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Research Roundup

March 27, 2012, Volume 58, No. 27

Mayo Clinic, Penn and Partners to Explore New Ways to Predict and Control Seizures
Mayo Clinic and partners from the University of Pennsylvania School of Veterinary Medicine, the University of Minnesota College of Veterinary Medicine and College of Pharmacy, the Perelman School of Medicine at the University of Pennsylvania, and NeuroVista Corporation have been awarded a $7.5 million grant (U01) from the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health (NIH). The research involves studying new ways to predict and control epileptic seizures in dogs and people.

Epilepsy affects approximately 1 percent of the human population, with an estimated 50 million people worldwide currently suffering from the disorder. The hallmark of epilepsy is the seizure—a sudden and often violent event that strikes patients without warning. The goal of the research is to use information gleaned from real-time electroencephalograms (EEG) to consistently detect impending seizures, and develop methods of preventing these seizures through use of fast-acting drug therapies.

The grant awards $1.5 million a year for up to five years. The principal investigators of the studies are Greg Worrell, Mayo Clinic; Ned Patterson, University of Minnesota College of Veterinary Medicine; Jim Cloyd, University of Minnesota College of Pharmacy; Charles Vite, University of Pennsylvania School of Veterinary Medicine; Brian Litt, Perelman School of Medicine at the University of Pennsylvania; and Kent Leyde, chief technology officer of NeuroVista Corporation of Seattle, Washington.

NeuroVista, a Seattle-based company developing novel technologies for the management and treatment of epilepsy, has developed an implantable device system that continuously collects and analyzes EEG data to detect impending seizures. The system uses an external patient-carried device with a very simple interface—three colored lights—to indicate the risk of an impending seizure to the patient. The system is currently undergoing study in clinical trials in human patients being conducted in Australia. The NIH-funded research will involve applying the NeuroVista technology to dogs with naturally occurring epilepsy, and extending the technology by using it to guide the administration of fast-acting drugs to prevent seizures. It is hoped that this work will translate to a similar solution for human patients.

"This collaboration with three major academic centers creates a powerful engine for innovation in the treatment of epilepsy," said Kent Leyde. "We are excited about the opportunity to advance the promising research in this field and translate what we learn in canines into the clinical environment."

"This epilepsy management system technology shows promise for detecting and predicting seizures in dogs and people," notes Dr. Doug Sheffield, vice president of clinical research for NeuroVista. "This technology has the potential to profoundly impact epilepsy research and patient care."

"Despite over 15 drugs currently available for the chronic treatment of epilepsy, approximately 25-35 percent of people continue to have persistent and serious seizures even when receiving the most advanced medical care," added Dr. Cloyd. "For those whose epilepsy is well-controlled by medication, they must often cope with significant and debilitating side effects."  

"The constant fear and uncertainty as to when the next seizure is going to strike often exacts a serious toll on the quality of life for patients and their families. The problem for patients with epilepsy is they actually only have seizures a small percentage of their lifetime, but they're on medication continuously," said Dr. Patterson.

"There is a real need for technology to inform patients about when seizures are likely to occur and to alert caregivers when seizures strike," said co-investigator Dr. Brian Litt, a neurologist and bioengineer at the Perelman School of Medicine.

While the long-range goal of the studies is to find better ways to treat human patients, Dr. Vite, assistant professor of veterinary neurology said, "as I remind everyone, I am a veterinarian, and this technology will be of value to animals as well." Drs. Vite and Patterson each treat hundreds of dogs with epilepsy at their respective university veterinary clinics.

"Our goal is reliable seizure forecasting in conjunction with timely, effective short-term intervention, and this could lead to more effective treatment for both canine and human epilepsy," added Dr. Worrell.

$3.5 Million to Study New Approaches to Prevent the Effects of Stress in Military Personnel
An interdisciplinary team of researchers from the Perelman School of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia (CHOP), including specialists in neurobiology, psychiatry, and biomedical imaging, have received a $3.5 million grant from the Defense Advanced Research Projects Agency (DARPA) to study how to enhance stress resilience in military personnel.

"This is an exciting opportunity to rapidly translate basic science results on brain circuitry and biomarkers of stress resilience from animal models into human populations," said the study's principal investigator, Dr. Seema Bhatnagar, assistant professor of anesthesiology and critical care at Penn/CHOP. "The goal of these studies is to identify and validate novel treatment strategies that target significant health problems in military personnel, particularly post-traumatic stress disorder (PTSD). Such strategies have potential application for treating psychiatric health problems in individuals in the general population as well."

