University Times

Grants awarded to researchers

The National Institute of Mental Health has granted social work professor Carol Anderson $321,622 to create an infrastructure to facilitate mental health research careers of social work faculty. Her work will address three areas: coercion and adherence in the seriously mentally ill, help-seeking and barriers to mental health treatment in women and families, and a pathway to care for the undiagnosed population at risk.

The engineering school's Thomas J. Cain has been awarded $750,000 from the Pennsylvania Department of Community and Economic Development to administer a program supporting the continuing education component of the Pittsburgh Digital Greenhouse's Electronic Design Education Program.

The National Heart, Lung and Blood Institute has granted $555,865 to psychology professor Stephen Manuck for biobehavioral studies of cardiovascular disease.

Jonathan Wolff of the University Center for International Studies has received a $432,103 Freeman Foundation grant to promote greater understanding of Asia by providing opportunities for more Pitt students to study Asian languages, cultures and civilization; by sharing expertise with the community through an outreach program, and by improving use of electronic media to enhance access to resources concerning Asia.

The National Institute of Environmental Health Sciences has awarded $673,602 to the medical school's Reza Zarnegar to study hepatocyte growth factor gene transcription and function in the liver.

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NIH grant awarded to musculoskeletal research center

Savio L-Y. Woo, the A.B. Ferguson Professor of Orthopaedic Surgery and director of Pitt's Musculoskeletal Research Center (MSRC), together with James Wang, co-director of the Mechanobiology Laboratory, has been awarded a $2.1 million grant by the National Institutes of Health for a project, "MCL Healing: Interdisciplinary Studies."

The research project also is in collaboration with Chris Niyibizi of the MSRC's Ferguson Lab and consultants Leaf Huang of Pitt, Cy Frank of the University of Calgary, Canada, and Stephen Badylak of Purdue University. Together, they will use new and innovative approaches including antisense gene therapy on Type III & Type V collagens and functional tissue engineering techniques involving the use of small intestinal submucosa (SIS) to improve the healing of injured knee ligaments.

This is the third time the NIH has renewed this project. It began more than 20 years ago when Woo received funding for 15 years from the Veterans Administration in San Diego to study the function of knee ligaments, including the determination of fundamental tissue properties and how they are influenced by various biological factors.

Concurrently, this research established a foundation for accurate and repeatable experimental protocols by studying the effects of multiple experimental factors. This was followed by a series of studies involving the development of a ligament rupture model in animals to investigate the time course of healing in response to different treatment modalities. These studies have shaped current clinical management of ligament injuries including the important concept of "controlled motion is good" after MCL injury and that surgical repair of a ruptured MCL has no benefit.

Scientifically, a major finding of this research was that healing ligaments result in a greater quantity of a lesser quality tissue. Therefore, recent efforts have focused on the use of growth factors, gene therapy and cell therapy as methods to improve ligament healing and perhaps the possibility to regenerate ligaments

By using novel tools that include antisense gene therapy and SIS scaffolds, this most recent NIH competitive renewed grant will attempt to restore the biochemical composition and tissue organization of the healing MCL to normal levels. Further, it is hoped this work will lead to a greater understanding about the roles of collagen types III and V, collagen fibrillogenesis, and collagen orientation during wound healing.

With the recently renewed grant, total NIH funding for the MSRC exceeds $10 million dollars.

MSRC was established in 1990 as an interdisciplinary research center in the Department of Orthopaedic Surgery. It cultivates bioengineers, biologists and surgeons to work together to solve clinical orthopaedic problems.

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OCD to provide research data

Pitt's Office of Child Development (OCD) will be providing evidence-based research on the state's childhood care and education delivery system to Pennsylvania's new Early Care and Education Task Force, created last month by Gov. Mark Schweiker.

Pitt's OCD, Penn State's College of Health and Human Development, and Temple University's Center for Public Policy have formed a University Children's Policy Collaborative, which will examine existing and potential programs and services for children from birth to age 8 and then make recommendations to the 33-member task force.

Each university will explore a different component: The Penn State research team will observe activity at 400 early childhood sites, Temple will conduct a survey of Pennsylvania parents who are consumers of early childhood services, and Pitt's OCD research will be three-pronged — a review of national research literature to assess best practices; a statewide survey of providers of early childhood services, and a survey of organizations, colleges and universities that train professionals in early childhood services.

"This is a wonderful opportunity for the universities to work together and to provide the state with balanced, nonpartisan information on early childhood services," said Robert McCall, who, along with Christine Groark, is co-director of OCD. Other OCD personnel assisting with the project are Robert Nelkin, director of policy initiatives; Wendy Ethridge, project manager for policy initiatives, and Pitt graduate student Kelly Mehaffie.

The task force will issue two reports to Schweiker this fall that will contain evidence-based, cost-effective strategies that can be passed on to the next administration.

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Habitat size determines productivity/diversity relationship

The size of the habitat is crucial to determining the relationship between the biodiversity and the individual productivity of species, according to a study by scientists at Pitt and the University of Chicago. The study was published in the March 28 edition of Nature.

