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April 3, 2003


Pitt receives $2.5 million for NIH-funded study of heart disease in lesbians

Pitt has received a $2.5 million National Institutes of Health (NIH) grant to study risk factors for coronary heart disease (CHD) in lesbians. This is the first such study of its kind and will focus on the physiological, behavioral and psychosocial factors related to the development of CHD.

Epidemiologists Deborah J. Aaron, School of Education, Nina Markovic, School of Dental Medicine, and Michelle E. Danielson, Graduate School of Public Health, are co-researchers for “Cardiovascular Disease Risk Factors and Sexual Identity in Women” and members of the Center for Research on Health and Sexual Orientation at Pitt.

“This is the first large-scale, clinic-based study examining the risk of heart disease in lesbian women funded by the National Institutes of Health,” said Suzanne Haynes, senior science adviser at the Office of Women’s Health, Department of Health and Human Services, Washington, D.C. “Five years ago, the Institute of Medicine identified research priorities for lesbian health. The first priority was to conduct research that would lead to a better understanding of the physical health status of lesbians. Heart disease is the No. 1 cause of death in all women, and the funding of this project by the National Heart, Lung and Blood Institute is truly a landmark event in developing a better understanding of the risk of heart disease in lesbians.”

There has never been a comprehensive examination of CHD risk in a large sample of women who identify themselves as lesbians or how their pattern of risk factors or overall risk for CHD may differ from demographically similar heterosexual women.

The Pitt project, to be conducted over a four-year period, will examine the potential differences in the prevalence and pattern of risk factors for CHD in 1,000 women, 500 self-identified lesbians and 500 heterosexuals. The women will be matched for age, socioeconomic status and ethnicity.

The study is funded completely by the NIH’s National Heart, Lung and Blood Institute.


Grant received for Mongolia studies

The Asian Studies Center of the University Center for International Studies and the University Honors College have been awarded a curriculum development grant for studies in Mongolia by the Fulbright-Hayes Committee of the U. S. Department of Education.

The Honors College has enjoyed an expanding range of institutional liaisons in Mongolia through its summer field projects for Pitt undergraduates.

Titled “Contemporary Mongolia,” the $66,000 project involves four weeks of research and consultation in Mongolia by post-secondary faculty from around the United States seeking to add Mongolian studies to their undergraduate curricula. The 10 selected faculty participants in “Contemporary Mongolia” will meet with Mongolian academic colleagues in Ulaanbaatar and conduct research throughout Mongolia in a wide range of disciplines to enlarge U.S. undergraduate curricula with Mongolian case studies.

The grant covers all expenses and includes in-country briefing sessions, field trips and access to library holdings as well as curriculum development sessions conducted by Asian studies and Honors College staff.

“Contemporary Mongolia” encompasses four components: pre-departure preparation consisting of independent study kits and annotated bibliographies created by an Asian studies bibliographer; a four-week segment of field research and materials acquisition in Mongolia conducted by the American Center for Mongolian Studies, the North American Mongolian Business Council, the Honors College and Asian studies; an in-country segment of curriculum development to organize and synthesize materials and to conceptualize themes on general issues regarding international studies and globalization, and a phase of curriculum sharing and dissemination in which a web-based archive of materials and research findings will be created for other scholars interested in adding Mongolian studies to their undergraduate curricula.

The project extends from July 17 through Aug. 14, 2003. Participants will be chosen on a rolling basis through their application to the Honors College. Interested applicants should contact Amy Eckhardt at 412/624-6881, or send an e-mail to


Failures in cloning of primates may signal impossibility of human reproductive cloning

Fundamental flaws in embryonic development may make therapeutic cloning of nonhuman primates difficult, and reproductive cloning of primates — nonhuman and human alike — impossible, a team of researchers from the Pittsburgh Development Center reported in last week’s issue of the journal Science.

Basic molecular obstacles were observed that blocked normal cell development despite the use of four different techniques of nuclear transfer, according to Gerald P. Schatten, senior author of the study and director of the Pittsburgh Development Center at the Magee-Womens Research Institute.

In therapeutic cloning, limited cell division is induced in an unfertilized egg cell to produce embryonic stem cells. In reproductive cloning, an egg cell with a donor nucleus is implanted into a living surrogate female in an attempt to make a successful pregnancy.

