk populations in four underserved Southeastern counties is among the preliminary Health Care Innovation Award recipients announced today by Health and Human Services Secretary Kathleen Sebelius.

The collaborative effort titled, “From Clinic to Community: Achieving Health Equity in the Southern United States,” is spearheaded by Duke University Medical Center and the University of Michigan’s National Center for Geospatial Medicine.

The $9,773,499 award will be used to implement programs in collaboration with the Durham County Health Department (Durham, NC), Cabarrus Health Alliance (Cabarrus County, NC), Mississippi Public Health Institute (Quitman County, MS), Marshall University and Mingo County Health Department (Mingo County, WVa).

"Diabetes is a devastating problem, but is especially far-reaching in the Southeastern region of the United States,” says Robert M. Califf, MD, vice chancellor for clinical research at Duke, and leader of the project.

“Previous approaches have not been able to stem the tide. Changing the course of the diabetes epidemic requires a radically new approach. By combining the modern technology of electronic records and geospatial mapping with a new workforce of community-based health care professionals, we believe we can achieve the triple aim of better outcomes, better health care and lower cost."

“Geospatial mapping and analysis will combine medical information and community information so that interventions can meet both individual patient and larger community needs,” said Marie Lynn Miranda, director of Michigan’s National Center for Geospatial Medicine, which includes an office in Durham.

“This will allow researchers to visualize complex relationships among the locations of diabetes patients, patterns of healthcare, and available social resources. The information will serve as the basis for intervention design, decision support, and real-time monitoring of interventions.”

The Duke-led program will employ local home care teams who will provide patient-centered coordinated care to improve outcomes and lower cost -- reducing hospital and emergency room admissions and using preventive care to curb the need for amputations, dialysis, and cardiac procedures with estimated savings of over $20 million.

Over the three-year period, the collaborative program will train an estimated 88 health care workers and create an estimated 31 new jobs. These workers include information officers, health integrators, and community health workers who will use new technologies to facilitate communication, education, and care delivery.

The Duke program is one of 26 innovative projects nationwide chosen for their potential to save money, deliver high quality medical care, and enhance the health care workforce.

The preliminary awardees announced today are expected to reduce health spending by $254 million over the next three years. CMS’ Center for Medicare and Medicaid Innovation is administering the awards through cooperative agreements over three years.

“We can’t wait to support innovative projects that will save money and make our health care system stronger,” said Secretary Sebelius. “It’s yet another way we are supporting local communities now in their efforts to provide better care and lower cost.”

Preliminary awardees were chosen for their innovative solutions to the health care challenges facing their communities, as well as their focus on creating a well-trained health care workforce that meets the need for new jobs in the 21^st century health system.

Keeping Obesity Rates Level Could Save Nearly $550 Billion Over Two Decades

Mon, 07 May 2012 00:00:00 +0000

Researchers have forecast the cost savings and rise in obesity prevalence over the next two decades in a new public health study.

"Keeping obesity rates level could yield a savings of nearly $550 billion in medical expenditures over the next two decades," according to lead author Eric Finkelstein, PhD, associate research professor in the Duke Global Health Institute, as well as deputy director in the Health Services Research Program at Duke-NUS Graduate Medical School in Singapore.

The forecasting study also found that 42 percent of the U.S. population could be obese by 2030.

The findings suggest the U.S. health care system could be burdened with 32 million more obese people within two decades. Action is needed to keep rates from increasing further, according to the research from Duke University, RTI International, and the Centers for Disease Control and Prevention (CDC).

The study, based on data from the Behavioral Risk Factor Surveillance System and state-level data from the Bureau of Labor Statistics and other organizations, was published in the American Journal of Preventive Medicine on May 7.

The study also forecasts an increase in the number of individuals with severe obesity, with rates rising to 11 percent by 2030. Severe obesity is defined as a body mass index over 40 or roughly 100 pounds overweight.

Severely obese individuals are at highest risk for the health conditions caused by excess weight, resulting in substantially greater medical expenditures and rates of absenteeism.

"Should these forecasts prove accurate, the adverse health and cost consequences of obesity are likely to continue to escalate without a significant intervention," notes senior author Justin Trogdon, PhD, of RTI.

The study was released May 7 at CDC's Weight of the Nation conference in Washington, D.C.

"We know more than ever about the most successful strategies that will help Americans live healthier, more active lives and reduce obesity rates and medical costs," said William H. Dietz, MD, PhD, director of CDC's Division of Nutrition, Physical Activity and Obesity.

"People need to make healthy choices, but the healthy choices must first be available and accessible in order to make them," Dietz said. "In the coming days at our Weight of the Nation conference, CDC and its partners will emphasize the proven, effective strategies and solutions that must continue to be applied to help make the healthy choice the easy choice."

On May 8, a set of potential solutions will be released at the CDC conference. The Institute of Medicine will issue a new report, "Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation," which provides the results of a comprehensive review of obesity prevention-related recommendations. The report will identify strategies and action steps that have the greatest potential to speed up progress in combating the obesity crisis.

To view the study, "Obesity and Severe Obesity Forecasts through 2030," visit www.ajpmonline.org on May 7 after noon Eastern Time, or for a copy, contact AJPM Editorial Office at 858-534-9340 or eajpm@ucsd.edu.