Jonathan M. Chase, an assistant professor of community ecology in Pitt's Department of Biological Sciences, and Mathew A. Leibold, of the University of Chicago, studied wetland plants, both submerged and emergent, and wetland animals — amphibians and invertebrates such as insects and snails — near the Kellogg Biological Station run by Michigan State University. Chase found similar patterns at Pitt's Pymatuning Laboratory of Ecology near Linesville, Pa.

"Ecologists have long recognized that species diversity in a particular site is affected by many factors, but that primary productivity is one of the most important," said Chase. "Primary productivity is often determined by available nutrients, light, rainfall and the like. However, there is a lot of confusion and controversy about just how diversity varies with productivity."

Ecologists define primary productivity in flora as the efficiency of collecting carbon, in the form of carbon dioxide, through photosynthesis. Chase and Leibold found that in small habitats, the productivity/diversity relationship followed a hump-shaped pattern where species diversity increases at first, then declines as the primary productivity increases. In larger habitats, the researchers found that the relationship followed a steady increase, with no subsequent decline.

Researchers define a small-scale habitat as being a small pond, for instance, and a large-scale habitat as a series of ponds in a watershed that could be as large an area as a county or state.

"This 'scale dependence' happens because small communities become more different from one another as productivity increases, and thus the entire diversity of the large scale increases, even though the diversity on the small scale decreases," Chase explained. "Our work was in wetlands, but similar results are likely to hold in a variety of different types of ecosystems. In addition, our work might help to explain large patterns such as the increases in species diversity as you move to the tropics."

The natural inclination to always associate higher productivity with more diversity is not the case, and Chase said that several recent studies of small-scale habitats do not support that assumption.

"For example, if one species is very productive, it might be able to 'steal' all the resources, and biodiversity would be very low," he said. "At very low productivity, there are very few species. At intermediate productivity, more species can exist, but at high productivity, a few species can use all of the resources, and biodiversity gets low again. However, we found things are different when you look at a different spatial scale, like a whole watershed of several ponds. Here, diversity increases consistently as productivity increases.

"So, the main question is, 'How can diversity go down at high productivity at the small scale, but continue to increase at the larger scale?' We found that it could do this because the types of species that lived in different high productivity ponds were highly variable," Chase continues. "In some ponds, a group of species lived together, but in nearby ponds, an entirely different group of species lived together. So, if you add the two groups up, you get high biodiversity, even though in a single pond, there was low biodiversity. This clarifies the dilemma of why diversity goes down with increasing productivity in small-scale habitats, but goes up in large-scale ones."

Chase said his work with Leibold holds several implications for understanding the effects that humans have on the environment.

"Many human actions, such as fertilizer runoff from farmers' fields, increase the amount of nutrients that enter wetlands. Our work helps us to understand what the effects of these actions might have for species diversity of plants and animals within single ponds and within entire watersheds."

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Test identifies patients at risk for severe organ rejection

A simple blood test takes much of the guesswork out of predicting who is at risk for severe organ rejection, according to results of two Pitt studies.

The test, called ELISA (enzyme linked immunosorbent assay), indicates if a patient has specific antibodies that are trained to fight the presence of foreign antigens.

According to results in studies of pediatric heart and adult lung transplant patients, ELISA does a better job of identifying patients with sensitized immune systems than the widely used, less sensitive test called PRA based on lymphocytotoxicity, which determines a percentage of panel reactive antibody. Having more reliable information may help clinicians tailor therapies to prevent rejection from actually occurring.

Indeed, in a retrospective study of pediatric heart transplant patients, four of the five "rejecters" were not identified as being sensitized by conventional PRA.

"ELISA identified children not considered sensitized by conventional PRA yet who are clearly at risk for rejection. Knowing in advance who may warrant more intense immunosuppression following heart transplantation is very useful clinical information," explained Sabrina Tsao, a cardiology fellow with the pediatric heart transplant program at Pitt's School of Medicine and Children's Hospital of Pittsburgh.

Using blood samples of 36 patients obtained within a month before transplantation, researchers performed the ELISA test to see if results correlated with their actual clinical course. They found that ELISA determined 10 of 36 patients were susceptible to organ rejection. Five of these 10 actually developed severe rejection within a month, compared to three of the 26 negative-ELISA patients who developed rejection.

"Having this information before transplantation might have changed how we treated patients prone to rejection. While we'll want to study a greater number of patients, the results of this study suggest ELISA should be part of our routine clinical care," added senior author Steven A. Webber, associate professor of pediatrics at Pitt's medical school and director of the pediatric heart and lung transplant program at Children's Hospital of Pittsburgh.

Eight of the 10 ELISA-positive patients had congenital heart disease and probably were more sensitized to certain antigens because of blood transfusions received during past open-heart surgeries.

In a similar study involving 75 adult lung transplant patients who underwent ELISA testing after transplantation, six of 14 deemed positive developed persistent, acute rejection within the first 100 days of transplantation compared to nine of 61 who were negative. Similar results were obtained at follow-up periods up to a year.

