DukeHealth.org: Duke Health News

New Methods Needed to ID Cardiac Catheterization Candidates

Wed, 10 Mar 2010 00:00:00 -0500

It's time to rethink how patients are selected for cardiac catheterization, say doctors at Duke University Medical Center, after reporting in a new study that the invasive procedure found no significant coronary artery disease in nearly 60 percent of chest pain patients with no prior heart disease.

“Our data show that up to two-thirds of the patients undergoing invasive cardiac catheterization do not have significant obstructive disease,” says Manesh Patel, MD, a cardiologist with the Duke Heart Center. He’s the lead author of the study published in the March 11 issue of the New England Journal of Medicine.

“We’re spending a lot of energy and money to evaluate chest pain which often leads to cardiac catheterization, which, we now know, often finds that patients don’t have significant obstructive disease,” Patel says. “Our research shows that our methods for identifying patients at risk for obstructive disease need significant improvement.”

More than 10 million Americans experience chest pain each year and many undergo testing like cardiac catheterization to determine if blocked arteries are the culprit. It’s standard care for people who experience heart attack or unstable chest pain.

The invasive test is not cheap, nor is it without some risk. But it allows doctors to visualize the vessels and arteries leading to the heart.

The main goal of cardiac catheterization is to identify the presence, location, and severity of coronary atherosclerosis, Patel says. "This is done with the understanding that some patients with severe obstruction may benefit from angioplasty or bypass surgery to relieve symptoms and to reduce the risk of a heart attack or death."

The researchers identified two million people who underwent cardiac catheterization at 663 hospitals nationwide over a four-year period.

About a fifth of those patients had stable chest pain without a previous diagnosis of heart disease. Most of them had undergone a noninvasive test before catheterization, but only 38 percent of patients turned out to have significant obstructive disease.

What is needed, Patel stresses, is a re-evaluation of the entire decision-making process of caring for patients with chest pain. That runs the gamut from how patients’ histories are taken, how risk factors are assessed, to the role of diagnostic testing.

Patel and other Duke researchers who co-authored the NEJM paper are working on several efforts to address these concerns. They include national standards on appropriate use of technology, and clinical trials to evaluate different non invasive imaging technologies.

The NEJM study was funded by the American College of Cardiology’s National Cardiovascular Data Registries-Cath PCI. Co-authors include Eric Peterson, MD, David Dai, J. Matthew Brennan, MD, and Pamela S. Douglas, MD, of Duke University Medical Center, Rita F. Redberg, MD and Ralph G. Brindis, MD of University of California at San Francisco, and H. Vernon Anderson, MD of the University of Texas Health Science Center, Houston, TX.

New Insight on How Fast Nicotine Peaks in the Brain

Mon, 08 Mar 2010 00:00:00 -0500

Nicotine takes much longer than previously thought to reach peak levels in the brains of cigarette smokers, according to new research conducted at Duke University Medical Center.

Traditionally, scientists thought nicotine inhaled in a puff of cigarette smoke took a mere seven seconds to be taken up by the brain, and that each puff produced a spike of nicotine. Using Positron Emission Tomography (PET) imaging, Duke investigators illustrate, for the first time, that cigarette smokers actually experience a steady rise of brain nicotine levels during the course of smoking a whole cigarette.

The findings, scheduled to appear online in the Early Edition of Proceedings of the National Academy of Sciences (PNAS) the week of March 8, could lead to more effective treatments for smoking addiction.

“Previously it was thought that the puff-by-puff spikes of nicotine reaching the brain explained why cigarettes are so much more addictive than other forms of nicotine delivery, like the patch or gum,” says Jed Rose, PhD, director of the Duke Center for Nicotine and Smoking Cessation Research.

“Our work now calls into question whether addiction has to do with the puff-by-puff delivery of nicotine. It may actually depend in part on the overall rate at which nicotine reaches and accumulates in the brain, as well as the unique habit and sensory cues associated with smoking.”

Yet, when the researchers compared 13 dependent smokers to 10 non-dependent smokers, they were surprised to find the dependent smokers had a slower rate of nicotine accumulation in the brain. “This slower rate resulted from nicotine staying longer in the lungs of dependent smokers, which may be a result of the chronic effects of smoke on the lungs,” surmises Rose.

The difference in rate of nicotine accumulation in the brain doesn’t explain why some people become addicted to cigarettes and others don’t.

“Even if you correct for the speed of delivery, our study showed the non-dependent smokers eventually experienced the same high levels of nicotine in their brain as dependent smokers, yet they did so without becoming dependent. The real mystery is why.”

Rose says the absence of addiction in these smokers could be due to genetic differences, differences in the way they smoke, or differences in the psychological effects they derive. “We’re still not able to fully explain why these people are able to smoke without becoming addicted.”

Despite the questions raised, the study provides important insights into the role of the speed and level of brain nicotine levels, and which receptors in the brain are at work.

“Different receptors respond to nicotine at different levels of sensitivity,” says Rose. “Knowing the levels of nicotine that are really getting to the brain gives us clues as to which receptors are more likely to be important for the dependence-producing effects of cigarette smoking.”

This research was supported by a grant from Phillip Morris USA and Phillip Morris International, but the companies played no role in the design or conduct of the study, data analysis or presentation of results.

Co-authors on this paper include Alexey G. Mukhin, Stephen J. Lokitz, Timothy G. Turkington, Joseph Herskovic, Frédérique M. Behm, all of Duke University Medical Center, and Sudha Garg and Pradeep K. Garg of Wake Forest University Baptist Medical Center, Winston-Salem, NC.

