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November 25, 1998


Researcher gets grant for studies on medication adherence

Jacqueline Dunbar-Jacob, director of the School of Nursing's Center for Research in Chronic Diseases, has been awarded a $1.5 million grant for research on medication adherence in patients with rheumatoid arthritis.

"This is an especially important area of focus because about one-half of patients who are given medication for rheumatoid arthritis and other chronic conditions simply don't take their medication as prescribed," Dunbar-Jacob said.

The study's goal is to evaluate strategies for improving medication adherence, she said. In addition, the research team will examine what impact adherence has on clinical and cost-effective outcomes.

The study will compare the efficacy of two interventions to promote adherence to pharmaceutical therapy in these patients: telephone counseling or mailed self-instruction compared with standard care. Patients will be followed for one year.

In a previous study, Dunbar-Jacob and her team, comprised of staff members from the schools of health and rehabilitation sciences, nursing and medicine, studied 135 patients for about one year. Patients received a telephone-delivered intervention or standard care. The team found that the telephone intervention worked better and, in this larger study, the researchers want to determine if the intervention could be delivered in a mailed self-instructional format.


Surgeons use new technique for severe, recurring CTS

To treat patients with severe recurrent carpal tunnel syndrome, surgeons at UPMC Health System are performing a novel technique in which they wrap a vein around the involved nerve to insulate it from recurrent compression and the development of painful scar tissue from previous unsuccessful surgeries.

Dean Sotereanos, associate professor of orthopaedic surgery, recently described the technique to peers at meetings of the European Federation for Hand Surgery and the American Society for Surgery of the Hand.

Carpal tunnel syndrome (CTS) affects one in 10 people and is the most common type of compressed nerve condition, according to Sotereanos. Its symptoms are: chronic wrist pain, numbness and tingling in the thumb, index and middle fingers, hand and wrist that also can shoot through the upper arm. The pain seems to worsen at night and with increased activity. CTS sufferers usually are those who perform repetitive and forceful movements with their hands over long periods of time, such as typists and computer operators. CTS also can be caused by broken or dislocated wrist bones, arthritis, thyroid conditions, diabetes, and hormonal changes in females during menopause or pregnancy.

CTS results from compression of the median nerve, which travels through the carpal tunnel from the forearm to the hand and fingers. The tunnel is bordered by wrist bones, ligaments, tendons and muscles that make up the biomechanical network for wrist motion. The tendons are surrounded by a smooth lubricating membrane called the synovium, which becomes swollen and irritated in people with CTS. The swollen tissue compresses the median nerve, causing pain, tingling and numbness.

In many cases, CTS can be treated by resting the hand and wearing a splint. For some patients, an anti-inflammatory steroid injection may provide temporary relief. If these treatments prove ineffective, a surgeon may perform the traditional procedure of cutting the ligament over the carpal tunnel to relieve pressure on the nerve. "However, CTS remains a challenging problem for surgeons since between 14 and 32 percent of surgical patients have recurrent symptoms and require repeated surgeries due to the build-up of irritating scar tissue around the nerve," said Sotereanos.

"Other soft-tissue wrapping techniques have been developed – such as with muscle, fat or fascia flaps – but these often are associated with complications, and their outcomes are unpredictable. From our research thus far, we have seen that good tissue compatibility and minimal complications occur with vein wrapping," he said.

Sotereanos's team performs the vein-wrapping technique only on patients with severe recurrent CTS who have had at least two previous failed surgeries for CTS. They are the only surgeons in the world to perform this procedure for CTS using the patient's own vein.

During the operation, the nerve is gently freed from surrounding scar tissue. A segment of the saphenous vein is taken from the patient's lower leg and incised longitudinally. The vein then is wrapped around the median nerve in a candy-striped fashion and ultimately serves as an insulator from surrounding scar tissue. The concept is to prevent recurrent scar tissue around the nerve and allow for better functional outcome.

The post-surgical routine is identical to that of the traditional nerve release procedure for CTS. The overall recovery period generally takes three months to allow for healing, according to Sotereanos.

"Since initiating clinical studies for this procedure in 1993, we have performed the operation on 22 patients at UPMC, 80 percent with good to excellent long-term results," Sotereanos said.


NCI chooses Pitt as one of three sites for biocombinatorial chemistry research

A Pitt research team has received a five-year, $5 million federal grant to speed drug discovery through revolutionary means: biocombinatorial chemistry.

The National Cancer Institute (NCI) grant to Pitt is one of only three nationwide. Biocombinatorial chemistry is an emerging field characterized by the rapid, parallel synthesis of large "libraries" of organic compounds used for testing in biological systems.

