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February 3, 2005

Research Notes

Federal grant funds study of oral health disparities in underserved populations

The National Institute of Dental and Craniofacial Research (NIDCR) has awarded an additional $1.47 million to the University’s School of Dental Medicine for a joint project with West Virginia University to determine the causes of oral health disparities in underserved populations.

In 2003, NIDCR awarded Pitt and WVU $6.1 million to conduct research aimed at determining how genetics and other familial factors contribute to oral health disparities in Appalachia, specifically in Webster and Nicholas counties in West Virginia. The new grant will allow the researchers to expand the scope of their research to include studying how environmental and behavioral factors can affect oral health and will expand the reach of the research to rural areas in Pennsylvania, namely Bradford and Burgettstown.

“Our preliminary work done on this project has already uncovered some important clues as to why people in Appalachia have poor oral health,” said Mary L. Marazita, associate dean for research and head of the division of oral biology at Pitt’s School of Dental Medicine and professor of human genetics at the University’s Graduate School of Public Health. “By expanding the reach of this project into rural Pennsylvania and by expanding criteria to incorporate the study of genetics, behavior, microbiology and environment into a single conceptual framework, we hope to find a large number of risk factors that cause oral health disparities in the region’s underserved populations, allowing us to better treat the population and to develop interventions to reduce the disparity.”

Information will be gathered from a cross-section of families on health behaviors, economic status, family structure and family environment to determine if any of these factors impact oral health. Blood samples also will be taken to determine if there are any genetic factors that contribute to poor oral health. Researchers also will study community-level factors that affect the accessibility of dental care.

According to “Oral Health in America: A Report from the Surgeon General,” there are widespread disparities in oral health care in the United States; many Americans are uninformed about oral health, and oral health services are inaccessible to some populations. In addition, there is not adequate data to determine the cause of these disparities, making the planning and implementation of effective prevention and treatment programs difficult.

Other researchers on this grant include: Robert Weyant, Ralph Tarter and Brion Maher from Pitt and Richard Crout, Dan McNeil, Sharon Wenger, John Thomas, Hilda Heady and Marybeth Hummel of West Virginia University.

Protein appears to protect against heart disease

Reduced blood concentrations of a protein called adiponectin appear to indicate a significant risk of cardiovascular disease in one of the first studies to focus on risk of the disorder among patients with diabetes mellitus type 1, previously known as juvenile diabetes. Recent studies suggest that adiponectin, a protein specific to fat tissue, is involved in obesity, diabetes and heart disease.

Results of the study are published in the January issue of Diabetologia, a leading journal affiliated with the European Association for the Study of Diabetes.

“Most studies looking at adiponectin concentrations have been in the non-diabetic population or in people with type 2 diabetes,” said Trevor Orchard, professor of epidemiology, medicine and pediatrics at the University’s Graduate School of Public Health (GSPH) and senior author of the study. “Given our previous work linking insulin resistance to heart disease in type 1 diabetes, we wanted to evaluate whether adiponectin levels in these individuals might be predictive of future cardiac events.” Adiponectin has been closely linked with insulin resistance, a known risk factor for heart disease.

Adiponectin is one of the most abundant circulating proteins in human plasma, explained Dr. Orchard, who also is medical director of the nutrition lipid program at the UPMC, a clinic to which doctors refer patients with lipid metabolism disorders. “Adiponectin also seems to act as an anti-inflammatory molecule,” he said.

Investigators found that for people with type 1 diabetes, decreased concentration of adiponectin was associated with increased risk for coronary artery disease (CAD). “Interestingly, this effect was independent of conventional risk factors such as smoking, cholesterol levels or body weight,” said research associate Tina Costacou, the study’s first author. “Remarkably, it also was a better predictor than our markers for inflammation and insulin resistance, as well as other factors.”

For the newest evaluation, participants were identified from the Pittsburgh Epidemiology of Diabetes Complications Study, a 10-year prospective follow-up study of childhood onset type 1 diabetes mellitus. In the study, patients with CAD were matched with controls who did not have heart disease. Blood samples from 28 cases and 34 controls were matched for gender, age and duration of diabetes.

“Regardless of CAD status, higher levels of adiponectin were observed among female participants in comparison to their male counterparts,” said Costacou, explaining that adiponectin levels in blood samples from women averaged 20.8 micrograms per milliliter, versus 16.5 micrograms per milliliter for men. “This is a significant difference,” she said.