“The chromosomes do not split properly,” said Schatten, who also is professor and vice chairman of the departments of obstetrics, gynecology and reproductive sciences and of cell biology at Pitt’s School of Medicine. “From the very first cell division, development is inappropriate in vital ways.”

In the current study, Schatten and his colleagues used known methods of nuclear transfer on 724 eggs retrieved from female rhesus macaques. Although 33 embryos were transferred into surrogates after initial cell division, no pregnancies were established. Imaging of DNA and basic cell structure revealed that while cell division continued in a superficially normal manner, chromosomal problems existed within each individual cell.

“We used antibodies to tag the cell proteins and DNA so that we could track progress,” said Calvin Simerly, associate professor of obstetrics, gynecology and reproductive sciences at Pitt and the paper’s first author. “When cells divide, there are very basic things that are supposed to happen, and they just didn’t happen.”

Among the key structures involved in cell division is the mitotic spindle, which functions to precisely align and separate chromosomes. However, in cells originating as a result of nuclear-transfer, examination of spindle configuration revealed chaotic structures and unequal chromosome counts. Even the most basic proteins involved in spindle formation were absent or inadequate, said Simerly, who also is an investigator with the Pittsburgh Development Center.

“Current techniques such as those used to create Dolly the sheep, mice and other domestic animals do not work in nonhuman primates,” added Schatten. “I don’t want to say that this will never happen. Given enough time and materials, we may discover how to make it work. It just doesn’t work now.”

In addition to Schatten and Simerly, researchers who contributed to the study are Christopher Navara, Kowit-Yu Chong, Laura Hewitson, Gabriella Gosman, Saviero Capuano and Christopher Payne, all of the Pittsburgh Development Center; Tanja Dominko of CellThera in Worcester, Mass., and Duane Compton of Dartmouth Medical School.

The study was funded in part by the National Institute of Child Health and Human Development; the National Center for Research Resources; the National Institute of Environmental Health Sciences, and private philanthropy.


Trial indicates spray improves lung function in transplant patients

An aerosol form of the anti-rejection drug cyclosporine allows for improved lung function in lung transplant patients, according to researchers at the University of Pittsburgh Medical Center (UPMC) who presented their findings April 10 at the annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation (ISHLT).

Patients whose lungs were capable of depositing greater amounts of the drug had better lung function over the course of the two-year study than those who deposited less after inhalation or than patients who inhaled a spray with a placebo drug, researchers reported. 

Their results, obtained in a study of 15 patients, are the first to emerge from a larger, multi-year clinical trial looking at the effectiveness of aerosol cyclosporine spray, which is inhaled directly into the lungs, for the prevention of rejection in lung transplant patients.

It is the only study of its kind involving an anti-rejection drug designed to be delivered directly to the tissue of a transplanted organ. The concept was developed and the clinical trial initiated more than 10 years ago at Pitt by Aldo T. Iacono and Bartley P. Griffith.

“We plan to examine several endpoints in our study, including whether aerosolized cyclosporine is an effective method to prevent rejection, causes fewer systemic side effects and has a positive impact on organ function,” said Iacono, principal investigator of the study. “There is reason to believe that this drug, when given in addition to systemic immunosuppression, may im-prove overall outcomes for lung transplant recipients who received the drug compared to patients given placebo, and final results are being analyzed.

“However, this most recent analysis — our first from the 68-patient study — indicates that aerosol cyclosporine specifically enhances lung function in patients who deposit higher concentrations of the drug,” added Iacono, who is associate professor of medicine and surgery and director, pulmonary transplant medicine at UPMC.

The general hypothesis behind the Pitt clinical trial is that an aerosolized form of the standard immunosuppressant agent cyclosporine will achieve higher concentrations in the transplanted lung than through intravenous or oral means, thus preventing rejection more effectively. In addition, inhaling the drug directly into the lungs may make it less likely that systemic infections or complications such as kidney toxicity would occur. Because the drug deposits itself inside the lungs, it coats the tissue in a manner akin to a topical corticosteroid that is applied to skin. 