This initiative, conceived to discover new cancer drugs, is a combined effort by researchers from the School of Medicine's pharmacology department, the Faculty of Arts and Sciences' chemistry department, the Graduate School of Public Health's environmental and occupational health department and a private Pittsburgh-based company, Cellomics, Inc.

Through biocombinatorial chemistry, Pitt investigators will create novel chemical compounds at the chemistry department's new Combinatorial Chemistry Center and then test them elsewhere in the University to learn whether they interrupt cellular activities that can lead to cancer. Pitt researchers also will create a repository for newly manufactured compounds that then can be acquired and tested by outside investigators.

"Every day, scientists are discovering the molecular bases of disease and, in the process, revealing many new potential drug targets. Biocombinatorial chemistry is the most comprehensive approach to designing highly specific drugs that work," said John S. Lazo, principal investigator on the grant, Allegheny Foundation professor and chairperson of Pitt's pharmacology department, and co-director of the University of Pittsburgh Cancer Institute's Molecular Therapeutics/Drug Discovery program.

"Biocombinatorial chemistry offers a stark contrast to current methods of drug discovery, which have a long lag time from drug synthesis to application in the clinic with patients. By contrast, biocombinatorial chemistry is expected to offer the public optimally effective, safe medications quickly," Lazo said.

Biocombinatorial chemistry exploits the discovery of genes and their proteins, which serve as molecular targets for drugs because they control biological processes that often lead to disease.

"With this approach, we start with a chemical compound called a platform that locks onto a specific molecular target. We change the platform incrementally to quickly produce hundreds of compounds that we can screen against that given target," said Peter Wipf, co-investigator on the grant and professor in the chemistry department, where he directs the Combinatorial Chemistry Center. "Through this process, we can readily learn what specific compound structure is best at disrupting a biological pathway." "Biocombinatorial chemistry has particular importance for diseases like cancer, where you want to provide a highly specific drug that will effectively and selectively kill tumor cells without damaging other healthy cells and potentially creating dangerous side effects," Lazo added.


Altered brain chemistry in patients with bulimia exists even after recovery

Researchers at Western Psychiatric Institute and Clinic have found evidence that altered brain chemistry contributes to development of bulimia nervosa and persists even after recovery from the disorder.

The study, authored by psychiatry professor Walter H. Kaye, appeared in the October issue of Archives of General Psychiatry.

Women with bulimia nervosa, when binging and purging, are known to have alterations of brain serotonin activity and mood as well as obsessions with perfectionism. Serotonin is a neurotransmitter that helps regulate mood.

This study found that these alterations and symptoms persisted after recovery from bulimia nervosa, suggesting that they are not merely a consequence of abnormal eating behaviors. Theoretically, altered serotonin activity could cause anxious and obsessive behaviors and affect the control of appetite and thus contribute to a vulnerability to bulimia nervosa.

"The development of an eating disorder is often attributed to the effects of our cultural environment, such as the mass media, which places a heavy emphasis on slimness. But while all women are exposed to these cultural mores, only a small percentage develop an eating disorder. Our study may have identified a biological risk factor that plays a part in deciding who develops a disorder," Kaye explained. "This study is important because it will help shift focus to the underlying causes of bulimia nervosa so that we can develop better treatments in the future and possibly identify people at risk for the disorder before it occurs." Bulimia nervosa affects about 1-3 percent of women and most commonly occurs in women of normal body weight. Onset is usually during adolescence and is characterized by binging and purging, by vomiting or using laxatives. Women with the disease often have a distorted image of their bodies, changes in brain chemistry and psychiatric symptoms such as depression, anxiety, obsessive-compulsive disorder and alcohol or other substance abuse. Though researchers know the symptoms and effects of bulimia, its causes have yet to be uncovered.

Because malnutrition associated with eating disorders affects brain chemistry, Kaye and his colleagues compared 31 healthy volunteer women to 30 women who had recovered from bulimia nervosa, were of normal body weight, had regular menstrual cycles and had not binged or purged for more than a year.

Researchers assessed the recovered bulimia nervosa participants for persistent behavior disturbances and measured cerebrospinal fluid levels of the major metabolites of the neurotransmitters serotonin, dopamine and norepinephrine. They also gave participants a non-therapeutic drug, m-chlorophenylpiperazine (m-CPP), that affects the serotonin system and elicits hormonal and behavioral responses.

Kaye's team found that, compared to the healthy volunteers, the recovered women had increased levels of the serotonin metabolite and more negative moods and obsessions with perfectionism and exactness. The levels of the other brain chemicals, dopamine and norepinephrine, were normal in comparison. In addition, group members had more anxiety and disorganized behavioral responses to m-CPP.