LC Industries Donates $12 Million to Duke Eye Center

Thu, 04 Mar 2010 00:00:00 -0500

LC Industries, the largest employer of visually impaired people in the country, has made a $12 million gift toward the creation of a new state-of-the-art Duke Eye Center, announced Victor J. Dzau, MD, Chancellor for Health Affairs Duke University, and CEO, Duke University Health System.

While the creation of this facility is ultimately subject to approval through the state’s Certificate of Need process, as well as university and health system governance approvals, it is possible that a new Duke Eye Center facility could be built on the Duke Medicine campus as early as 2013.

“This state-of-the-art facility will provide the highest quality of eye care to our patients as well as facilitating the translation of discoveries being made on the research side to breakthrough innovations in clinical care for people with various eye diseases and conditions,” said Dzau. “I can’t think of a better partnership for this vitally important work than a company that has set the standard in this country for its employment of people who are visually impaired, and one of the nation’s premier eye centers. This gift is very much appreciated.”

“This gift takes our company’s commitment to people with visual impairments to a new level,” said Bill Hudson, president of Durham-based LC Industries, and a member of the Duke Eye Center Advisory Board. “We want to play a meaningful role in the process that leads to cures for the common causes of blindness.”

Vision loss is quickly becoming a major health problem as the population ages and the rate of eye disease increases. The National Eye Institute predicts the number of people who are blind or visually impaired will jump from three million to more than five million by the year 2020.

Likewise, the rise in diabetes cases in the U.S. is expected to impact the incidence of major eye diseases including diabetic retinopathy, cataracts, and glaucoma. Today, close to eight percent of Americans have diabetes, which is the leading cause of new cases of blindness in adults 20-74 years of age.

A recent study estimates the number of diabetes patients who have diabetic retinopathy will increase from 5.5 million to 16 million by 2050.

The Duke Eye Center is consistently ranked among the top-ten eye centers in the country by several organizations. Its renowned research facility, the Albert Eye Research Institute, is home to scientists and researchers who work together to take knowledge from the laboratory bench to the clinic.

But space is lacking at the building currently housing the Duke Eye Center. Over the last five years, the Eye Center has grown 9 percent annually in both surgical procedures and clinic visits. Today, more than 80,000 patients are treated there annually.

“For years, we have been bursting at the seams in our current facility,” says David Epstein, MD, Chairman of Ophthalmology in the Duke University School of Medicine and Chairman of the Duke Eye Center. “Between the exploding demands for our specialty and sub-specialty clinical services, and our expanding research portfolio, a new facility is the only way we can continue to provide the people of North Carolina with the kind of care they have come to expect of Duke.”

With this gift, an extensive planning process has been initiated with hopes that a Certificate of Need for the new facility will be filed with the state in late 2010 or early 2011, with construction commencing immediately upon approval should approval be granted. The balance of the fund-raising necessary to complete this project will be on-going throughout this process.

”This gift, which will be completed over time, is a testament to our long-term commitment to the company’s current and future employees,” says Dick Hutson, chairman of LC Industries’ Board of Directors. “This gift reflects the mission and values of the organization, and we believe Duke is uniquely capable of maximizing its impact on behalf of patients.”

Duke-UNC Lead National Initiative to Reform Primary Care

Thu, 04 Mar 2010 00:00:00 -0500

Saying “failure to act now could put the health of our communities and the economy of the country in jeopardy,” a blue-ribbon panel of national health care experts, chaired by leaders from Duke Medicine and University of North Carolina at Chapel Hill, have released a series of recommendations to expand the ranks of primary care health care professionals.

The report’s recommendations relate to dramatically changing the way primary care is valued, delivered, and integrated into health systems; improving educational and training models to attract, nurture, and train primary care professionals; and advancing the science, teaching, practice, and policy development relevant to primary care.

The report was sponsored and funded by the Josiah Macy, Jr. Foundation and co-chaired by Victor J. Dzau, MD, Chancellor for Health Affairs, Duke University, and CEO Duke University Health System, and Linda Cronenwett, PhD, RN, FAAN, professor of nursing and former dean, University of North Carolina at Chapel Hill School of Nursing.

“There is a critical need to move from talking about the near catastrophic situation in primary care, to taking the firm steps needed to turn this situation around as quickly as possible,” said Cronenwett. “There was remarkable consensus among the meeting participants regarding the recommendations that were put forth and now the challenge is to inspire all of the necessary stakeholders to action.”

Participants in creating the recommendations included allopathic and osteopathic physicians, nursing professors, nurse practitioners, and physician assistants, deans, academic health center executives, plus, among others, representatives from government, payors, as well as the American College of Physicians, RAND Health, Department of Veteran Affairs, Institute of Medicine, Robert Wood Johnson Foundation, and the Agency for Healthcare Research and Quality.

“Although we don’t know how the health care reform debate will be resolved, we do know that it will ultimately be impossible to effectively increase access to care without addressing the primary care issue,” said Dzau. “Our recommendations call for a comprehensive reform of the nation’s primary care system that includes expansion of workforce, increased infrastructure and support, reforming education and training of providers. While this is a major national issue, the primary care workforce shortage in North Carolina continues to be a significant threat to our health care delivery system. I am pleased to partner with UNC Dean Emeritus Cronenwett in leading this national initiative that we believe also has great relevance to the people of North Carolina.”