Even independent of gender, however, results of the Pittsburgh study suggest that adiponectin has a substantial protective role against CAD. “There was a remarkable 63 percent reduction in risk of CAD for each 6.3 microgram per milliliter increase in serum adiponectin levels,” said Orchard. “These results are striking despite the relatively small number of patients in the study. Our results – the first to show such a strong predictive power for heart disease prospectively in any population – raise the possibility that adiponectin concentration may prove not only a useful marker of cardiovascular risk, but also a potential therapeutic agent for prevention, particularly among high-risk individuals.”

The study was funded by the National Institutes of Health.

In addition to Orchard and Costacou, other authors are J.C. Zgibor and R.W. Evans, both of GSPH and researchers from LipoScience, Raleigh, N.C., the Medical University of South Carolina and the University of Vermont.

UPB publishes county health assessment

The Center for Rural Health Practice at Pitt’s Bradford campus has published the McKean County Community Health Assessment, which highlights priority health issues identified in residents of McKean County.

“This report is the culmination of a year’s worth of effort to analyze and prioritize the health issues faced here in McKean County,” said Michael Meit, director of the Center for Rural Health Practice. “Not only does it help us to better understand and address the issues that confront us, but it will be of use to all our community agencies as they plan health initiatives and seek additional resources to support these critical efforts.”

The research team, led by Ravi Sharma of the University’s Graduate School of Public Health, based its findings on data from a variety of sources including the U.S. Census Bureau, Pennsylvania Department of Health birth and death statistics, the Pennsylvania Cancer Registry and community focus groups. Also, the center sponsored the collection of additional data for McKean County through the Behavioral Risk Factor Surveillance Survey, which was conducted by the Centers for Disease Control and Prevention in cooperation with the Pennsylvania Department of Health.

Using these data sources, Sharma and the Health assessment team analyzed a variety of health status indicators, including the incidence of cancer, heart disease, high blood pressure, blood cholesterol, diabetes, child abuse and obesity; behavioral health risks, including cigarette smoking, the use of alcohol and other drugs, lack of exercise, late or no prenatal care, and poor nutrition; and health resources/access to services, including the availability of services through hospitals, physicians, public health, mental health/social service providers, dentists, family planning and long-term care facilities.

Support for the McKean County Community Health Assessment was provided by Bradford Regional Medical Center, Highmark Blue Cross/Blue Shield and the Center for Rural Health Practice through funds provided by Rep. John Peterson, R-Pa. Copies of the McKean County Health Assessment can be obtained by calling the Center for Rural Health Practice at 814-362-5050.

Potentially harmful caregiver behavior more likely in spouse

Potentially harmful caregiver behavior is more likely in spouse caregiving situations where recipients have greater needs for care and caregivers are more physically ill, cognitively impaired and are at risk for clinical depression, according to an article authored by Pitt researchers in the February 2005 issue of the Journal of the American Geriatrics Society (JAGS).

Caring for a sick or disabled relative has been linked to compromised caregiver health, and risk factors for negative caregiver outcomes have been studied extensively, according to authors Scott Beach, director of survey research at Pitt’s University Center for Social and Urban Research (USCUR) and Richard Schulz, professor of psychiatry and director of USCUR, along with other researchers from the University of Georgia and the University of Texas Southwestern Medical Center.

However, little attention has been given to care recipient and caregiver health as risk factors for potentially harmful behavior by informal caregivers, they said.

The researchers studied 265 caregiver/carerecipient dyads. Caregivers primarily were responsible for an impaired, community-residing family member 60 years or older who needed help with at least one activity of daily living or two instrumental activities of daily living. The researchers found the potential for breakdown, under certain conditions, of the typically nurturing caregiving situation that maintains or promotes the well being of sick or disabled family members. According to the JAGS article, such breakdowns appear likely when caregivers themselves suffer ill health when taking care of a sick or disabled spouse. The results suggest that the risk profiles for negative long-term caregiver outcomes are similar to those for potentially harmful behavior by informal caregivers.

The study was supported by the National Institute on Aging.

Minimally invasive stem cell procedure improves heart function in heart failure patients

Patients with severe congestive heart failure who had exhausted all other treatment options showed markedly improved heart function following a procedure in which their own stem cells were deployed directly into the heart by way of four tiny incisions in the chest, according to results of a trial presented recently at the 41st Annual Meeting of the Society for Thoracic Surgery.