Increased Fructose Consumption May Deplete Cellular Energy in Patients with Obesity and Diabetes

Wed, 02 May 2012 00:00:00 +0000

Obese people who consume increased amounts of fructose, a type of sugar that is found in particular in soft drinks and fruit juices, are at risk for nonalcoholic fatty liver disease (NFALD) and more its more severe forms, fatty inflammation and scarring.

Now researchers at Duke University Medical Center believe they better understand what mechanism may account for fructose-related liver injury.

Chronic fructose consumption in a diet puts people at risk for depleting their store of critically important molecules called ATP, which provide liver cells (and other body cells) energy for important cellular processes, including metabolism.

"The stores of liver ATP are decreased in obese and/or diabetic individuals who chronically consume increased amounts of fructose-containing beverages," said lead author Manal Abdelmalek, MD, MPH, associate professor of Gastroenterology and Hepatology at Duke.

The study was published online at the Hepatology journal site on May 2.

Nonalcoholic fatty liver disease is currently the leading cause of chronic liver disease in the United States. This condition can lead to elevated liver enzymes, inflammation and rarely even advanced scarring (cirrhosis) in individuals who do not drink alcohol. In obesity and/or diabetes, the ability of the cells to optimally make ATP may already be impaired.

Unlike other simple sugars, fructose requires ATP for its metabolism. The inability to optimally generate cellular energy as well and the continued consumption of ATP from chronic fructose ingestion can result in the liver's depletion of energy. ATP depletion may increase risk for inflammation and scarring in the liver.

"The state of being insulin resistant impairs the ability of a vital enzyme, AMP kinase, to make new ATP molecules," Abdelmalek explained. "Increased fructose consumption, and excess utilization of ATP favors the increase in molecules that lead to increased fatty acid synthesis as well as increased uric acid."

The researchers also noted that more uric acid is produced in the body when excess fructose is consumed. Too much uric acid is associated with conditions that include gout, high blood pressure, cardiovascular disease, type 2 diabetes, metabolic syndrome and uric acid stones, a form of kidney stones.

The silver lining is that measuring the amount of uric acid in these individuals may help doctors predict the presence and monitor the severity of nonalcoholic fatty liver disease, Abdelmalek said.

Research Abdelmalek published in the Journal of Hepatology in 2008 showed that, within a small subset of patients, fructose-containing beverages were associated with NAFLD compared to patients with comparable weight, age, and gender. Her 2010 research, published in Hepatology, went further and linked fructose with the liver injury and scarring (fibrosis).

The current study evaluated adults enrolled in the NIH-sponsored Look Ahead Fatty Liver Disease Ancillary Study headed by senior author Jeanne M.Clark, M.D., MPH, at Johns Hopkins University. The researchers analyzed dietary questionnaires collected in patients who underwent a magnetic resonance imaging to measure liver fat as well as an intravenous fructose challenge to evaluate the liver's ATP stores and response to ATP depletion.

Patients enrolled in the Look Ahead study had been counseled on lower dietary sugar consumption for the management of diabetes. Despite the overall lower levels of fructose use in this study population, the researchers found evidence of liver ATP depletion in those who consumed more fructose.

"The fact we found a difference in liver ATP stores at lower levels of dietary fructose intake does suggest that higher fructose consumption (as would occur with the consumption of processed food and sweetened beverages) could deplete the liver of energy and thus risk causing worse metabolic problems and potentially even liver injury," Abdelmalek said. In the past 30 years, Abdelmalek and authors wrote, fructose consumption has more than doubled.

Other authors include Dr. Anna Mae Diehl, chief of the Duke Division of Gastroenterology and Hepatology in the Department of Medicine; Mariana Lazo, Alana Horska, Susanne Bonekamp and Jeanne M. Clark, Departments of Epidemiology, Russel H. Morgan Department of Radiology and Radiological Science and Medicine, at Johns Hopkins University, Baltimore; Division of Metabolism, Edward W. Lipkin, Endocrinology & Nutrition, University of Washington, Seattle; Ashok Balasubramanyam, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston; John P. Bantle, Division of Endocrinology & Diabetes. University of Minnesota, Minneapolis; and Richard J. Johnson, Division of Nephrology, University of Colorado, Denver.

The study was supported by NIH/NIDDK grants and the Johns Hopkins University School of Medicine General Clinical Research Center, plus a NIH/NIDDK Career Development Award.

Genes May Explain Why Some People Turn Their Noses Up at Meat

Wed, 02 May 2012 00:00:00 +0000

If you don't like the taste of pork, the reason may be that your genes cause you to smell the meat more intensely, according to a new study.

Duke University Medical Center scientists, working with colleagues in Norway, found that about 70 percent of people have two functional copies of a gene linked to an odor receptor that detects a compound in male mammals called androstenone, which is common in pork. People with one or no functional copies of the gene can tolerate the scent of androstenone much better than those with two, the researchers said.

Hiroaki Matsunami, PhD, a Duke associate professor of molecular genetics and microbiology, had previously discovered and described the genetics of the odor receptor for androstenone (OR7D4). But it wasn't until a group of pork scientists in Norway contacted him that he launched an experiment to learn more precisely at a genetic level how humans perceive the smell of meat.

The Norwegian team had practical reasons for the study: It was concerned what might happen in Europe if a castration method for swine were outlawed. Currently, female pork meat and castrated male pork meat are sold in Europe. The researchers were curious how consumers might respond to meat from noncastrated males.