The new studies build on previously funded Penn/CHOP DARPA Phase 1 basic research. In the previous studies, the team examined neural circuits in the brain that are affected by stress exposure and how these circuits, in turn, can lead to dysfunction in physiology and behavior. From those investigations, the researchers were able to identify targets that could enhance resilience to stress and biomarkers of resilience to stress.

In the second phase, the team will validate the stress-resilience targets and test new stress-management strategies. The research will involve both basic research and translational studies and will also involve active duty personnel and veterans being treated for post-traumatic stress disorder (PTSD) at the Philadelphia VA Medical Center and two other military institutions. The Penn/CHOP team is one of two awardees in the nation to receive Phase 2 funding for their work.

"PTSD is a common and often disabling condition that is a direct outgrowth of extremely stressful experiences. Yet we know that, exposed to similar stressors, some people develop PTSD while others do not," said Dr. Mitchel Kling, associate professor of psychiatry at Penn. "The clinical and translational studies to be done in the second phase of our research will allow us to directly test the relevance of findings from the preclinical studies to the evaluation and treatment of individuals with PTSD and better illuminate the complex genetic and environmental underpinnings of PTSD."

The ultimate goal of the new Phase 2 studies is to help identify the types of events that produce the most severe psychological problems and to identify vulnerable individuals that could benefit from early treatment, or to prime these individuals to prevent these problems from emerging in the first place. The new research may also help to identify those individuals who need specific types of treatments, whether psychological, pharmacological and/or rehabilitative.

The team will also look into the effects of currently administered drugs in promoting stress resistance or stress vulnerability. Many of these drugs are currently approved by the Food and Drug Administration (FDA) and prescribed for common medical conditions such as hypertension. The findings could lead to the development of novel pharmacological and other types of treatment strategies for psychological health problems.

"The new, integrative approach implemented in our studies has exciting potential for providing a more complete depiction of both the kind and degree of brain pathology in these disorders," said Dr. James Gee, associate professor of radiology at Penn. "The unique expertise of our multidisciplinary team is critical to the success of this ongoing research initiative."

Co-investigators of the research teams include Drs. Ted Abel, Sheryl G. Beck, Rita Valentino at Penn/CHOP and Phillip Gehrman, Paolo Nucifora, and Richard Ross, at the Philadelphia VA Medical Center/Penn as well as Investigators at Camp LeJeune and the National Intrepid Centre for Excellence at the Walter Reed National Military Medical Center.

Discovering and Characterizing a 300-Million-Year-Old Peat-forming Forest at a Site Near Wuda, China
Pompeii-like, a 300-million-year-old tropical forest was preserved in ash when a volcano erupted in what is today northern China. A new study by University of Pennsylvania paleobotanist Hermann Pfefferkorn and colleagues presents a reconstruction of this fossilized forest, lending insight into the ecology and climate of its time.

Dr. Pfefferkorn, a professor in Penn's department of earth and environmental science, collaborated on the work with three Chinese colleagues: Jun Wang of the Chinese Academy of Sciences, Yi Zhang of Shenyang Normal University and Zhuo Feng of Yunnan University.

Their paper was published last month in the Early Edition of the Proceedings of the National Academy of Sciences.
The study site, located near Wuda, China, is unique as it gives a snapshot of a moment in time. Because volcanic ash covered a large expanse of forest in the course of only a few days, the plants were preserved as they fell, in many cases in the exact locations where they grew.

"It's marvelously preserved," Dr. Pfefferkorn said. "We can stand there and find a branch with the leaves attached, and then we find the next branch and the next branch and the next branch. And then we find the stump from the same tree. That's really exciting."

The researchers also found some smaller trees with leaves, branches, trunk and cones intact, preserved in their entirety.

Due to nearby coal-mining activities unearthing large tracts of rock, the size of the researchers' study plots is also unusual. They were able to examine a total of 1,000 m2 of the ash layer in three different sites located near one another, an area considered large enough to meaningfully characterize the local paleoecology.

The fact that the coal beds exist is a legacy of the ancient forests, which were peat-depositing tropical forests. The peat beds, pressurized over time, transformed into the coal deposits.