The panel’s recommendations include the following:

1. Incentives to dramatically change the way primary care is valued, delivered, and integrated into health systems.

Create financial and other incentives for the development of innovative models of primary care and the advancement of knowledge about outcomes.
Coupled with efforts to increase the number of physicians, nurse practitioners, and physician assistants in primary care, state and national legal, regulatory, and reimbursement policies should be changed to remove barriers that make it difficult for NPs and PAs to serve as primary care providers and leaders of patient-centered medical homes or other new models of primary care delivery.
Promote stronger ties between academic health centers and other primary care sites and the communities they serve, setting goals and standards for accountability for primary prevention as well as individual and population health.
Invest in primary care health information technologies that support data sharing, quality improvement, patient engagement, and clinical care, with the aim of continuously improving the health and productivity of individuals and the population.
Implement all-payor payment reforms that more appropriately recognize the value contributed by primary care.

2. Improving current educational models to more effectively attract, nurture, and train the primary care workforce of the future.

Create incentives for innovative projects in health professions education, enlisting funding partners from government, industry, philanthropy, and payors.
Medical schools, nursing schools and other schools for the health professions should implement actions known to increase the number of students and trainees choosing careers in primary care.
Interprofessional education should be a required and supported part of all health professional education.
Increased funding to the Department of Health & Human Services to fund interprofessional training, preparation of the primary care workforce, and leadership development programs to produce clinicians to lead new models of primary care.

3. Advancing the science, teaching, practice, and policy development related to primary care.

Develop leaders with a focus on advancing the curricula and learning opportunities for preparing competent primary care clinicians, scientists, and policymakers of the future.
Support the further development of science and the scientific leadership necessary to advance the translation of best practices into primary care delivery for the improvement of patient and community health.
Include representatives of all primary care providers in the leadership of delivery systems and in groups that are responsible for developing health care policies at the state and federal level.

Early Test for a Killer of the Sickest

Wed, 03 Mar 2010 00:00:00 -0500

An early test for fungal infections that measures how a patient's genes are responding could save the lives of some very sick patients. Researchers at Duke University’s Institute for Genome Sciences & Policy have devised an early gene-expression test for the fungal pathogen Candida that worked in mice.

It is an entirely new and more rapid way to reveal an infection which occurs in very sick or immunocompromised patients, particularly critical care patients.

Candidemia can kill 10-15 percent of critically ill patients within the first 24 hours of infection. If the disease goes undetected for up to three days, the mortality rate rises to 30 percent.

Now that the gene-based test has worked well in mice, the Duke scientists are gathering human specimens to devise a similar test to be used in people.

“This study provides the basis for development of a blood-gene expression test in humans to detect a life-threatening infection earlier than can be done using currently available methods,” said Geoffrey Ginsburg, MD, PhD, director of Duke University's Center for Genomic Medicine in the Institute for Genome Sciences & Policy, professor of medicine, and the senior author of the study.

“Earlier detection will lead to earlier treatment and save lives. This work is also part of a portfolio of blood gene-expression-based tests we are developing to detect viral, bacterial, and now fungal infections that will lead to more precise diagnosis and more appropriate therapies for infectious disease. This is personalized medicine.”

The findings, which appear in the journal Science Translational Medicine, mark the beginning of an entirely new way of diagnosing infectious disease, said co-lead author Aimee Zaas, MD, assistant professor of medicine in the Duke Division of Infectious Diseases and International Health, and the Duke Institute for Genome Sciences & Policy. “We are redefining the way that physicians identify infectious disease using a combination of host-based blood RNA tests with traditional microbiology methods.”

One of the challenges in diagnosing candidemia is that it often appears to be similar in symptoms to other serious bloodstream infections. To discriminate whether a patient has a bloodstream fungal infection versus a bacterial infection often can take 48 to 72 hours until blood culture tests are completed and even then the results may only be positive 50 percent of the time.

People most at risk for candidemia include patients hospitalized in intensive care units, those who’ve had abdominal surgery, those receiving antibacterial therapies, those with central line catheters, and those who are immunosuppressed.

“Our results show that this new gene-signature test works well to find candidemia in mice that had the infection versus mice without infection,” said Zaas, who is also an assistant professor in the Department of Molecular Genetics and Microbiology at Duke. “We were very pleased to learn that we could further distinguish the fungal infection from a staph infection, another bloodstream disease that shares the same set of symptoms.”

The team of scientists sees the findings as a jumping off point for producing gene-expression signatures to detect a number of infections. They pursued the candidemia test first because of the high mortality rate in hospitalized patients with that hard-to-treat infection.

The scientists performed an analysis of gene expression -- which genes are turned on and active -- in the blood samples of mice that were exposed to Candida albicans (C. albicans) and a group of healthy control mice.

They looked at genes that are associated with immune response and found there were 20 sets of 60 to 80 genes being expressed together. One group of genes in particular distinguished the infected samples from the control samples.

Likewise, they were able to combine data from the C. albicans group with data from a group of mice infected with Staphylococcus aureus, which is sometimes found in hospitalized patients. The team identified two groups of genes that could discriminate among the three groups of mice (healthy, those with candidemia, and those with a staph infection).

They also developed distinct groups of genes that correlated with samples at different time points during the course of Candida infection. Using these groups of genes, the researchers could differentiate between an early and a late infection.

Other authors include co-lead author Hamza Aziz of the Duke University School of Medicine, Joseph Lucas of the Institute for Genome Sciences & Policy, and John R. Perfect, of the Division of Infectious Diseases and International Health and the Department of Medicine. Funding for the project came from the Wallace H. Coulter Foundation and the Duke Institute of Genome Sciences & Policy.

New Smoking Cessation Therapy Proves Promising

Tue, 02 Mar 2010 00:00:00 -0500

A novel technology for delivering nicotine to the lungs may soon give smokers a new way to kick the habit.