The level of androstenone in noncastrated pigs ranges up to 6.4 ppm. In Norway the level of androstenone in immunocastrated (using hormones) pigs is from 0.1 to 0.2 ppm, and in surgically castrated pigs the rate approaches zero.

The findings raise the possibility that more consumers will dislike meat if castration is banned and more meat from noncastrated animals is sold, Matsunami said.

The study was published May 2 online in the PLoS One open-access journal.

A total of 23 subjects were recruited: 13 consumers and 10 professional sensory assessors. When all of the subjects were divided into sensitive and insensitive cohorts according to a smell test that was previously devised, all of the androstenone-sensitive subjects had the RT/RT genotype, with two copies of the functional RT gene.

"I was surprised at how cleanly this experiment showed who smelled what," Matsunami said. "The results showed that people with two copies of the functional variant of the gene for that odor receptor thought that the meat smelled worse with higher levels of androstenone added."

For the experiment, the researchers added only biological levels of androstenone to existing pork meat, up to the limit of what might be found in male wild boars.

Matsunami said it would be fascinating to see results done on certain populations, including people in the Middle East, where pork has been omitted from diets for centuries.

"I would also like to know about odor receptor variants in indigenous populations, such as people who live near the Arctic Circle and who never eat these meats. What is their genotype?" Matsunami said. Vegetarians as a group may also have a genetic predisposition against the smell of meat, but all of these ideas need to be scientifically studied, he said.

Matsunami also speculated whether meat inspectors with both copies of the functional variant, who presumably would be more sensitive to higher levels of androstenone, might make different decisions in their jobs.

The availability of the humane genome has given us the tools for revising sensory and consumer science involving flavor perception, said co-author professor Bjørg Egelandsdal of the Institute of Chemistry, Biotechnology and Food Science at the University of Life Science, in Ås, Norway.

"This could be very useful in product development, to learn which flavor sensors are correlated with which flavors. More research is needed, but we may be able to revise the way we recruit consumer groups for evaluating product development."

Another practical solution for meat producers would be to find other compounds that are safe to ingest, but that might block the androstenone receptors to reduce that scent in meat.

Other authors included researchers from the Norwegian Meat Research Centre in Oslo; the Institute of Chemistry, Biotechnology and Food Science at the University of Life Sciences in Ås, Norway; the Nofima research group in Ås, Norway; and Monell Chemical Senses Center in Philadelphia.

Funding was provided by the Norwegian Research Council and the U.S. National Institutes of Health (NIH) and an NIH-HRSA fellowship. No funding came from pork or agricultural industries.

Large-Scale Analysis Finds Majority of Clinical Trials Don't Provide Meaningful Evidence

Tue, 01 May 2012 00:00:00 +0000

The largest comprehensive analysis of ClinicalTrials.gov finds that clinical trials are falling short of producing high-quality evidence needed to guide medical decision-making.

The analysis, published today in the Journal of the American Medical Association, found the majority of clinical trials is small, and there are significant differences among methodical approaches, including randomizing, blinding and the use of data monitoring committees.

"Our analysis raises questions about the best methods for generating evidence, as well as the capacity of the clinical trials enterprise to supply sufficient amounts of high quality evidence to ensure confidence in guideline recommendations," said Robert Califf, MD, first author of the paper, vice chancellor for clinical research at Duke University Medical Center, and director of the Duke Translational Medicine Institute.

The analysis was conducted by the Clinical Trials Transformation Initiative (CTTI), a public-private partnership founded by the Food and Drug Administration (FDA) and Duke. It extends the usability of the data in ClinicalTrials.gov for research by placing the data through September 27, 2010 into a database structured to facilitate aggregate analysis. This publically accessible database facilitates the assessment of the clinical trials enterprise in a more comprehensive manner than ever before and enables the identification of trends by study type.

The National Library of Medicine (NLM), a part of the National Institutes of Health, developed and manages ClinicalTrials.gov. This site maintains a registry of past, current, and planned clinical research studies.

“Since 2007, the Food and Drug Administration Amendment Act has required registration of clinical trials, and the expanded scope and rigor of trial registration policies internationally is producing more complete data from around the world,” stated Deborah Zarin, MD, director, ClinicalTrials.gov, and assistant director for clinical research projects, NLM. “We have amassed over 120,000 registered clinical trials. This rich repository of data has a lot to say about the national and international research portfolio."

This CTTI project was a collaborative effort by informaticians, statisticians, and project managers from NLM, FDA and Duke. CTTI comprises more than 60 member organizations with the goal of identifying practices that will improve the quality and efficiency of clinical trials.

“Since the ClinicalTrials.gov registry contains studies sponsored by multiple entities, including government, industry, foundations and universities, CTTI leaders recognized that it might be a valuable source for benchmarking the state of the clinical trials enterprise,” stated Judith Kramer, MD, executive director of CTTI.

The project goal was to produce an easily accessible database incorporating advances in informatics to permit a detailed characterization of the body of clinical research and facilitate analysis of groups of studies by therapeutic areas, by type of sponsor, by number of participants and by many other parameters.

“Analysis of the entire portfolio will enable the many entities in the clinical trials enterprise to examine their practices in comparison with others,” says Califf. “For example, 96 percent of clinical trials have ≤1000 participants, and 62 percent have ≤ 100. While there are many excellent small clinical trials, these studies will not be able to inform patients, doctors, and consumers about the choices they must make to prevent and treat disease.”