In the study, researchers looked at 15 single-lung and double-lung transplant patients who were randomized to receive aerosol cyclosporine as an adjuvant therapy along with standard oral immunosuppression, most often tacrolimus. While immunosuppressive agents generally are given beginning at the time of transplantation, the aerosol cyclosporine was introduced approximately six weeks after transplantation once patients were medically stable and able to use a nebulizer, a device similar to an inhaler, that delivers the spray.

As part of the trial, patients underwent the 30-minute treatment — breathing the mist containing aerosolized cyclosporine in a mixture with propylene glycol to help deliver the drug — three times a week for two years. They were then followed for an additional two years. 

To examine how much and where the drug was being deposited in the lung tissue, researchers performed a one-time imaging study about six months after transplantation, whereby a radioactive isotope was added to the nebulizer to allow visualization of the drug inside the lungs and surrounding tissues.

“Because anatomy and physiology differ from patient to patient, the drug is deposited in tissue in varying degrees,” said Timothy E. Corcoran, a research assistant professor of medicine and bioengineering at Pitt’s schools of medicine and engineering, who reported the findings at the ISHLT meeting.

Although each patient was given about the same cyclosporine dose (300 mg), single-lung transplant recipients absorbed between 2.2 and 9.2 percent of the dose (mean 6.2 percent) in their transplanted lung and double-lung transplant recipients deposited between 3.3 and 7.1 percent (mean 5.4 percent). 

How much of the drug found its way into the lungs, particularly in the far reaches of the tissue, correlated with lung function. Researchers determined such changes in lung function by using a patient’s best lung function test performed within 100 days after transplantation and making comparisons every 100 days, up to 700 days after transplantation.

Patients who deposited at least 5 mg of the drug showed significant improvement in lung function over time, whereas patients who deposited less than 5 mg and patients who were given an aerosol spray containing a placebo drug demonstrated decline in lung function over the same period. For instance, single-lung recipients who deposited at least 5 mg of the drug showed a 15 percent improvement at 200 days and a 25 percent improvement in lung function by 600 days. Patients who absorbed less of the drug or received placebo had a steady decline in lung function of up to 10 percent below their baseline function by day 600.

The researchers are working to develop techniques that will enhance deposition of the aerosol cyclosporine so that all transplant patients can have maximum benefit from the treatment.

“Aerosol cyclosporine appears to have a cumulative positive effect because there was a significant correlation between improvement in lung function tests and dose at all time points studied. Furthermore, the percentage change in lung function increased with each milligram of drug deposited in the periphery of the lung,” reported Corcoran, a biomedical engineer and expert in aerosol drug delivery.

In addition to the lung function study, other results from the aerosol cyclosporine trial presented at the ISHLT meeting found that patients who developed post-transplant lymphoproliferative disease (PTLD), a complication from immunosuppression involving tumor growth that is often fatal, fared much better if they were being treated with the spray. The usual treatment for PTLD is to reduce radically or eliminate immunosuppression until the tumors disappear, but rejection of the transplanted organ can result. Aerosol cyclosporine afforded clinicians with the option of halting oral, or systemic immunosuppression, while continuing aerosol delivery directly to the lungs, thereby decreasing the likelihood that rejection would occur or lung function would suffer. Five of seven patients who developed PTLD survived, compared to seven patients from an earlier era who all died, reported Sebastian Gilbert, a resident in cardiothoracic surgery; Kenneth R. McCurry, assistant professor of surgery and director of lung and heart-lung transplantation, and others from UPMC.

In addition to Iacono and Corcoran, other authors of the lung function study include McCurry; Adriana Zeevi, James H. Dauber, Diedre A. Smith, Gilbert Burckart and Wayne F. Grgurich, all from UPMC; Gerry C. Smaldone of State University of New York, Stony Brook; and Bartley P. Griffith, formerly at UPMC, and now at the University of Maryland.

The aerosol cyclosporine trial was supported by grants from the National Heart, Lung and Blood Institute and the American Lung Association. Novartis Pharmaceuticals Corporation provided the researchers with cyclosporine powder, which was used to produce the aerosolized form of the drug.


Pitt dental researchers to study oral health disparities in Appalachia

Researchers from Pitt’s School of Dental Medicine, in cooperation with West Virginia University’s School of Dentistry, have received a seven-year, $6.3 million grant from the National Institute of Dental and Craniofacial Research to determine factors that contribute to oral health disparities in Appalachia.