When compared to the nicotine vapor delivery system used in the Nicotrol/Nicorette inhaler, the new technology proved more effective at delivering nicotine to the blood stream. As a result, it provides immediate relief of withdrawal symptoms, according to Duke University Medical Center researchers.

Users also reported the new nicotine delivery method was more tolerable than the current inhaler because it caused less throat irritation.

“We wanted to replicate the experience of smoking without incurring the dangers associated with cigarettes, and we wanted to do so more effectively than the nicotine replacement therapies currently on the market,” said Jed Rose, PhD, director of the Duke Center for Nicotine and Smoking Cessation Research where the technology is being developed.

He presented the data today at the Society for Nicotine and Tobacco Research (SRNT) in Baltimore, MD.

The Nicotrol inhaler is a smoking cessation therapy that delivers nicotine vapor to the mouth and upper airways, but little of it reaches the lungs.

Duke’s new technology employs a unique method to deliver nicotine to the lungs. In today’s presentation, the researchers show the new lung delivery technology results in rapid absorption of nicotine that provides immediate relief of withdrawal symptoms and also re-creates some of the familiar sensations that are pleasurable to smokers.

Current methods that deliver medicine to the lungs -- metered dose sprays, dry powder inhalers or nebulizers that create a fine mist -- do not replicate the natural inhalation used by smokers when drawing on a cigarette.

And, because medication residue often deposits in the mouth and throat, doses aren’t always high enough to ensure the appropriate amount reaches the lungs.

Duke’s new technology combines the vapor phase of pyruvic acid, which occurs naturally in the body, and nicotine. “When the two vapors combine, they form a salt called nicotine pyruvate,” explains Rose. “This reaction transforms invisible gas vapors into a cloud of microscopic particles which is inhaled, just like a smoker inhales from a cigarette.”

In a study of the new Duke technology, nine healthy smokers inhaled 10 puffs of nicotine pyruvate in increasing doses, 10 puffs from a Nicotrol/Nicorette inhaler cartridge, and 10 puffs of room air (placebo). Blood was drawn before and after each set of inhalations.

When the results were analyzed, the Duke researchers noted rapid increases in plasma nicotine concentrations following the nicotine pyruvate inhalations and less complaints of harshness/irritation when compared to the Nicotrol/Nicorette control cartridge. The smokers also said their cravings for cigarettes were substantially alleviated following the nicotine pyruvate inhalations.

“Compared to the current nicotine vapor inhaler, we are able to give smokers more nicotine, although still less than a cigarette, with less irritation, resulting in reduced cravings,” said Rose. “Thus we are able to achieve a therapeutic effect with greater tolerability.”

More research is needed to examine the safety and effectiveness of prolonged use of the inhalation system, and to assess its role in helping people quit smoking. But, Rose says if all goes well, he anticipates the product could become commercially available within three to five years.

He also says the novel inhalation system may one day prove useful for delivery of other medications. Duke has filed patent applications on the new technology, which was invented by Rose and his colleagues, including his brother, Seth D. Rose, PhD, Duke colleague, Thangaraju Murugesan, PhD, and James E. Turner, an inventor of the Nicotrol/Nicorette inhaler.

Collaborators on the project included Turner, Murugesan, and Frederique M. Behm of Duke University Medical Center, Chris J. Wynne, of the Christchurch Clinical Studies Trust, Christchurch, New Zealand, and Murray Laugesen, of Health New Zealand Ltd., Christchurch, New Zealand.

Timberlyne Family Medicine Changing Location, Name

Wed, 24 Feb 2010 00:00:00 -0500

Timberlyne Family Medicine is moving to a new, larger location in August and will be renamed Duke Primary Care Timberlyne.

Duke Primary Care Timberlyne’s address will be 77 Vilcom Circle, Suite 200, Chapel Hill, NC, 27514.

The new location is just a quarter mile east on Weaver Dairy Road in the Vilcom Center. Our offices will be on the second floor of Dawson Hall.

As Duke Primary Care Timberlyne, we will continue to offer a broad spectrum of primary care services, with the addition of radiology. Larger exam rooms and a larger lab area will help us better meet the needs of our patients. Our hours, phone number, and friendly staff will remain the same.

We look forward to seeing you at our new site, expected to open at the end of August 2010. For more information, contact Lori Wilkinson at 919-942-8500.

Butner-Creedmoor Family Medicine Changing Location, Name

Wed, 24 Feb 2010 00:00:00 -0500

Butner-Creedmoor Family Medicine is moving to a new, larger location in September 2010 and will be renamed Duke Primary Care Butner-Creedmoor.

Duke Primary Care Butner-Creedmoor’s address will be 2503 East Lyon Station Road, Creedmoor, NC, 2755-9112.

The new site is just a short distance from our present location on East Lyon Station Road and will feature larger exam rooms and an expanded lab area to better serve the needs of our patients.

At Duke Primary Care Butner-Creedmoor, you will find the same friendly staff and comfortable environment you have come to expect from Duke Medicine. Our services, hours, phone, and fax number will remain the same.

We look forward to seeing you in our new location this fall. For more information, contact Teresa Cummings at 919-528-1535.

New Data Provides Roadmap for Stroke Care in North Carolina

Tue, 23 Feb 2010 00:00:00 -0500

Ten years of statewide data on stroke prevention and treatment services in North Carolina will provide a map for future care, according to Duke University Medical Center research.

“The ultimate goal is to have it organized so that no matter where a patient in North Carolina has a stroke, they have access to the most readily available state-of-the-art acute treatment,” said Larry B. Goldstein, MD, director of Duke University Medical Center’s Stroke Center and lead author of the research.