The analysis showed heterogeneity in median trial size, with cardiovascular trials tending to be twice as large as those in oncology and trials in mental health falling in the middle. It also showed major differences in the use of randomization, blinding, and data monitoring committees, critical issues often used to judge the quality of evidence for medical decisions in clinical practice guidelines and systematic overviews.

"These results reinforce the importance of exploration, analysis and inspection of our clinical trials enterprise,” said Rachel Behrman Sherman, MD, associate director for the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research. "Generation of this evidence will contribute to our understanding of the number of studies in different phases of research, the therapeutic areas, and ways we can improve data collection about clinical trials, eventually improving the quality of clinical trials.”

An analysis-ready copy of the ClinicalTrials.gov database is now available at www.ctti-clinicaltrials.org. Specialists from numerous therapeutic areas are now scrutinizing the contents to better understand how the number and characteristics of clinical trials match the perceived needs of the research communities.

This dataset will be useful for academic institutions and also for pharmaceutical and device companies to produce reports showing the completeness of their data entry compared to other institutions. Advocacy groups can chronicle the number and types of trials in their area of interest.

Data quality is likely to improve as a function of the accountability fostered by this transparency.

The results of other projects conducted by CTTI can be found on the CTTI web site along with general information about the organization.

Duke Team Turns Scar Tissue into Heart Muscle Without Using Stem Cells

Thu, 26 Apr 2012 00:00:00 +0000

Scientists at Duke University Medical Center have shown the ability to turn scar tissue that forms after a heart attack into heart muscle cells using a new process that eliminates the need for stem cell transplant.

The study, published online April 26 in the journal Circulation Research, used molecules called microRNAs to trigger the cardiac tissue conversion in a lab dish and, for the first time, in a living mouse, demonstrating the potential of a simpler process for tissue regeneration.

If additional studies confirm the approach in human cells, it could lead to a new way for treating many of the 23 million people worldwide who suffer heart failure, which is often caused by scar tissue that develops after a heart attack. The approach could also have benefit beyond heart disease.

"This is a significant finding with many therapeutic implications," said Victor J. Dzau, MD, a senior author on the study who is James B. Duke professor of medicine and chancellor of health affairs at Duke University. "If you can do this in the heart, you can do it in the brain, the kidneys, and other tissues. This is a whole new way of regenerating tissue."

To initiate the regeneration, Dzau's team at Duke used microRNAs, which are molecules that serve as master regulators controlling the activity of multiple genes. Tailored in a specific combination, the microRNAs were delivered into scar tissue cells called fibroblasts, which develop after a heart attack and impair the organ's ability to pump blood.

Once deployed, the microRNAs reprogrammed fibroblasts to become cells resembling the cardiomyocytes that make up heart muscle. The Duke team not only proved this concept in the laboratory, but also demonstrated that the cell conversion could occur inside the body of a mouse -- a major requirement for regenerative medicine to become a potential therapy.

"This is one of the exciting things about our study," said Maria Mirotsou, PhD, assistant professor of cardiology at Duke and a senior author of the study. "We were able to achieve this tissue conversion in the heart with these microRNAs, which may be more practical for direct delivery into cells and allow for possible development of therapies without using genetic methods or transplantation of stem cells."

The researchers said using microRNA for tissue regeneration has several potential advantages over genetic methods or transplantation of stem cells, which have been difficult to manage inside the body. Notably, the microRNA process eliminates technical problems such as genetic alterations, while also avoiding the ethical dilemmas posed by stem cells.

"It's an exciting stage for reprogramming science," said Tilanthi M. Jayawardena, PhD, first author of the study. "It's a very young field, and we're all learning what it means to switch a cell's fate. We believe we've uncovered a way for it to be done, and that it has a lot of potential."

The approach will now be tested in larger animals. Dzau said therapies could be developed within a decade if additional studies advance in larger animals and humans.

"We have proven the concept," Dzau said. "This is the very early stage, and we have only shown that is it doable in an animal model. Although that's a very big step, we're not there yet for humans."

In addition to Dzau, Mirotsou and Jayawardena, study authors include: Bakytbek Egemnazarov; Elizabeth A. Finch; Lunan Zhang; Kumar Pandya; J. Alan Payne; Zhiping Zhang; and Paul Rosenberg.

Funding for the study was provided by the National Heart, Lung and Blood Institute; the Edna and Fred L. Mandel Jr. Foundation; the Foundation Leducq; Mirotsou is supported by the American Heart Association National Scientist Development Award; Rosenberg is supported by the NIH.

Study authors reported no conflicts.

Duke Primary Care of Galloway Ridge Changing Address

Wed, 25 Apr 2012 00:00:00 +0000

Duke Primary Care of Galloway Ridge will move to a new address within the Galloway Ridge retirement community at Fearrington Village on May 21, 2012.

The new address will be 50 Craggenmore Close, Galloway Ridge, Pittsboro, NC, 27312 -- just a short distance from our current location. Our phone number will remain the same.

Our goal is continue to provide our patients with exceptional health care, information, and assistance to empower them to make informed decisions regarding their health.

If you have questions about the move, please contact us at 919-545-2134.