The scientists were able to date the ash layer to approximately 298 million years ago. That falls at the beginning of a geologic period called the Permian, during which Earth's continental plates were still moving toward each other to form the supercontinent Pangea. North America and Europe were fused together, and China existed as two smaller continents. All overlapped the equator and thus had tropical climates.

At that time, Earth's climate was comparable to what it is today, making it of interest to researchers like Dr. Pfefferkorn who look at ancient climate patterns to help understand contemporary climate variations.

In each of the three study sites, Dr. Pfefferkorn and collaborators counted and mapped the fossilized plants they encountered.  In all, they identified six groups of trees. Tree ferns formed a lower canopy while much taller trees—Sigillaria and Cordaites—soared to 80 feet above the ground. The researchers also found nearly complete specimens of a group of trees called Noeggerathiales. These extinct spore-bearing trees, relatives of ferns, had been identified from sites in North America and Europe but appeared to be much more common in these Asian sites.

They also observed that the three sites were somewhat different from one another in plant composition. In one site, for example, Noeggerathiales were fairly uncommon, while they made up the dominant plant type in another site. The researchers worked with painter Ren Yugao to depict accurate reconstructions of all three sites.

"This is now the baseline," Dr. Pfefferkorn said. "Any other finds, which are normally much less complete, have to be evaluated based on what we determined here."

The findings are indeed "firsts" on many counts.

"This is the first such forest reconstruction in Asia for any time interval, it's the first of a peat forest for this time interval and it's the first with Noeggerathiales as a dominant group," Dr. Pfefferkorn said.

Because the site captures just one moment in Earth's history, Dr. Pfefferkorn noted that it alone cannot explain how climate changes affected life on Earth. But it helps provide valuable context.

"It's like Pompeii: Pompeii gives us deep insight into Roman culture, but it doesn't say anything about Roman history in and of itself," Dr. Pfefferkorn said. "But on the other hand, it elucidates the time before and the time after. This finding is similar. It's a time capsule and therefore it allows us now to interpret what happened before or after much better."

The study was supported by the Chinese Academy of Science, the National Basic Research Program of China, the National Natural Science Foundation of China and the University of Pennsylvania.

Decreasing the Risk of Failure to Thrive with New Feeding Device
A novel feeding device developed at the School of Nursing may decrease the risk of failure to thrive (FTT), which currently affects half of all newborns with congenital heart defects even after their surgical lesions are corrected.

Dr. Barbara Medoff-Cooper, Ruth M. Colket Professor in Pediatric Nursing and director of the Center for Biobehavioral Research of Penn Nursing, invented a device that analyzes an infant's ability to organize feeding by sucking, swallowing, and breathing effectively. This device, developed in collaboration with Penn Engineering, allows healthcare professionals to assess infants at risk for dysfunctional feeding and poor weight gain as often seen in both premature infants and infants with complex congenital heart disease. The data also can be correlated with growth or developmental problems that may occur during the first year of life.

"Feeding actually speaks loudly to us about the brain," said Dr. Medoff-Cooper. "If a child is feeding well, it gives us one fewer major issue to worry about. Conversely, even a full-term infant who is not feeding well is at high risk for developmental problems."

Dr. Medoff-Cooper conducted the first comprehensive evaluation of feeding difficulties in infants with complex congenital heart defects. Her work has demonstrated that feeding behaviors can predict developmental outcomes in high-risk infants because of the complicated interplay of movements and physiologic responses needed in the feeding process. The premise of her work is that feeding effectiveness corresponds to how well infants will achieve other developmental milestones.

Mentoring Provides Health Benefits for African-American Veterans with Diabetes
Intervention by peer mentors has a statistically significant effect on improving glucose control in African-American veterans with diabetes, according to a study by researchers at the Perelman School of Medicine at the University of Pennsylvania and the Philadelphia VA Center for Health Equity Research and Promotion (CHERP). Full results of the study were published in the March 20 issue of the Annals of Internal Medicine.

In the study 118 African-American veterans aged 50-70 years old with persistently poor diabetes control were randomly assigned to three groups: those receiving their usual care (the control group for the study), those receiving peer mentoring, and those offered financial incentives if their glucose control improved. Mentors were matched with the diabetes patients according to sex and age.

"Our goal was to determine whether peer mentors or financial incentives would help African-American veterans improve their glycosylated hemoglobin levels (HbA1c)—a marker of diabetes control—better than conventional care," said Dr. Judith A. Long, associate professor of medicine in the department of general internal medicine at the Perelman School of Medicine, and lead author of the study. "We performed this study in an African-American population because African-Americans have higher rates of diabetes and more complications resulting from the disease than other populations."