Goldstein led a survey in 1998, 2003, and 2008 that asked every hospital in North Carolina to complete a two-page questionnaire. The North Carolina Stroke Prevention and Treatment Facilities Survey was supported through a grant from the North Carolina Department of Health and Human Services.

Surveys from 1998 and 2003 show some tests useful for the evaluation of stroke patients became more widely available in the state, but basic organizational features for stroke care -- the use of stroke care maps, protocols for intravenous tissue plasminogen activatpor (tPA) and stroke teams -- did not change at all, Goldstein said.

In 1998, only 18 percent of the state’s hospitals met basic criteria for stroke care. The number increased slightly to 21 percent in 2003, and now about 40 percent of the population lives in a county with at least one Primary Stroke Center.

The results are published online in Stroke and Goldstein will present the data at the International Stroke Conference in San Antonio, Texas on Wednesday, February 24, 2010.

“This information shows not only the changes that have occurred in North Carolina over a 10-year period, but provides information to help statewide planning so that stroke patients will have the quickest care possible,” Goldstein said.

Anyone suffering a stroke needs to be able to reach a hospital that’s equipped and organized to care for people with acute stroke as quickly as possible, he said. “With stroke care, time lost is brain lost.”

The American Heart Association has placed an emphasis on promoting statewide systems for stroke care. The AHA’s goal involves educating a continuum of people involved with stroke care, including the public, emergency medical services, and facilities equipped to care for a stroke patient.

Some counties have no acute care hospitals, so how that county organizes its plan to transport stroke patients to the nearest facility is going to be different than in a county where there are several different facilities available, Goldstein said.

In January, North Carolina Emergency Medical Services began requiring every EMS provider in the state to have a plan for how they are going to transport potential stroke patients to the nearest appropriate facility.

“This new comprehensive data establishes a roadmap for stroke care available in North Carolina,” Goldstein said.

“By clustering the organizational features within a specific hospital, we developed a basic set of criteria that a hospital would need to be able to provide optimal basic care for a stroke patient,” Goldstein said.

Although the organizational features improved for many basic stroke centers between 2003 and 2008, the number of patients with access to a basic stroke center stayed flat or even declined, he said.

This information is going to be used by the North Carolina Stroke Advisory Council as it promotes the development of stroke systems in the state, he said. In 2006, the North Carolina legislature established the council charged with promoting the development of coordinated stroke care in the state.

The survey data can help statewide planning for establishing Primary Stroke Centers and locating basic stroke care facilities to provide acute stroke management even though they may not have all the bells and whistles, the money or an infrastructure to support Primary Stroke Center designation, Goldstein said.

This is already happening regionally, he said. “There is now a Primary Stroke Center at East Carolina University’s Pitt County Memorial Hospital, where there was basically nothing east of Raleigh in 2003.”

Having this type of information could really help direct us as we try to develop that organized system of stroke care throughout the state of North Carolina, he said. “This is really intended to help guide our planning and has served as a model for other states and countries.”

Tiny Molecules May Tell Big Story about Cardiovascular Disease Risk

Mon, 22 Feb 2010 00:00:00 -0500

Tiny bits of molecular “trash” found in circulating blood appear to be good predictors of cardiovascular disease and untimely death, say researchers at Duke University Medical Center.

The discovery, published online in the April issue of the journal Circulation Genetics, comes from the largest study of its kind for cardiovascular disease, and is the first to identify specific metabolic profiles associated with coronary artery disease, heart attacks and death among patients who have undergone coronary catheterization.

The Duke study analyzed metabolites, the molecular debris left over after the body breaks food down into energy sources and building blocks of cells and tissues.

Scientists believe metabolites may be useful in diagnosing disease, said Svati Shah, MD, MHS, a cardiologist in the Duke Heart Center, the Duke Center for Human Genetics and the lead author of the study. But the tiny molecules are notoriously hard to identify, quantify and characterize.

Shah has been studying metabolic signatures in heart disease for several years and led earlier research showing that metabolic profiles associated with early-onset coronary artery disease can be inherited.

Shah and William Kraus, MD, professor of medicine at Duke and the senior author of the study, wanted to know if they could isolate and identify particular metabolites associated with coronary artery disease.

They began their investigation with information in Duke’s CATHGEN biorepository which holds health records and blood samples from nearly 10,000 patients who had come to Duke over the past eight years for catheterization.

Collaboration with Christopher B. Newgard, PhD, director of Duke’s Sarah W. Stedman Center for Nutrition and Metabolism, allowed Shah, Kraus and others to accurately quantify and characterize the metabolites.

Researchers selected 174 patients who had experienced early-onset coronary artery disease (CAD) and compared them to 174 controls who had undergone catheterization but who were not found to have CAD. Using a panel of 69 metabolites previously identified as potentially involved in the development of CAD, they examined the metabolic profiles in both groups.

“We found two sets, or clusters of metabolites that seemed to differentiate between the two groups,” says Shah.

Next, they tested the two sets of metabolites to see if they could differentiate between patients of any age who had CAD and those who did not. Again, the two sets of metabolites were able to discriminate between the two groups.

In order to evaluate the ability of the metabolites to predict risk of heart attack or death, the researchers also created an “event group” comprising 314 patients from all groups who suffered a heart attack or death during a follow-up period of almost three years. They compared metabolic profiles between those who suffered a heart attack or death with those who did not.

Using multiple analytic and statistical methods, they found two factors that were clearly associated with coronary artery disease and one factor that predicted greater risk of heart attack or death among patients with coronary artery disease.

“When we added these biomarkers to traditional clinical risk models, we found that they increased the accuracy of projected risk,” says Shah.