Just a Few Cell Clones Can Make Heart Muscle

Wed, 25 Apr 2012 00:00:00 +0000

Growth of the zebrafish heart from embryo to adult is tracked using colored cardiac muscle clones, each containing many cellular progeny of a single cardiac muscle cell. Here, a large clone of green cardiac muscle cells (top) expands over the surface of many smaller clones in a growing heart. Photo credit: Vikas Gupta

Just a handful of cells in the embryo are all that's needed to form the outer layer of pumping heart muscle in an adult zebrafish.

Researchers at Duke University Medical Center used zebrafish embryos and careful employment of a new technique that allows for up to 90 color labels on different cells to track individual cells and cell lines as the heart formed.

The scientists were surprised by how few cells went into making a critical organ structure and they suspect that other organs may form in a similar fashion, said Kenneth Poss, PhD, professor in the Duke Department of Cell Biology and Howard Hughes Medical Institute.

The study appears online in Nature on April 25.

"The most surprising aspect of this work is that a very small number of cardiomyocytes (heart muscle cells) in the growing animal can give rise to the thousands of cardiomyocytes that form the wall of the cardiac ventricle," said Vikas Gupta, lead author, who is in the Duke Medical Scientist Training Program for MD and PhD degrees.

Gupta found that about eight single cells contributed to forming the major type of heart muscle in the wall of the zebrafish heart -- and just one or two cells could create anywhere from 30 to 70 percent of the entire ventricular surface.

"Clonal dominance like this is a property of some types of stem cells, and it's a new concept in how to form an organ during development," Poss said.

Another surprise was the way the patches of cloned cells formed muscle.

"It was completely unexpected," Gupta said. "I thought the wall would simply thicken in place, but instead there was a network of cells that enveloped the ventricle in a wave. It was as if a cell at your shoulder grew a thin layer of new cells down your arm surface."

Gupta said this opens an area for investigation to see whether or not a process like this repeats in the hearts of mammals, and perhaps in other internal organs.

Poss said the cell clones appear to have the ability to cover as much of the ventricular surface as possible before other cells start appearing and growing at the surface.

"Our suspicion is that the muscle cells that initiate large clones are not much different from other muscle cells -- they just get to the surface of the heart first," Poss said.

They used the analogy of a sperm getting to the egg first, among all the millions of possible sperm cells.

Poss said the manner in which these muscle cells envelope the heart could lead to new therapies.

"Researchers may be able to channel this developmental process to help damaged hearts or failing hearts to grow muscle that will reinforce the ventricular walls," he said. "Someone who's had a heart attack would want this ability to generate new muscle to cover a scar naturally, and it's attractive to think that the help might come from a small number of muscle cells within a population."

The color-label technique was originally developed by other biologists and was critical to allow the researchers to track heart cell populations.

"You can label individual cells very early in an embryo with a permanent color and those cells and their progeny will keep that color," Poss said. "You can learn what an individual cardiomyocyte did, and its neighbor, and that cell's neighbor and so on, until you've covered much of the whole ventricle of the developing zebrafish."

Poss said it makes sense that this growth process works by a gradual layering process, especially for the heart.

"It's speculative, but for the heart to maintain circulation in a relatively slowly growing animal, a process like this to build the heart might be a way of gradually increasing its circulatory strength to keep up."

Funding for the study came from a National Heart, Lung, and Blood Institute (NHLBI) Medical Scientist Training Program supplement. Dr. Poss is an Early Career Scientist of the Howard Hughes Medical Institute. This work also was supported by grants from the National Heart, Blood and Lung Institute and the American Heart Association.

Brain Cancer Patient Raises $38,000 for “Angels Among Us” Race in Durham

Tue, 24 Apr 2012 00:00:00 +0000

Running the Boston Marathon is a crowning achievement for many road racers, but Tom O’Donnell of Apex felt especially elated earlier this month when he lined up among the other 22,000 athletes for the prestigious event.

Three years earlier, O’Donnell was diagnosed with a brain tumor, and after undergoing surgery and treatment at the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, he made a vow to savor life, to push his body, to steel his mind.

So he ran. And ran and ran.

“I thought, ‘What if I can’t run ever again?’” O’Donnell said. “Running became a privilege. I felt really alive. I liked the way it made me feel -- I loved it.”

Just six weeks after his first surgery, O’Donnell entered a 5K race, and he has been running ever since, culminating in his qualification to run in Boston this year.

Fresh off that heady experience, O’Donnell said he is looking forward to entering this Saturday’s Angels Among Us road race in Durham, which benefits brain tumor research at Duke’s Tisch Center.

In previous years, he would challenge friends and loved ones to donate money to his Angels team, collecting an impressive $2,000 to $3,000. But this year, pinning his fund-raising to his Boston Marathon run, his total soared: $38,000.

“I never dreamed it would be that much,” he said.

The contribution will help organizers achieve their $1.8 million fundraising goal for the 19^th annual “Angels Among Us” event, which also includes a family walk through the Sarah P. Duke Gardens. All proceeds benefit the Preston Robert Tisch Brain Tumor Center.

“People come from all over the country to participate in this race,” said event organizer Ellen Stainback. “We have families from as far away as Oklahoma, Iowa, Florida. But all the proceeds from the race go directly to research needs at the brain tumor center at Duke.”

Brain tumors are diagnosed in about 22,000 people a year in the United States -- and about 13 percent of cases are in children, according to the National Cancer Institute. The prognosis varies widely depending on the type of tumor, with some being completely curable and others having a median survival of less than 12 months.