Diabetes patients receiving their usual care were notified of their starting levels and recommended goals for HbA1c. Those in the mentor group were assigned mentors who previously had poor glycemic control but now had good control. Mentors participated in hour-long one-on-one training, including motivational interviewing techniques, and were informed that they would receive $20 per month if the diabetes patient confirmed that they had talked at least once a week. Those in the financial incentive group were told they would earn $100 if their HbA1c dropped by one point and $200 if it dropped by two points or to a level of 6.5%.

In the six-month study, intervention by the peer mentors had a statistically significant effect in improving glucose control. On average, diabetes patients in the mentor group saw their HbA1c drop by approximately one percent (from 9.8 to 8.7). HbA1c levels in the financial incentive group dropped from 9.5 to 9.1, while the control group saw the smallest change (from 9.9 to 9.8).

The authors of the study note that several factors may have contributed to the success of the peer mentor intervention. First, those in the mentor group may have benefited from a culture of camaraderie among the veteran participants. Second, social altruism may be a powerful motivator if patients are provided with a mechanism to help each other. Third, a history of mistreatment and distrust in the health care system may make peer support particularly effective for minorities. Finally, the financial incentive may have motivated mentors to call more frequently.

Previous studies have shown that social support can improve diabetes self-management behaviors, such as adhering to medication, diet, exercise and blood glucose monitoring. However, these studies generally involved nurse phone calls or home visits from community health workers, which require expensive professional or semi-professional staff members. In addition, support from families and friends is often not a viable alternative because many high-risk patients are socially isolated, while others may not want to engage relatives or friends in discussions about their medical problems. Finding family members and friends who are able to assume caretaker roles is also often a challenge for many patients.

"Our study raises the possibility that a more informal, flexible means of providing one-on-one peer support through peer coaches or mentors could potentially provide larger benefits at low cost," said Dr. Kevin G. Volpp, professor of medicine and health care management and director of the Center for Health Incentives and Behavioral Economics in the Perleman School of Medicine, and the principal investigator on the grant that funded the study.

In addition to Dr. Long and Dr. Volpp, co-authors are Erica C. Jahnle from Penn LDI CHIBE, Diane M. Richardson from the Philadelphia VA CHERP, as well as George Loewenstein, from Carnegie Mellon University.

Policy and Leadership Vacuum Undermines Higher Education in Washington State
Washington State's higher education system is adrift, failing to grant bachelor's degrees to enough Washingtonians and forcing the state's high-tech economy to rely on talent imported from other states and countries, according to a study from researchers at the Graduate School of Education.

GSE Professors Joni Finney and Laura Perna from Penn's Institute for Research on Higher Education have found a lack of statewide leadership, failed efforts to restructure higher education governance, skyrocketing tuition during an economic downturn, a budget crisis that has the potential to undermine the state's ability to meet its need-based financial aid commitments and a disjointed higher education system, among other findings in "State Policy Leadership Vacuum: Performance and Policy in Washington Higher Education."

"When it comes to higher education, what Washington needs from its policymakers is a set of clear goals and an ambitious agenda to help more citizens get the college degrees required to compete for jobs in the state's high-tech economy," Dr. Finney said. "What it's getting instead is an abdication of leadership and steep tuition increases that threaten to end the dream of a college education for thousands of Washingtonians."

In the second installment of a five-state, two-year study, the researchers determined that Washington lags behind most other states in the total number of bachelor's degrees produced per capita. Only 40 percent of students who start ninth grade enter college on time.  In addition, one-third of adults ages 18-64 have earned only a high school diploma while one-fourth of adults ages 18-64 range have not earned even a high school diploma.

"Washington: State Policy Leadership Vacuum" reports that college is becoming less affordable in Washington.  From 1999 to 2009, median family incomes declined by 1.9 percent, but tuition increased by 42 percent at public two-year colleges and by 39.5 percent at public four-year colleges and universities.

The study found that high-profile planning efforts to reform higher education have produced few tangible results.  For instance, Washington Learns called for a statewide tuition policy, better accountability and expanded opportunities for Washington residents to attend college, but none of this occurred.  In the same vein, the Strategic Master Plan for Higher Education in Washington has also fallen short of expectations.