It’s the largest NIH grant ever made to the Pitt dental school.

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. 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.

“The population of Appalachia has the worst oral health in the United States, but we don’t know what the specific causes of these disparities are,” said Mary L. Marazita, associate dean for research and head of the Division of Oral Biology at Pitt’s dental school and professor of human genetics. “The primary reason we don’t know the causes is that there has never been a study done in this population.”

Through the grant, researchers will evaluate patients in existing Rural Health Consortium Clinics in Webster and Nicholas counties in West Virginia. Information will be gathered from a cross-section of families from the area 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. Through this information, researchers hope to identify as many risk factors as possible.

“We don’t know why the people of Appalachia experience such a high incidence of oral disease. It could be for environmental, social, economic or genetic reasons,” said Marazita. “But once we isolate the cause or causes, we can better treat the population and implement oral disease prevention programs, hopefully reducing the oral health disparity in Appalachia.”

Other researchers on this grant include Pitt’s Robert Weyant, Thomas Hart, Ralph Tarter and Walter Bretz, as well as several West Virginia University professors.


Protected stenting may be good alternative for high-risk patients with carotid stenosis

In high-risk patients with carotid stenosis, placement of a stent with an umbrella-like filter to open the carotid artery may be a safer alternative to endarterectomy surgery, according to a study presented by a University of Pittsburgh Medical Center (UPMC) physician, at the recent meeting of the American College of Cardiology.

“Our study found that using a stent with a filter resulted in an almost 50 percent reduction in stroke in high-risk patients, when compared to endarterectomy surgery,” said study coordinator Mark H. Wholey of UPMC. “This study represents a nationally growing trend toward a less invasive, less-expensive procedure than conventional endarterectomy surgery, which entails anesthesia, a longer hospital stay and 5 to 9 percent incidence of cranial nerve palsy, and which is basically a more expensive procedure.

“The overall stroke rate after 30 days was only 5.3 percent. The 30-day total major adverse event rate, defined as all-cause stroke, death and myocardial infarction, was 7.8 percent. Most of the strokes were minor and the patients recovered to normal baseline within 30 days. Only 1.4 percent of the patients had major disabling stroke,” Wholey said.

The aim of the multi-center clinical trial was to assess the safety and efficacy of the Acculink carotid stent system and filter device in the treatment of high-risk surgical patients and non-surgical patients with carotid stenosis.

Carotid arteries supply blood to the brain. When they become narrowed by plaque, blood flow to the brain is reduced, which increases the risk of stroke. A surgical procedure called endarterectomy is performed to remove the blockage and re-open the arteries to increase blood flow to the brain.

In the stent procedure, a small flexible catheter with a metallic stent positioned at the end is placed in the narrowed region of the carotid artery. The stent, when deployed, expands and compresses the plaque against the blood vessel wall, thereby enlarging the opening in the carotid artery and maintaining blood flow to the brain. When the catheter is removed, the stent remains in place as a fixed scaffold to keep the artery open. During this study, a filter device was inserted between the stent and the brain to catch particles and debris from the clot and prevent them from flowing into the brain. In the study, debris was present in 50 percent of the filter baskets that were evaluated microscopically.

In the study, called the ARCHeR (Acculink for Revascularization for Carotids in High Risk Patients) trial, all of the participants had at least one risk factor that made them poor surgical candidates and approximately 45 percent of the patients had two or more of these risk factors. A significant number of patients had prior endarterectomy and recurrent stenosis following the surgery. Many patients had the opposite carotid artery occluded and totally blocked, and the lesion site also had a very high grade narrowing of 80 percent or greater.

The mean age of the 437 study participants was 69 years. High-risk characteristics of the patients included unstable angina (26 percent), diabetes (39 percent), hypertension (83 percent) and high cholesterol (68 percent). Of the participants, 28 percent had a previous stroke and 28 percent had a heart ejection fraction of less than 30 percent. All others had renal failure, advanced chronic lung disease and prior heart surgery. Patients were assessed by an independent neurologist prior to the study and during follow-up.