For O’Donnell, the prognosis looks good. With little rest after the grueling race in Boston -- temperatures neared 90 degrees this year and took a toll on many of the runners -- he is looking forward to his next challenge. And tomorrow’s run.

"There are many reasons why people run,” O’Donnell said. “I run to give others hope; I run for those who are unable to; I run because I can. I cannot think of a better reason."

About “Angels Among Us”

The annual road race has raised nearly $12 million for brain tumor research at Duke since its inception.
When it started in 1994, the event collected $27,000. Last year’s run pulled in more than $1.8 million.
Nearly 5,000 people participated last year.
Participants arrive from across the country and include current patients, survivors and the families and friends of people diagnosed with brain tumors.
This year’s run will be held Saturday, April 28 at 8 a.m. on the Duke campus, and is followed by awards, the family walk and a survivor’s walk. Go to www.angelsamongus.org for additional details.

For more information about this year’s event, call Ellen Stainback at 919-684-4784

Duke Medicine Breaks Ground for New Eye Center Clinical Building

Fri, 20 Apr 2012 00:00:00 +0000

Duke Medicine officials held a ceremonial ground-breaking Friday for a new, state-of-the-art Duke Eye Center building that will add much-needed clinical examination space and enhance the patient experience.

“This ceremony celebrates the team effort that has turned our dream of building a new Eye Center clinical facility into a reality,” said Victor J. Dzau, MD, chancellor for health affairs at Duke University and CEO of the Duke University HealthSystem.

“Through the collaborative efforts of our legion of generous donors, the Health System, the School of Medicine and the faculty, we can now move forward with our goal to expand our current vision care services, and take our commitment to provide the highest quality eye care to the next level.”

Planning for the clinical eye center building began in 2010, when Duke received a $12 million donation from Durham-based LC Industries, the largest employer of visually impaired people in the country.

“This is a vision that has come true,” says William Hudson, president of LC Industries and chairman of the Eye Center Advisory Board. “We developed a relationship with the Eye Center early on because it is a perfect partnership. We provide jobs for the visually impaired, we provide educational opportunities, but we can’t conduct research on eye diseases or offer vision care. The Eye Center takes over where we leave off. This new facility is a win-win for everyone.”

The construction project, expected to take three years to complete, includes plans for a 127,000-square-foot facility. The four-story building will house expanded clinical services designed to improve workflow and maximize patient care and convenience.

It will be constructed in the parking lot adjacent to the current Wadsworth Eye Center building along Erwin Road, and will be connected on the clinic and operating-room levels to provide access to existing services. A new circular, covered drop-off area will connect the new facility to the parking deck, and a new outdoor courtyard is planned between the current and new building.

The new facility comes at a time when demand for vision services is growing at an alarming rate. According to the National Eye Institute, blindness or low vision affects 3.3 million Americans age 40 and up and is projected to reach 5.5 million by the year 2020.

Similar demands for increased services are being felt at the Duke Eye Center, which consistently ranks among the top 10 eye centers in the country by several organizations.

During the past five years, the Duke Eye Center has grown eight percent annually in both surgical procedures and clinic visits. Today, roughly 50 physicians see more than 80,000 patient visits each year.

“When our current space was built more than 30 years ago, it was designed for 12 doctors who saw 15,000 patient visits per year,” says David Epstein, MD, chairman of ophthalmology in the Duke University School of Medicine and director of the Duke Eye Center. “The current facility was also not designed to house the new technology that is now available.

“The new building will be more patient-centric, with better patient flow and easier access to the diagnostic evaluations and treatments they need. We have great doctors who deliver great care, but a new facility is the only way we can continue to provide the people of North Carolina with the kind of advanced eye care they have come to expect at Duke.”

Voice Disorder Productivity Losses Comparable to Chronic Diseases

Wed, 18 Apr 2012 00:00:00 +0000

Patients with voice problems have nearly as many days of short-term disability claim and work productivity losses as those with chronic conditions like asthma, heart disease, and depression, according to new findings from Duke University Medical Center researchers.

Per claim, voice disorders account for up to 40 lost workdays and about $3,400 in short-term disability payments annually.

“The impact of vocal disorders on work productivity has not been fully appreciated,” says Seth Cohen, MD, an otolaryngologist at the Duke Voice Care Center. “This study further demonstrates the far-reaching impact they have on society.”

The findings were presented today at the American Laryngological Association meeting in San Diego.

In recent months, well-known professional singers including John Mayer, Adele, and Keith Urban have reportedly scaled back work-related responsibilities due to vocal issues. Cohen says everyone who needs their voice for their profession is at risk.

According to published data, five to 10 percent of the workforce relies on their voice as the primary tool of their trade.

Cohen and colleagues examined short-term disability (STD) claims related to dysphonia, the catch-all medical term for voice disorders. The mean age of persons making claims was 45.9; more than half (53.2 percent) were male. The mean number of workdays absent per claim during a 12-month period was 39.2. Mean STD payments per claim in 12 months were $3,408.68. Mean lost wages per claim in 12 months were calculated at $4,437.89.

Prior studies have found that between 6.6 percent and 7.5 percent of adults have voice problems. In the current study, of 18,466 patients with an STD claim, 2.1 percent were due to a voice disorder.

