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March 4, 1999


Nursing prof receives grant to study medication adherence in HIV patients

Judith Erlen, associate professor of nursing at Pitt's School of Nursing and associate director of the Center for Research in Chronic Disorders, has received a grant totaling more than $960,000 from the National Institute of Nursing Research for her four-and-a-half year study on medication adherence in patients with HIV infection.

Erlen wants to determine whether a habit-training and problem-solving intervention will enhance adherence to antiretroviral therapy drugs that are used to decrease viral load and increase CD4 T-cell counts, and whether this will have any impact on patient s' quality of life.

"In some patients infected with HIV, their condition worsens because they may not be adhering to their specific medication regimen," Erlen explained. "As part of this study, we will examine not only their adherence, but factors contributing to adherence, such as social support, problem-solving mechanisms, side-effect management, the patients' daily routines and how to fit their medication schedule into that routine."

Erlen is conducting a randomized clinical trial comparing two groups, each consisting of 110 patients. One group will receive their usual care and a 12-week telephone intervention designed to assist them to take their medications correctly. This will be followed by 12 weeks of maintenance and monitoring.

Nurses making the telephone calls will talk with the patients about a particular topic related to adherence each week. These topics range from making sure the patients have an understanding of the medications they are taking to managing side effects to developing strategies that will help remind them when to take their medications. Patients also will be asked to think about what they do each day and keep a diary of the day's events. The other group of 110 patients will receive only their usual care.


UPMC begins study to grow blood vessels in the leg

Vascular surgeons at UPMC Health System are participating in a clinical study of a gene therapy treatment to stimulate the growth of new blood vessels in the legs of people with peripheral vascular disease (PVD).

PVD is the narrowing of the arteries of the lower leg resulting in a decreased blood supply. Similar to chest pain in people with a decreased blood supply to the heart, people with PVD experience severe leg pain called claudication, which makes walking difficult or impossible. In severe cases the blockage may lead to limb amputation. PVD affects more than one million people in the United States. Current treatment for PVD includes exercise and drug therapy; but in most cases, surgical revascularization is required.

"The gene therapy is in early clinical development to determine its ability to improve blood flow by inducing new blood vessel formation in patients with moderate disease who are not yet candidates for surgery or for those with severe disease for whom surgery is no longer a treatment option," said Jeffrey D. Trachtenberg, assistant professor of surgery in Pitt's vascular surgery department and principal investigator in the study.

The new blood vessel growth, called angiogenesis, is stimulated by a protein called vascular endothelial growth factor (VEGF). The gene for this protein is inserted into the skeletal muscle cells of patients with the help of a modified human virus, which is responsible for colds. The adenovirus is modified so that it will not produce an infection.

"The VEGF gene is normally found in the human body; and in this study, we are exploiting the gene's ability to stimulate angiogenesis," said Trachtenberg.

UPMC is one of three centers nationally participating in the randomized phase I trial. Forty patients nationwide will be studied, with about a dozen enrolled at UPMC. Since the study is randomized, some of the patients will receive the VEGF treatment while others will receive a placebo.


Cocaine, tobacco use increase risk of miscarriage, Pitt study finds

Tobacco smoking and cocaine use independently contribute to spontaneous abortion (miscarriage), according to results of a landmark study led by Roberta B. Ness of the Graduate School of Public Hea lth (GSPH). Results were reported last month in The New England Journal of Medicine.

"This is the first study to show that cocaine use is linked with subsequent risk of miscarriage and that cocaine use is associated with miscarriage independent of tobacco use," said Ness, who is an associate professor of epidemiology, director of the canc er epidemiology program of the University of Pittsburgh Cancer Institute and director of the epidemiology of women's health program at GSPH.

"This research emphasizes that virtually any exposure to illicit drugs is dangerous for a pregnant woman and her fetus," said Alan I. Leshner, director of the National Institute on Drug Abuse (NIDA), National Institutes of Health, which provided partial f unding for the study. "With addiction, an individual's compulsion to use drugs may well be greater than her ability to protect her health and pregnancy. The need for adequate treatment for these women is critical." The rates of substance use were high in the study group of 970 inner-city, pregnant women of lower socioeconomic status. The report is based on 400 of those women who had miscarriages and 570 who carried their pregnancies past 22 weeks. Almost 30 percent had evidence of cocaine use in the previous few months, and over one-third currently smoked.

Both current smoking and cocaine use significantly increased the risk of miscarriage. In fact, the study reports that 24 percent of the risk for miscarriage in study women could be related to cocaine and tobacco use.

"Cocaine has been previously associated with low birthweight," Ness said. "Our findings suggest that it and tobacco can interfere with pregnancy, and that they act early in gestation." "Tobacco use is, perhaps, the greatest environmental contributor to neonatal health problems," she said. "Young women are also the fastest growing population to take up smoking. For both these reasons, it is vitally important that we tackle the problem of tobacco use during pregnancy. Ongoing research is evaluating the effectiveness of smoking cessation programs during pregnancy. Evaluation and implementation of such programs should be a priority.