"Gov. Chris Gregoire has tried to restructure higher education governance with little success," Dr. Finney said.  "A major reorganization mandated by the Legislature for 2012—eliminating the Higher Education Coordinating Board and replacing it with two agencies—is unlikely to solve the problem of a fragmented higher education system in which various sectors and institutions fail to speak with one voice and are sometimes at odds with one another on policy questions."

The report identifies the misalignment between high school graduation requirements and college admission requirements, and a lack of statewide higher education priorities.

In addition, compared to other groups, Washington's Hispanic population, now at 10 percent and expected to grow rapidly, has lower high school graduation rates, lower scores on standardized tests and lower rates of college participation and completion.  African-American residents in Washington also face persisting lower achievement.

"By 2018, 67 percent of all jobs in Washington will require workers who have at least some post-secondary education or training.  But, Washington isn't doing nearly enough to make sure that its own citizens can compete for such jobs," Dr. Perna said. "Based on trends in degree production and population growth projections, Washington must increase its annual production of associate and bachelor's degrees by 6.2 percent each year in order for 55 percent of its workforce, ages 25-64, to hold at least an associate degree by 2020."

Other states in the study are Illinois, Georgia, Maryland and Texas.    

The full report is available at www.gse.upenn.edu/irhe/srp/washington

Sleepless in the South: State and Regional Prevalence of Sleep Disturbance
Researchers at the Perelman School of Medicine at the University of Pennsylvania have put sleeplessness on the map—literally. The research team, analyzing nationwide data collected by the Centers for Disease Control and Prevention (CDC), has produced the first state-by-state sleep maps for the United States, revealing that residents of Southern states suffer from the most sleep disturbances and daytime fatigue, while residents on the West Coast report the least amount of problems. The results are published online in the Journal of Clinical Sleep Medicine.

"Sleep disturbance is a major public health concern. However, geographic dispersion of sleep problems, and the factors that may play a role in why some states or regions get better sleep, have been largely unexplored," said Dr. Michael A. Grandner, research associate at the Center for Sleep and Circadian Neurobiology at Penn and lead author of the study. "Our study generated the first sleep maps for the US that include data on sleep disturbance and daytime fatigue across most of the country."

The findings suggest that, in general, those in the South are most likely to report sleep disturbance and daytime fatigue, and those in the West are least likely. Of the states where data was collected, Oklahoma, Arkansas, Mississippi, Alabama, and West Virginia ranked in the highest bracket for each category. The researchers note that this finding is consistent with other geographic studies, showing that many of the states that report worse sleep and fatigue problems are the same states that tend to report higher prevalence of other conditions, such as obesity, and that the pattern differed slightly between men and women.

The new study evaluated state-based prevalence of self-reported sleep disturbance and daytime fatigue across 36 US states/territories using data from 157,319 people who took part in the 2006 Behavioral Risk Factor Surveillance System (BRFSS).  The BRFSS is an annual, state-based, random digit-dialed telephone interview survey of adults aged 18 years and older from all over the US, conducted by the CDC. It is the world's largest telephone survey, designed to monitor health-related behaviors in the general population.  

The prevalence estimates for each state/territory were based on weighted figures derived from the census, so that every age, sex, and race/ethnicity combination was included relative to how often they were reported in the US census—helping to ensure that the data accurately reflect the general population. Overall, a pattern was found where some states reported higher prevalence of sleep disturbance and/or daytime fatigue, and that these differences could not be completely accounted for when adjusted for demographics (age, sex, race/ethnicity), socioeconomics (education, income, employment), mental health (depression, general mental health), physical health (general health, overall physical health, healthcare access, obesity), and substance use (alcohol, smoking).

To better understand the sleep patterns, the researchers examined a number of underlying possibilities, such as demographics, obesity, health, and even weather and sunlight patterns in the different states. They determined that regional differences in mental health, race/ethnicity, and access to medical care were the strongest factors that explain these differences.

"The take-home message from this study is that different regions of the country sleep better than others," said Dr. Grandner. "We should begin to use this data to track patterns of poor sleep and try to understand why these patterns occur. Sleep is such an important part of overall health, we need to do everything we can to help give a good night's sleep to those in the highest-risk regions."

Dr. Grandner and his colleagues note that targeted public health campaigns about healthy sleep patterns in states/regions that are most prone to sleep problems and increased screening programs for sleeplessness symptoms may help better guide individuals with sleep issues to medical care.


Almanac - March 27, 2012, Volume 58, No. 27