By comparison, studies using similar methodology found 6.4 mean workdays lost due to STD in asthmatics, 47 STD days in individuals with heart disease, and 52.8 STD days in depressed individuals. Mean productivity loses based on lost wages per STD claim in 12 months were $719 for asthmatics, $1,685 for depressed individuals, and $5,867 for heart disease patients.

While the study is the largest assessment of indirect costs related to vocal disorders, Cohen says it has limitations and most likely under-estimates the true societal impact. “We could only calculate short-term disability based on individuals who filed claims related to dysphonia,” he says.

The data do not take into account people with dysphonia who don’t have STD benefits and could not file a claim, or the impact on long-term disability, childcare, and on-the-job productivity losses.

Still, Cohen stresses the impact of vocal disorders on work productivity could be minimized if society recognized vocal disorders as a public health problem, and more emphasis was placed on raising awareness for the importance of seeking medical care when necessary.

“We know that only 5 to 20 percent of people with vocal disorders actually see a doctor,” Cohen said. “People at risk for dysphonia need to understand that prevention is possible. They also need to see their doctor to obtain early detection and appropriate treatment.”

Experts Identify Critical Genes Mutated in Stomach Cancer

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

An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School (Duke-NUS) in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.

The study, which appears online on April 8, 2012 in Nature Genetics, paves the way for treatments tailored to the genetic make-up of individual stomach tumors.

Stomach cancer is the second leading cause of cancer death globally with more than 700,000 deaths each year, and is particularly common in East Asia.

Treatment of this deadly disease is often difficult and unsuccessful because of late detection of tumors and a poor understanding of the causes. In the United States, less than a quarter of patients survive more than five years after diagnosis, even after treatment.

"Until now, the genetic abnormalities that cause stomach cancers are still largely unknown, which partially explain the overall poor treatment outcome," said Patrick Tan, MD, PhD, senior author of the study and associate professor in the Cancer and Stem Cell Biology Program at Duke-NUS. Tan also leads the Genomic Oncology Program at the Cancer Sciences Institute of Singapore and is a group leader at the Genome Institute of Singapore.

Using state-of-the-art DNA sequencing technology, the research team analyzed tumor and normal tissue from stomach cancer patients, which led to the discovery of the novel gene mutations.

"This technology allows us to read the DNA sequence of the genes in each cancer genome," said co-senior author Steven G. Rozen, PhD, who heads the Computational Systems Biology and Human Genetics Laboratory in Duke-NUS. "This is also a major team effort involving both basic scientists and clinicians."

The team included scientists and clinicians from three research groups affiliated with Duke-NUS, including one headed by co-senior author Teh Bin Tean, MD, PhD, director of the NCCS-VARI Translational Research Laboratory at the National Cancer Center Singapore.

"Our study is one of the first gastric cancer studies to investigate the vast majority of human genes at the single nucleotide level," Teh said. "We screened 18,000 human genes and identified over 600 genes that were previously unknown to be mutated in stomach cancer."

Two of the 600 genes identified that were associated with stomach cancer, FAT4 and ARID1A proved to be particularly interesting. A further analysis of about 100 stomach tumors found these genes to be mutated in 5 percent and 8 percent of stomach cancers, respectively.

In some patients, portions of the chromosome containing the two genes were found to be missing, providing further evidence that genetic defects affecting these genes occur frequently in stomach cancer.

Lab experiments demonstrated the importance of these two genes in driving stomach cancer, as manipulation of FAT4 and ARID1A function altered the growth of stomach cancer cells.

"More research is required to realize the clinical implications of these findings. ARID1A and FAT4 are likely also involved in many other cancer types, not just stomach cancer," noted Tan, whose research team is actively working on translating the results of this study into clinical applications.

With more than 100,000 new cases worldwide of stomach cancer each year likely to be caused by mutations in FAT4 or ARID1A, drugs against these targets may someday lead to more effective treatment of stomach tumors and other cancers.

In addition to Duke-NUS and the National Cancer Center Singapore, the study also involved collaborators from the Cancer Sciences Institute of Singapore; Genome Institute of Singapore; National University of Singapore; Singapore General Hospital; Van Andel Research Institute, Michigan, USA; Northwestern University, Chicago, USA; Yonsei Cancer Center, Seoul, South Korea; Queen's University, Belfast, UK; and Wellcome Trust Sanger Institute, Hinxton, UK.

Support for this study was provided by the National Medical Research Council, as part of the Singapore Gastric Cancer Consortium. Funding was also received from the Cancer Sciences Institute of Singapore, Duke-NUS Graduate Medical School, Genome Institute of Singapore (Agency for Science, Technology and Research), and the Lee Foundation.

About Duke-NUS Graduate Medical School

The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in N. Carolina, USA, and the National University of Singapore (NUS).

Duke-NUS offers a graduate entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature.

Duke-NUS also offers M.D./PhD and PhD programs. As a player in Singapore's biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research.

Follow-up Studies to the RV144 HIV Vaccine Trial Provide Clues About How the Vaccine May Have Protected Against HIV

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

Researchers have gained important clues about immune system responses that could play a role in protecting people from HIV infection in follow-up studies from the world's largest HIV vaccine trial to date. Results from laboratory studies based on the trial were published in the New England Journal of Medicine.

The HIV vaccine trial in Thailand, called RV144, showed that the group receiving the vaccine regimen was estimated to be 31.2 percent less likely to be infected than those who didn't get the vaccine, and researchers set out to learn why.