"The use of cocaine," she continued, "probably varies substantially over different populations. In one national survey, five percent of women of childbearing age reported cocaine use in the past month. Marital status is associated with reduced use, and yo ung age is associated with increased use. The rates in our study are particularly high, probably because they reflect inner-city, indigent, young, unmarried women."


Study suggests clot-dissolving drug effective up to six hours after onset of stroke

Data from a recently completed multi-center trial, presented last month at the American Heart Association's 24th annual International Conference on Stroke and Cerebral Cir culation in Nashville, suggest an investigational clot-dissolving drug can lessen the neurological disability associated with stroke.

The drug, r-ProUK, was developed by Abbott Laboratories of Abbott Park, Ill. Abbott plans to submit the trial data in support of an FDA new drug application in mid-1999.

"For people who will have moderate-to-severe strokes, this new medication offers hope that they will be able to benefit from this treatment approach — even as long as six hours after onset," said Lawrence Wechsler, director of UPMC Health System's Stroke Institute and Pitt professor of neurology and neurological surgery, who led the Pittsburgh component of the study.

Few stroke patients receive treatment within three hours of their stroke, the treatment window for TPA, a drug previously approved for dissolving clots, according to UPMC stroke experts.

Stroke is the third leading cause of death and the most common cause of adult disability in the United States, according to the National Institutes of Health. Each year, 700,000 Americans suffer a stroke. Approximately 30 percent die, and 20-30 percent be come severely and permanently disabled.


Pitt researcher identifies breast cancer predictors

Results of a study published last month in the Annals of Internal Medicine suggest that in the near future a simple blood test to detect levels of sex hormones could predict which women are at the highest risk of developing breast cancer.

With this information, physicians could determine who would be good candidates for medications that can reduce the risk of the disease.

Jane A. Cauley, associate professor of epidemiology at the Graduate School of Public Health (GSPH), led the multi-center, federally funded study.

"In our study of older women, we found those with the highest levels of either serum estradiol or testosterone were three times more likely than expected to develop breast cancer," Cauley said. "This magnitude of risk is much higher than that observed for other breast cancer risk factors."

She explained, "Each year more than 180,000 women are diagnosed with breast cancer in the United States. Although well-established risk factors exist for breast cancer, more than 90 percent of all women have at least one of these factors and, individually , each factor only modestly increases a woman's risk of developing the disease."

The research involved participants from the Study of Osteoporotic Fractures and included 97 women who developed breast cancer and 244 randomly selected controls. All women were white, 65 years of age or older and not receiving estrogen. The estimated inci dence of breast cancer was lowest (4 per 10,000 women/year) in women with the lowest blood levels of estradiol and testosterone. Conversely, the incidence of breast cancer was highest (65 per 10,000 women/year) in women with the highest concentrations of both hormones.

This research strengthens previous reports indicating that hormone levels influence the risk of breast cancer, according to Cauley. "This type of information could help clinicians direct high-risk women to consider chemoprevention for breast cancer," she said. "Results from the Breast Cancer Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation Trial have shown that certain medications can reduce the incidence of breast cancer."

Unlike previous reports, results of this study showed that testosterone and estradiol independently contributed to breast cancer risk. For many years, researchers have known that estradiol, a metabolic product of estrogen, fuels the growth of some breast cancers. The way that testosterone may contribute to breast cancer growth is unclear at this time, according to Cauley.

Studies are currently underway to determine whether selective estrogen receptor modifiers, or SERMS, can reduce the incidence of breast cancer in women who have high baseline measurements of estradiol. In addition, studies like the Women's Health Trial ha ve shown that dietary modifications can reduce blood levels of estradiol in post-menopausal women. In another study, the Women's Health Initiative, investigators are waiting to see whether reduced dietary fat will translate into a decrease in the number o f breast cancer cases.

Because absolute levels of hormones in older women are low, the study employed extremely sensitive, accurate assays to measure differences among levels in study participants. These sensitive assays are not yet clinically available, Cauley said.


Pitt scientists discover how viruses evolve

Pitt researchers have gained new insights about the evolution of bacteriophages, the viruses that infect bacteria. Their surprising discovery is that virtually all bacteriophages (phages) are members of one large, interrelated family.

These results were published March 5 in the Proceedings of the National Academy of Sciences.

Roger Hendrix and Graham Hatfull, professors in the biological sciences department, working with Maggie Smith at the University of Nottingham, U.K., arrived at these conclusions through analysis and comparison of the genomes of selected bacteriophages. (A phage's "genome" is its entire collection of genes.)

The findings were unexpected since many of the phage genomes do not appear related by the normal criteria of similarities in their DNA or protein sequences. The relatedness of these phages therefore had to be inferred from pairwise comparisons of several phages and phage-remnants found within bacterial chromosomes. This comparative genomic approach provides a compelling view of the overall global population of phages.

"Nature is extremely prolific at generating new types of viruses," Hendrix said. "There are more bacteriophages than all the other organisms in the biosphere put together and, remarkably, our results show that this whole mass of viruses is involved in an ongoing orgy of gene swapping on a global scale."

"It's a really efficient mechanism for generating new combinations of genes and therefore new varieties of viruses," said Hatfull.

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