While earlier studies have suggested that certain metabolites are associated with the presence and severity of CAD, researchers have not been able to identify most of the individual molecules within those profiles, says Shah, “which in the end meant that these studies were not that clinically useful.”

“Here, we specifically selected clusters of metabolites that we know are involved in multiple pathways of lipid, protein, and glucose metabolism -- pathways that are often disrupted in CAD -- and we showed that they are indeed associated with CAD and subsequent risk of cardiac events,” says Kraus. “These metabolic profiles may be a way from routine clinical use, but we feel they are a good first step in that direction.”

Colleagues from Duke who contributed to the study include James Bain, David Crosslin, Michael Muehlbauer, Robert Stevens, Carol Haynes, Jennifer Dungan, Kristin Newby, Elizabeth Hauser, Geoffrey Ginsburg and Christopher Newgard, director of the Sarah W. Stedman Nutrition & Metabolism Center.

Enzyme Deficiency Protects Hepatitis C Patients from Treatment-Related Anemia

Sun, 21 Feb 2010 00:00:00 -0500

Many people who undergo treatment for hepatitis C develop hemolytic anemia, a disorder that destroys red blood cells. In some cases, it is so severe they have to reduce their medication or stop therapy altogether.

But now, scientists in Duke University’s Institute for Genome Sciences & Policy (IGSP) have discovered two genetic alterations linked to a benign enzyme condition that keep some patients anemia-free.

They say the discovery, appearing online in the journal Nature, opens the door to treatment for patients who have never been considered candidates for therapy before and may also hold the key to new drugs that could prevent anemia from developing in the first place.

The protective mechanism is a deficiency in a gene called ITPA. “We found that patients who carried specific functional variants are strongly protected against developing anemia,” says David Goldstein, PhD, director of the Center for Human Genome Variation in the IGSP and a senior author of the study.

Previous studies had identified the genetic variants as the cause of a deficiency in the production of an enzyme, inosine triphosphatase. But it was only through a genome-wide association study that the Duke team was able to show that these same variants were protective against anemia induced by ribavirin, one of two necessary drugs in hepatitis C treatment.

About 180 million people worldwide are infected with the hepatitis C virus, and about 30 to 40 percent of them could develop some degree of treatment-related anemia, according to John McHutchison, MD, associate director for research at the Duke Clinical Research Institute and also a senior author.

“It’s a big problem. Hemolytic anemia reduces the level of hemoglobin in the blood and robs it of its ability to carry oxygen. Anything that could help us predict who is going to become anemic and who is not could help us better manage therapy and give all patients the best chance of a good outcome,” said McHutchison.

Goldstein and McHutchison, who had earlier worked together in identifying genetic variants that helped explain race-based differences in response to hepatitis C treatments, believed there was probably a gene-based solution to the anemia puzzle as well.

Working with first authors Jacques Fellay, MD; Alex Thompson, MD, PhD; and Dongliang Ge, PhD, investigators turned to a rich database already at hand: the records of 1286 individuals who had earlier taken part in the IDEAL study, a large, randomized, Duke-led clinical trial that compared leading therapies for hepatitis C.

Researchers separated the patients into three ethnic groups, (988 European Americans, 198 African Americans, and 100 Hispanic Americans) and analyzed their decline in hemoglobin levels during the first month of treatment.

The researchers conducted a genome-wide association study and found several polymorphisms -- single-letter DNA alterations -- also known as “SNPs or “snips” -- associated with reduced hemoglobin levels.

But finding an association is just a start: of more biological importance is the identification of the causal variants, the polymorphisms that directly influence hemoglobin levels.

Investigators discovered that the two variants known to cause ITPA deficiency appeared almost exclusively on chromosomes that also carried the protective version of the most associated SNP. Further statistical analysis proved that the two variants were indeed the source of protection from anemia.

McHutchison says the discovery is clinically important. “The beauty of this finding is that it may mean we could consider offering treatment to patients who have additional problems, like coronary artery disease or kidney disease. Right now, we are generally uncomfortable treating these patients because anemia could make their underlying condition worse. If a test could tell us which patients are not going to become anemic, we could consider treating them.”

“Most of us trace the birth of pharmacogenetics to a 1957 paper by Arno Moltulsky who argued that important drug responses may often depend on genetic differences among people that are invisible until an individual takes a certain drug,” says Goldstein. “These ITPA variants reflect this classic formulation of pharmacogenetics, and suggest to us that there are many other important variants that can and should be found through the careful genetic analyses of patients’ drug responses.”

Colleagues from Duke who contributed to the study include Curtis Gumbs, Thomas Urban, Kevin Shianna, Latasha Little and Andrew Muir. Other co-authors include Mark Sulkowski, from Johns Hopkins; and Ping Qiu, Arthur Bertelsen, Mark Watson, Amelia Warner, Clifford Brass and Janice Albrecht, from Schering-Plough Research Institute.

Schering-Plough Research Institute funded the study and has filed a patent application based on the findings. Ten of the study authors, including Goldstein, Thompson, Ge, Fellay, Urban, Shianna and McHutchison, are listed as inventors on the application.

Statins Inhibit Inflammation Within Prostate Tumors

Wed, 17 Feb 2010 00:00:00 -0500

Patients with prostate cancer who regularly use statins to lower their cholesterol may be enjoying a secondary benefit from the drugs: A new study from Duke University Medical Center shows that statins significantly lower the degree of inflammation within prostate tumors.

The response may, in part, explain why men on statins have a lower risk of disease progression.

Previous studies have shown that statins reduce systemic inflammation, but the Duke researchers were interested in finding out if the drugs reduced inflammation inside tumors, so-called intra-tumoral inflammation, that is believed to contribute to cancer recurrence after surgery.