Researchers analyzed samples from RV144 trial participants to look at immune responses in the vaccine recipients. The researchers found that different types of antibody responses were associated with a higher or lower rate of HIV infection.

"By studying those who became infected compared to those who did not, we believe we have found very important clues for how the RV144 trial might have worked," said Barton F. Haynes, MD, who led the study and is the Frederic M. Hanes Professor of Medicine and Immunology at Duke.

"The hypothesis is that protection in the trial was primarily mediated by antibodies. All of the antibody types studied have been isolated from RV144 vaccinees, and the antibodies' protective effect will be tested to see if they prevent acquisition of infection in non-human primate studies."

The RV144 trial provided the first evidence in humans that a safe and effective preventive HIV vaccine is possible, and it provided an opportunity to look for vaccine-induced immune responses that correlated with the rate of infection.

The current results are based on intensive laboratory studies of the patient specimens collected in the Thai trial. These studies are the result of nearly two years of work by more than 100 researchers at 25 institutions, who collaborated to understand how the RV144 vaccine regimen prevented HIV infection in some vaccine recipients.

The first finding is that antibodies specific to a particular region of the HIV envelope (outside coat) protein, called V1V2, correlated with lower infection rates among those who were vaccinated. Antibodies are proteins that the body produces to defend against harmful agents such as viruses or bacteria.

The hypothesis is that when these IgG antibodies bind to the V1V2 region of the outer coat of the virus, they might help prevent infection.

A second finding indicates that vaccine recipients with the highest blood levels of a different type of envelope protein binding antibody, known as IgA, had less protection from HIV than those with low levels. When compared with the placebo group, there was no difference in the rate of infection among the vaccinated group with high IgA antibodies and volunteers who received placebo, so the scientists believe that these IgA antibodies may have interfered with other vaccine-induced protective responses.

These findings, and the laboratory tests used in the studies, may help to explain the efficacy seen in RV144, and they will be tested in future studies to assess their importance to the protective effect of the vaccine.

Results from RV144, which involved more than 16,000 adult volunteers in Thailand, were published in the New England Journal of Medicine in October 2009. The results showed that the prime-boost combination of ALVAC® HIV and AIDSVAX® B/E was safe and lowered the rate of HIV infection by an estimated 31.2 percent compared with placebo (p=0.04) in a community-based population in Thailand. The vaccine combination was based on HIV strains that commonly circulate in Thailand.

"These studies reinforce and extend the results seen in the RV144 trial and provide new insights that may lead to a better and longer-lasting HIV vaccine," noted Col. Jerome Kim of the U.S. Military HIV Research Program (MHRP), senior author of the study.

These new laboratory studies inform new testable hypotheses that, if validated, may help scientists prioritize vaccine candidates for future clinical trials, potentially accelerating the development of a more effective vaccine.

Researchers noted that these results are unique to the RV144 regimen, and that different vaccines may protect against HIV in different ways. More research is needed to fully understand these results, and to determine if they can be generalized to other types of HIV vaccines or similar vaccines tested against other regional types of HIV.

These studies were conducted by a large international collaboration led by the Center for HIV/AIDS Vaccine Immunology (CHAVI), which Dr. Haynes directs and which is funded by the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID) and by the Collaboration for AIDS Vaccine Discovery, which is funded by the Bill & Melinda Gates Foundation.

The research was initiated and coordinated by the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, which receives funding from the U.S. Army Medical Research and Materiel Command and the Division of AIDS, NIAID, NIH. The statistical design and analyses were conducted by the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center.

Duke Integrative Medicine Now Accepts Insurance

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

Duke Integrative Medicine is now accepting health insurance for physician consultations, nutrition consultations, and health psychology, including behavioral health consultations and psychotherapy. Pediatric integrative medicine will also be covered for children over age five.

Duke Integrative Medicine (Duke IM) integrates Western scientific medicine with proven complementary therapies to address the whole person -- body, mind, spirit, and community.

The change in how patients can pay for services opens up this model of care to a larger segment of the population, says Adam Perlman, MD, executive director of Duke IM.

“Part of our challenge has been to broaden access,” says Perlman. “We take a very comprehensive approach to working with patients. How someone is feeling emotionally and spiritually, how they are dealing with stress and their physical environment, how connected they feel to loved ones and community can all have an impact on well-being. We want to partner with them and guide them through all aspects of their health, and insurance will allow us to do that for a much broader segment of the population.”

Initial consultations for new patients with Duke IM physicians are considerably longer and much more extensive than typical doctor appointments. “Patients feel very cared-for,” said Isabel Geffner, director of communications for Duke IM. “Every patient deserves that.”

Many of Duke IM’s adult patients seek treatment for chronic medical conditions, such as arthritis, fibromyalgia, and chronic back pain. Patients also seek integrative approaches to managing obesity, diabetes, and metabolic syndrome. “We help many cancer patients as well,” says Perlman. “We partner with them to help them gain a better sense of control, lessen the symptoms and side effects of treatment.”

Duke IM accepts most major insurance carriers for physician consultations and select insurance for health psychology, including behavioral health consultations and psychotherapy (Blue Cross Blue Shield PPO and Cigna Behavioral Health for Duke employees), and nutrition (Blue Cross Blue Shield and Wellpath for Duke employees). Some services offered by Duke IM are not covered by insurance. Patients should contact their insurance provider.

Learn more at dukeintegrativemedicine.org or call 919-660-6826.