The study, led by Amit N. Patel of Pitt’s McGowan Institute for Regenerative Medicine, is the first to use a minimally invasive surgical technique.

While preliminary, the results of the prospective randomized trial indicate that a minimally invasive approach to cell therapy is feasible for the estimated 40 percent of heart failure patients whose disease is unrelated to coronary blockages and who therefore cannot benefit from bypass procedures. Moreover, the experience so far suggests the novel stem-cell approach may be a viable treatment for these and other heart failure patients, reported Patel, director of clinical cardiac cell therapies at the McGowan Institute.

All 15 of the patients who received stem cell injections had some degree of improvement, some with dramatic results, while the conditions essentially remained unchanged in the 15 randomized to receive injections of their own blood serum.

“It is remarkable the level of improvement we’ve seen in these patients, who came to us with no other medical or surgical options available to them. However, we don’t yet fully understand how these cells work, whether they differentiate to become heart muscle cells or cells that promote vessel growth, or whether they serve as homing signals to other cells and substances that help with repair,” explained Patel.

The study took place at centers in South America. The research team obtained the necessary institutional and government health agency approval and each patient provided informed consent.

All 30 patients enrolled had severe heart failure (New York Heart Association heart failure classifications III and IV) with ejection fraction rates of less than 35 percent. Ejection fraction is a standard measure of heart function and is determined by the total amount of blood that the left ventricle pumps out per heart beat. A patient with good heart function has an ejection fraction of at least 55 percent.

Patients were scheduled to undergo the minimally invasive procedure but were unaware whether they would receive their own bone marrow stem cells or their own serum. Regardless, while under general anesthesia, each patient had bone marrow harvested from their hipbones. The cells believed to have the greatest therapeutic benefit, CD34+ cells, were isolated from the bone marrow and either injected into the hearts of patients randomized for therapy or placed in frozen storage if the patients were randomized to the control group. These patients received the same number of injections into the heart – about 25 to 30 – as the patients in the treatment group but instead of containing their stem cells, the injections were loaded with their serum. Neither group experienced any significant side effects or complications, including abnormal heart rhythms, which had been associated with other stem cell trials.

Prior to the study, the two groups had comparable ejection fraction rates. The treatment study group had an average rate of 26 percent, with the range between 21 and 34 percent, and the control group averaged 27 percent, with the range being 22 to 34 percent. Yet six months later, those receiving stem cells improved to an average rate of 46 percent, the lowest rate of improvement going up to 38 and the highest climbing to 52 percent. By comparison, the control patients average went up one percentage point, to 27, with a range between 22 and 31, indicating that some had worsening heart function.

With a six-month follow-up period now complete, the patients who had been randomized to receive the placebo treatment are now eligible to receive their own bone-marrow stem cells that had been kept frozen.

Last April, Patel reported the results of a trial looking at stem cell therapy given in conjunction with beating-heart bypass surgery for patients whose hearts were damaged by heart attack or chronic coronary disease. That study involving 20 patients also demonstrated the potential benefits of using a patient’s own bone marrow-derived stem cells to treat their ischemic heart disease.

Patel and his colleagues are in discussions with the U.S. Food and Drug Administration and hope to receive the agency’s approval to conduct a trial at the University that would involve giving stem cells to patients who are being implanted with heart assist devices. When a donor heart becomes available for transplantation, the native heart would be removed, allowing researchers the rare opportunity to look at the heart in its entirety and to more closely examine the effects of the stem cells.

If approved, the protocol will be performed under the umbrella of the newly established Center for Cardiovascular Cellular Therapy, a collaboration that includes the McGowan Institute, Pitt’s School of Medicine’s department of surgery, the University’s Schools of the Health Sciences and UPMC. The center will encompass clinical and research programs focused on the use of stem cells as an adjuvant treatment for a wide array of heart failure patients and for those with peripheral vascular disease.

In addition to Patel, co-authors include Robert L. Kormos of the McGowan Institute and researchers from the Benetti Foundation in Rosario, Argentina; the Asociacion Espanola Primera de Socorros Mutos in Montevideo, Uruguay, and Baylor University Medical Center in Dallas.

Trigger in brain plays key role in reproductive development

Puberty, that awkward phase when boys and girls are primed for their sexual reproductive years as men and women, appears to be triggered by the brain’s own version of “It takes two to tango,” whereby a signal literally gets turned on by a molecule that is produced by a gene aptly named KiSS-1.