“We found that preoperative statin use was associated with a 69 percent lower risk of intra-tumoral inflammation," said Lionel Bañez, MD, an assistant professor of surgery and urology at Duke and the lead author of the study. "We also discovered a trend suggesting greater risk-reduction with higher doses of the drugs.”

The study appears online in the journal Cancer Epidemiology, Biomarkers & Prevention.

Researchers examined tissue samples of tumors from 236 men undergoing surgery for prostate cancer at the Durham VA Medical Center. Researchers identified the samples as coming from statin-users or non-users, tracked the dose and frequency among the users, and graded the degree of inflammation in the tissue samples as absent, mild, or marked.

They found that 16 percent of the patients (37) took statins during the year prior to surgery. Most (92 percent) were on simvastatin. Eighty-two percent of the patients had inflammatory cells in their prostate tumors, with roughly one-third registering marked tumor inflammation.

After taking into consideration factors such as age, race, body mass index and other clinical variables, investigators found that statin use was associated with reduced inflammation within the tumors.

They also found that inflammation was more likely among older patients with more advanced cancers and who had experienced a longer time from biopsy to surgery.

“Increasing evidence suggests that statins may reduce risk of prostate cancer progression, and some studies have even suggested that widespread statin use over the past 15 years has contributed to a decline in prostate cancer mortality,” says Bañez.

So should all prostate cancer patients be on a statin? “No -- or at least not yet,” says Stephen Freedland, MD, associate professor of urology and pathology in the Duke Prostate Center at Duke University and the senior author of the study. “More studies have to be done before such a recommendation can be made. However, men taking statins for heart health may already be enjoying a beneficial side effect against prostate cancer.”

“If these findings are validated in additional studies, it would support the hypothesis that statins delay prostate cancer progression, in part, by reducing inflammation inside the tumor,” Bañez said.

The study was funded by the Department of Defense Prostate Cancer Research Program, the Department of Veterans Affairs, the Duke University Division of Urology and Department of Surgery and the American Urological Foundation/Astellas Rising Star in Urology Award.

Additional colleagues from Duke who contributed to the study include Joseph Klink, Jayakrishnan Jayachandran (deceased), Leah Gerber, and Elizabeth Masko. Other study co-authors include Amy Lark and Robin Vollmer, from the Veterans Affairs Medical Center in Durham, and Robert Hamilton, from the University of Toronto.

Duke Scientists Image Brain at Point When Vocal Learning Begins

Wed, 17 Feb 2010 00:00:00 -0500

Duke University Medical Center scientists crowded around a laser-powered microscope in a darkened room to peer into the brain of an anesthetized juvenile songbird right after he heard an adult tutors’ song for the first time.

Specifically, they wanted to see what happened to the connections between nerve cells, or synapses, in a part of the brain where the motor commands for song are thought to originate.

In the first experiment of its kind, they employed high-resolution imaging to track changes to individual dendritic spines, important points of contact between nerve cells.

“We expected to see the building of new spines and loss of old spines accelerate when the juvenile heard a tutor’s song for the first time,” said senior author Richard Mooney, PhD, a Duke professor of neurobiology. “Instead, we saw exactly the opposite: hearing a tutor song rapidly stabilized previously dynamic synapses.”

Juveniles with initially higher levels of spine turnover before hearing the tutor song subsequently learned more from their tutors. Because the scientists studied birds during their late adolescence, some may have been past their optimal learning period.

“Juveniles in which spines were already highly stable weren’t able to learn from their tutors,” said Todd Roberts, PhD, a postdoctoral fellow in the Department of Neurobiology who is lead author on the study, which was published online in the journal Nature on February 17.

In the "learners," hearing a tutor song rapidly stabilized spines.

Roberts said they were expecting to find higher "plasticity," the brain's ability to remodel connections in response to learning or injury. “We thought we would see an initial stage of higher plasticity, because it can take weeks or even months for a juvenile to copy the tutor song.”

The findings provide fundamental insight into how the brain changes during the juvenile's critical periods for behavioral learning. They also can guide future research aimed at restoring plasticity to synapses after the critical period closes, an important therapeutic goal in helping people regain function after an injury like hearing loss or stroke, Mooney said.

The researchers studied juvenile male songbirds that were kept only with females, which do not sing. They had been exposed to other calls and noises, but not the critically important song of a male tutor. “The adult male’s song is a signal that the juvenile’s brain seems to crave,” Mooney said.

As to why this rapid stabilization of dendritic spines might be important, Mooney said that the songbird brain, like people’s brains, is learning for an important goal, which is to perform a highly precise skill.

“Many skills, including communication skills, require great precision if you want to stay in the gene pool,” Mooney said. “A male songbird has to learn to sing precisely or he won’t attract a mate.”

The finding that a stable network of synapses rapidly forms after a young bird hears the tutor song suggests that an experience can act in a young brain to build stable connections between neurons, providing a foundation for learning new behaviors, like singing or speaking.

Roberts detailed the painstaking way that he and colleagues set up the experiment and imaged the individual dendritic spines. They used an engineered virus to infect certain nerve cells, which then expressed green fluorescent protein.

“Hit with the right wavelength of light from a powerful and concentrated laser beam, the neuron glows and we can even see its dendritic spines, which are tiny components of excitatory synapses,” Roberts said. The same neurons and spines were tracked and photographed for up to a month.

Co-authors included Katherine A. Tschida and Marguerita E. Klein of the Duke Department of Neurobiology. The study was funded by the National Science Foundation (NSF), the National Institutes of Health (NIH), a National Research Service Award from the NIH, an NSF pre-doctoral award and the Howard Hughes Medical Institute.