“We hope the results of this study will establish less-invasive carotid stenting as an important therapy for this large group of high risk patients suffering from carotid artery disease who are not candidates for standard carotid surgery,” said Wholey.

Wholey is chairman of the Pittsburgh Vascular Institute at UPMC Shadyside and a principal investigator for the ARCHeR trial. He reported these results at the American College of Cardiology meeting in Chicago on March 30.

The study was sponsored by Advanced Cardiovascular Systems Inc., a subsidiary of Guidant Corporation.


Increased osteoporosis risk linked to stomach reduction surgery

Women and men who have stomach reduction surgery to lose weight may be losing bone even when they take daily calcium supplements, putting them at risk for osteoporosis and bone fracture.

These findings from a Pitt study were presented April 13 in San Diego at the American Society of Nutritional Sciences program, part of the Experimental Biology 2003 meeting.

“While previous studies in the early days of stomach reduction surgery found bone loss following major weight loss, our current study found something surprising — that daily supplements of 1,000 mg of calcium and a vitamin D-rich multivitamin do not prevent the imbalance in bone cell turnover in post-surgical patients resulting in subsequent bone loss,” said the researcher who presented the results, Penelope Coates, postdoctoral fellow at the University of Pittsburgh Medical Center’s Osteoporosis Prevention and Treatment Center.

Study participants included 18 women and nine men who had undergone successful stomach reduction operations 10 months before and a control group of morbidly obese men and women who were waiting for the same type of surgery.

Measurements of certain metabolic proteins in the urine showed that the heavier, pre-operative patients were keeping their bone cells in balance, with new cells replacing old cells in equal amounts — a normal and continuous process in healthy adults. On the other hand, the post-operative research participants, who had been losing 8-10 pounds a month since their surgery, showed significant imbalance in bone turnover, with the regeneration of new cells lagging behind the destruction of old cells.

Coates and her colleagues then followed six individuals from the control group, measuring blood proteins and getting bone density readings at the hip and spine before their surgery and at three and six months following surgery. The researchers found that at six months, the study participants experienced up to an 8 percent drop in bone density in their hips. While such a difference can be normal for people losing significant amounts of weight, it could have devastating effects if the bone loss continued at that rate while a person continued to drop pounds.

Researchers also found that those who lost the most weight had the greatest imbalance in bone turnover, placing that group at greatest risk of bone loss and osteoporosis. Age, sex and hormone status, including whether women were pre- or post-menopausal, were not factors.

Coates and the research team are now trying to determine if the weight loss itself causes the problem or if the patients who lost the most weight are less efficient in absorbing calcium.

“Regardless of the reason for the imbalance in bone turnover, this study sends a clear message that major weight loss requires ongoing calcium and vitamin supplementation, as well as early and regular monitoring for bone loss,” Coates said. “These are young patients, and many of them have 40 or 50 years of life in front of them. At a time when they are losing weight and looking forward to new opportunities, they don’t want to have problems with osteoporosis.”

The researchers will soon begin a larger longitudinal study at the University of Pittsburgh Medical Center’s Osteoporosis Prevention and Treatment Center to further investigate bone loss in individuals who undergo stomach-reduction surgery.


Researchers get grants from state

Pennsylvania’s Department of Health has awarded grants totaling nearly $210,000 to scientists doing research to fight breast and cervical cancer. The grant recipients include three Pitt researchers, each of whom was awarded $35,000:

• Susanne Gollin of the Graduate School of Public Health for the project, “Dissection and Characterization of the Mechanism of 11q13 Gene Amplification in Breast Cancer Cells.”

• Elieser Gorelik of the School of Medicine’s pathology department for “Combined Antiangiogenic and Immune Therapy of Breast Cancer.”

• Baskaran Rajasekaran of the medical school’s molecular genetics and biochemistry department for “Proteolytic Activation of BRCA 1 Function.”

Funding for the grants was provided by Pennsylvanians who donated a portion of their state income tax refunds to the Breast and Cervical Center Research Fund or who made personal donations.

Of the five donation options on Pennsylvania’s income tax form, the Breast and Cervical Cancer Research Fund received the greatest number of contributions (23,000) for a total of $175,250. Rollover funds from the previous tax year increased the grants total to nearly $210,000.

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