ELISA is a simple test that takes about four hours to obtain a positive or negative result. Blood drawn from the patient contains the patient's own unique antibodies, which are put into contact with known human leukocyte antigens (HLA), molecules on the surface of all cells that characterize each person as unique and enable the immune system to recognize both self and foreign antigens. If the patient's antibodies bind with any of the antigens, then the test is considered positive.

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Value found in new way to report cervical abnormalities

New practitioner guidelines on the management of women with suspicious cellular changes identified during gynecological exams should improve screening methods to more easily detect significant changes that could lead to cervical cancer, according to a consensus statement published in last week's Journal of the American Medical Association.

Called the 2001 Bethesda System, the guidelines were formulated in part based on results from a large, four-center trial known as the ASCUS/LSIL Triage Study, or ALTS, which determined that testing women with mildly abnormal cellular changes for the presence of the human papillomavirus (HPV) is an important indicator of a more serious condition needing more aggressive treatment.

"Everyone agrees on how to manage high-grade disease," said Richard Guido, an assistant professor of obstetrics, gynecology and reproductive sciences at Pitt's School of Medicine and principal investigator of the ALTS study at Magee-Womens Hospital. "But with more subtle changes, the options are often up to the individual practitioner. These guidelines should help to illuminate the question."

ASCUS and LSIL are acronyms for two mild abnormalities detected in gynecological screening tests known as atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. The 2001 Bethesda System guidelines also shorten ASCUS to ASC, for atypical squamous cells.

The Papanicolaou, or Pap test, has been used since the 1950s in the United States as a screening tool to help detect cellular abnormalities in the cervix. Approximately 20 million Pap smears are performed annually in this country, said Guido.

Until now, most women with ASCUS results could be advised to undergo repeat Pap testing at specified intervals, even though such mild abnormalities often will disappear without treatment. What the ALTS study found, however, was that subsequent HPV testing could identify virtually all of the cases requiring immediate attention. Those women with mild changes detected by Pap who were HPV-positive were much more likely to have undetected precancerous conditions or cancer.

In 1996, the U.S. Food and Drug Administration approved a liquid-based screening test that some studies have shown to be more accurate at detecting precancerous cervical lesions. Nationwide, about 60 percent of screening exams now involve the liquid-based test, which can include follow-up HPV screening from the same sample without recalling the patient for another visit.

According to the Centers for Disease Control and Prevention in Atlanta, nearly 13,000 women are diagnosed with cervical cancer each year. Early detection efforts have substantially reduced the death rates from this cancer, but more remains to be done, CDC officials note. More than 4,000 women are expected to die of cervical cancer yearly, largely because they failed to take advantage of, or lacked access to, available screening.

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Research presented at heart assn. conference

Researchers from Pitt's Graduate School of Public Health presented study findings at the American Heart Association's 42nd annual Conference on Cardiovascular Disease and Epidemiology Prevention, April 23-26.

Presentations included the following:

Controlling systolic blood pressure early prevents heart disease in elderly

Hypertensive elderly individuals who begin blood pressure therapy before signs of heart disease appear may completely avoid the associated cardiovascular problems, according to Kim Sutton-Tyrrell, associate professor of epidemiology.

"We found that elderly individuals with untreated systolic hypertension are three times more likely to experience adverse cardiovascular events like heart attack, angina, stroke or heart failure than are elderly individuals with normal blood pressure," said Sutton-Tyrrell. "However, hypertensive study participants who underwent treatment for their high blood pressure greatly reduced their risk of adverse cardiovascular events, particularly if they were still free of detectable disease when they initiated treatment."

The Pittsburgh study consisted of 134 participants taking hydrochlorothiazide, a diuretic commonly prescribed for systolic hypertension (the "active" group), and 134 taking a placebo.

Polycystic ovary syndrome can lead to coronary artery calcification

Women with polycystic ovary syndrome (PCOS) are at risk for premature calcification in their coronary arteries — an early indication of cardiovascular disease, according to Evelyn O. Talbott, professor of epidemiology and principal investigator on the study. However, controlling weight and insulin sensitivity may reduce the risk.

PCOS, characterized by menstrual irregularities, chronic anovulation, excess hair growth and infertility, is a common reproductive endocrine disorder affecting 5 percent of the female population. Women with PCOS also experience several metabolic abnormalities, including insulin resistance, increased circulating insulin levels, abnormal blood lipid levels and increased central obesity ("apple body shape"). Until recently, PCOS was not recognized as a single, multi-dimensional disorder. Women suffering from it were instead treated for individual symptoms, particularly irregular menstrual periods and infertility.

"Preliminary results from our study suggest an association between the metabolic abnormalities experienced by women with PCOS, collectively termed metabolic Syndrome X or metabolic cardiovascular syndrome, and premature atherosclerosis in the coronary arteries," Talbott said. Coronary calcium deposits are an indicator of early, subclinical cardiovascular disease.