Kaye is principal investigator for a multinational study sponsored by the Price Foundation that hopes to pinpoint a genetic basis for bulimia nervosa. Research sites at U.S. universities in Pittsburgh, Philadelphia, New York and Los Angeles as well as Canada, Germany and Italy are recruiting 400 women and men with the disorder who also have a biological relative with similar eating problems. These relative pairs will provide blood samples for genetic analysis and will be interviewed.

The sites are seeking people with bulimia nervosa who have a relative with an eating disorder. Because these procedures can be performed where a patient lives, no traveling is required.

For more information, call 1-888-895-3886, or e-mail to: All communication is confidential, and participants are paid upon completion of the study.


Estrogen use by women past menopause leads to better survival for those with congestive heart failure

UPMC Health System cardiologists have found that postmenopausal women with congestive heart failure (CHF) have a lower mortality rate if they are on estrogen therapy.

The cardiologists' study results were presented Nov. 9 at the American Heart Associa-tion's 71st Scientific Session in Dallas by Steven Reis, Pitt assistant professor of medicine, director of the LHAS (Ladies Hospital Aid Society) Women's Heart Center, and co-director of the Magee Women, Infant, and Fetal Heart Program.

"Postmenopausal women with congestive heart failure have a substantially worse prognosis than young women. The purpose of our study was to determine whether post-menopausal estrogen use is beneficial in women who have symptomatic CHF," Reis said.

The study included 1,362 women with symptomatic CHF enrolled in three U.S. clinical trials involving vesnarinone, a drug for treating heart failure. Of these, 869 women were post-menopausal but were not using estrogen, 210 were post-menopausal estrogen users and 283 were premenopausal.

The study found that the mortality rate after 12 months was 27.6 percent for the first group of women, 16.4 percent for the second group and 11.6 percent for the pre-menopausal group.

"The use of estrogen was independently associated with decreased mortality," Reis reported. "Our study suggests that in CHF, premenopausal women and postmenopausal estrogen users have a lower mortality than postmenopausal women who do not use estrogen.

"Although the cellular and molecular mechanisms for these findings have not been defined, our results indicate that endogenous and exogenous estrogen is associated with a survival benefit among women with symptomatic CHF independent of age, vesnarinone use and CHF severity," Reis added.


Tests predict heart disease development in women

With stunning accuracy, researchers now can definitively predict which women in their 40s and 50s who have no clinical signs of atherosclerosis, or blockage of a blood vessel, will inevitably develop life-threatening heart disease.

Presented Nov. 10 at the 71st American Heart Association meeting in Dallas, the study by Pitt clinical researchers will help physicians determine which women should receive more aggressive therapy to avoid heart attack and stroke.

"The results from this prospective study are striking. Heart disease should be absolutely preventable in women whose profiles predict this complication," said Lewis Kuller, principal investigator on this research and University professor and chairperson of the Pitt Graduate School of Public Health's epidemiology department. The 15-year study is the first to evaluate the relationship of heart disease risk factors measured before menopause (pre-menopause) and the extent of subclinical disease in the coronary arteries and aorta as measured after menopause (post-menopause) by a new and under-utilized technology, electron beam computed tomography (EBCT), otherwise known as ultrafast CT. "Our findings showed that premenopausal women with traditional high risk factors – high levels of bad cholesterol (LDLc), low levels of good cholesterol (HDLc), high triglycerides, smoking and excess weight – developed disease as evidenced by EBCT," Kuller noted. "But, importantly, we also found that some pre-menopausal women without high risk factors had subclinical heart disease post-menopausally when monitored using EBCT." "EBCT provides an exceptionally accurate picture of subclinical atherosclerosis in the coronary arteries and aorta of postmenopausal women," said Daniel Edmundowicz, assistant professor of medicine, director of the Electron Beam CT Program and co-director of Preventive Cardiology at UPMC Health System's Cardiovascular Institute.

EBCT involves rapidly scanning the beating heart or aorta with X-rays to detect the presence of calcification. Calcium in these arteries indicates the presence of atherosclerosis and can be present long before obstructions occur.

For years, researchers have known that the incidence of heart disease in women rises sharply as they pass through menopause, a time of complex hormonal and physiological changes. Scientists have described many of the risk factors for women. Until now, though, there have been no thorough research analyses combining these known risk factors with results from new tests that detect subtle signs of atherosclerosis before this disease process is discovered using conventional diagnostic measurements, such as stress tests or angiography.

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