The couple – a biochemical equivalent to Adam and Eve – makes its sudden appearance in a region of the brain called the hypothalamus just as puberty begins, according to a study published in this week’s online edition of the Proceedings of the National Academy of Sciences (PNAS).

Until now, little had been known about what instigates the cascade of hormone secretions that, over time, produces puberty’s tell-tale physical changes, including the development of breasts in girls and voice change in boys. As such, this research begins to answer one of the most vexing questions about human development: What causes puberty to begin? How is it that the full repertoire of reproductive hormones can exist at birth, go into hiding at about four to six months of age, then reemerge in full force some 10 to 12 years later?

“Puberty is critical to human development. And while there is a fairly good understanding of how the endocrine system regulates the hormones involved, just how and when the brain activates this process has been a great mystery. An appreciation of puberty’s deep-seated neurobiological mechanisms could, for instance, help prevent precocious or delayed puberty from occurring in some children,” noted the study’s lead author, Tony Plant, a professor in the departments of cell biology and physiology and obstetrics, gynecology and reproductive sciences, as well as director of the Center for Research in Reproductive Physiology at the University’s School of Medicine.

The research, performed in collaboration with teams at Harvard University’s Massachusetts General Hospital and the Oregon National Primate Research Center, builds on the discovery made independently by both Harvard and French researchers that a gene called GPR54 is defective in children with a rare disorder that inhibits puberty’s onset. To better understand what role GPR54 plays in the initiation of puberty, as well as learn about KiSS-1, which in earlier rodent studies had been identified as a molecule that activates a signal receptor of GPR54, the researchers looked to the nonhuman primate, the only animal with a reproductive system in common with the human’s.

“We now have very good evidence that the GPR54 gene and its switch, the kisspeptin protein molecule produced by KiSS-1, are key to the initiation of puberty, when GnRH is released,” Plant said. “However, it’s unlikely that they act alone. Other signaling systems, some of which have probably yet to be identified in humans, help control GnRH release in primates.”

Besides learning that GPR54 and KiSS-1 are expressed inside the hypothalamus of primates at the time of puberty, the researchers also found that by giving animals kisspeptin they could, essentially wake up the reproductive hormones from their childhood hibernation. Within 30 minutes of kisspeptin being administered to male monkeys, LH, one of the hormones stimulated by GnRH secretion, was no longer dormant, with levels 25-times higher than its baseline of zero.

In addition to Plant, other authors of the PNAS paper are Muhammad Shahab, formerly a fellow working with Plant and now with the department of biological sciences at Quaidi-i-Azam University in Islamabad, Pakistan and researchers from the division of neuroscience at the Oregon National Primate Research Center, the reproductive endocrine unit at Harvard’s Massachusetts General Hospital.

Their research was supported by the National Institute of Child Health and Human Development of the National Institutes of Health.

Magee picked for national breast health  outcomes study 

Magee-Womens Hospital today announced it is one of 11 sites in the country selected to participate in the SEDE (Serial Evaluation of Ductal Epithelium) trial whose goal is to learn more about breast health over time in women at increased risk for developing breast cancer.

The SEDE trial will follow high-risk women over five years and collect information about changes in their breast health using a procedure called ductal lavage, which is a minimally invasive method of collecting cells from the breast milk ducts. These cells are then analyzed to determine if they are atypical.

“More than 95 percent of breast cancers originate in the milk ducts of the breast,” said Victor G. Vogel, principal investigator of the trial and director of the Breast Cancer Prevention Program of Magee-Womens Cancer Program of UPMC Cancer Centers. “By the time these early duct cell changes grow into a tumor large enough to detect on a mammogram, several years have passed. In this study, we will follow high-risk women over several years to examine the role these changes play in determining their chances of developing breast cancer.”

The five-year study will examine 906 women across the country. Women interested in participating in the study — offering free physician monitoring and exams, including ductal lavage – must be between the ages of 35-65; have a family history of breast cancer (multiple family members) or other known risk factors, and have no personal history of breast cancer.

Participants will need to visit the hospital about every six months to have clinical breast exams, nipple aspiration and possible ductal lavage for approximately three years. For the final two years of the study, information will be gathered on participants’ overall health, especially breast health.

The study is funded by Cytyc Corp., a medical device company that designs, develops, manufactures and markets products primarily focused on women’s health. For more information about the SEDE trial, call (412) 641-1302 or (888) KNOW RISK.

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