What the Brain Values May Not Be What it Buys

Tue, 16 Feb 2010 00:00:00 -0500

It’s no wonder attractive human faces are everywhere in media and advertising -- when we see those faces, our brains are constantly computing how much the experiences are worth to us.

New brain-imaging research shows it's even possible to predict how much people might be willing to pay for a particular face.

Researchers at Duke University Medical Center found that as participants were watching a sequence of faces, their brains were simultaneously evaluating those faces in two distinct ways: for the quality of the viewing experience and for what they would trade to see the face again.

The work was published in the Journal of Neuroscience online on February 16.

They showed college-aged men a parade of female faces, intermixed with images of money, while measuring brain activation using functional magnetic resonance imaging (fMRI). In a later experiment, the same participants could pay more or less money to view more or less attractive faces.

“One part of the frontal cortex of our participants’ brains increased in activation to more attractive faces, as if it computed those faces’ hedonic (quality of the experience) value," said senior author Scott Huettel, PhD, an associate professor of psychology and neuroscience who directs the Center for Neuroeconomic Studies at Duke. "A nearby brain region’s activation also predicted those faces’ economic value -- specifically, how much money that person would be willing to trade to see another face of similar attractiveness.”

During the fMRI experiment, heterosexual men viewed a set of female faces that had previously been rated for attractiveness by peers. Interspersed with the face pictures were pictures of money, shown in several denominations, which indicated real monetary gains or losses that the participant could later spend during the next phase of the experiment.

The participants made a series of economic decisions: Should they spend more of their money to see a more attractive face, or spend less money but see a less attractive face? Each participant made about one hundred of these decisions, spending from one to 12 cents each time.

The researchers measured fMRI activation while the participants viewed the faces and money. In a region near the front of the brain, the anterior ventromedial prefrontal cortex (VMPFC), there was increased activation when participants saw a more attractive face or saw a picture of a larger amount of money. That pattern of brain activation was relatively stable across participants in the study.

Yet, slightly farther back in the brain, within posterior VMPFC, the researchers also could see the relative activation to the faces compared to money, which strongly predicted how each person would later spend to see a more attractive face.

Huettel said that findings from neuroscience might lead to new directions in marketing. “People often respond to images in a very idiosyncratic fashion," he said. "While we can’t use neuroscience to identify the best images for every person’s brain, we could identify types of images that tend to modulate the right sorts of value signals -- those that predict future purchases for a market segment.”

Lead author David V. Smith, a graduate student in psychology and neuroscience, explained further: “Previous studies have shown that active decisions about the value of real goods, such as candy or consumer products, evoke activation in the VMPFC. Our study demonstrates that the VMPFC actually contains two signals for value: one that indicates how much value we are currently experiencing, and another that indicates how much we’d be willing to pay to have that experience again later.”

Why were all subjects male? “For this new study, we built on prior work from colleagues who showed that young adult males not only value the experience of seeing a female face, but will treat that experience like an economic good -- they will trade experience for money in a predictable manner,” Huettel said. “We expect that the functioning of the brain’s reward system is essentially similar between males and females. However, what sorts of stimuli seem attractive -- whether an image of a face or some other social cue -- may differ between the genders.”

Smith added that they plan to continue the research with other kinds of rewards, including different types of pictures. “A key issue in future research will be examining how different value signals are communicated between different parts of the brain to produce our decisions,” Smith said.

Other authors included Benjamin Hayden and Michael Platt of the Duke Department of Neurobiology and the Duke Center for Cognitive Neuroscience, and Trong-Kha Truong and Allen Song of the Duke Department of Radiology and the Brain Imaging and Analysis Center. The research was funded by grants from the National Institutes of Health (NIH).

Duke Raleigh Hospital Seeks Approval for New Operating Rooms as Part of Continued Expansion

Mon, 15 Feb 2010 00:00:00 -0500

Duke Raleigh Hospital today filed a Certificate of Need (CON) application with the state of North Carolina for two of three available new operating rooms that the state has determined are needed to meet surgical demands in Wake County.

Duke Raleigh's application is part of its Master Campus Plan that includes the recruitment of 14 additional subspecialty surgeons and the renovation and expansion of the hospital's surgical facilities to accommodate the kind of high-tech, complex cases that now largely characterize surgical services at Duke Raleigh.

"We are planning to renovate and expand surgical services at Duke Raleigh both to meet current demand, which now runs ahead of capacity, and to meet the growing needs of an aging population for subspecialty inpatient surgery," said Douglas Vinsel, president of Duke Raleigh Hospital.

"This application is yet another step in executing a master plan that is necessary to transform our facility from one that was designed for light elective surgery at its inception in the 1970s, to one that provides the people of Wake County sophisticated specialty and subspecialty care that is consistent with one of the country's leading academic health systems."

From 2006 to 2009, surgical volume at Duke Raleigh Hospital has increased 31 percent, and the number of procedures performed by Duke faculty at the hospital has increased more than 30-fold over the same time period.

While the application filed today specifically addresses a need related to subspecialty inpatient surgery capacity, outpatient surgeries at Duke Raleigh from 2006 to 2009 also increased by 35 percent.

"We are grateful for the foresight of the Division of Health Service Regulation in determining the need for these operating rooms in Wake County, and their commitment to ensuring the provision of necessary healthcare services for local patients and residents," said Vinsel. "We look forward to vigorously making our case for the need of these additional operating rooms at Duke Raleigh as part of our larger plan to better meet the healthcare needs in Wake County."