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May 27, 1999


WPIC studies treatments for children with disruptive behavior disorders

The National Institute of Mental Health has awarded a $2.75 million research grant to investigators at Western Psychiatric Institute and Clinic (WPIC) to evaluate the effectiveness of treatments for children with disruptive behavior dis orders.

The five-year study is among the first to compare the effectiveness of a combination of treatment services outside traditional clinic settings.

Researchers will evaluate the impact of community-based and clinic-based services on children's functioning and other important family outcomes, as well as assess the cost-effectiveness of these services.

"This study is an important step in understanding and measuring the benefits of diverse services that affect children's behavior and adjustment and family satisfaction with treatment," said principal investigator David Kolko, associate professor of child psychiatry and psychology.

The study will follow 140 children ages 6 to 11 with oppositional-defiant disorder or conduct disorder, two childhood disorders that frequently result in clinical referrals.

Treatment effectiveness will be measured using child, parent and teacher reports to determine any changes in behavior problems and changes in parent-child and social relations.

To be eligible, children ages 6 to 11 must be diagnosed with conduct disorder or oppositional defiant disorder and live within 30 minutes of Oakland. A parent or caregiver must be willing to participate. Treatment will be provided at no cost, for three t o six months. Participants can earn up to $100 for completing all interviews and forms. For more information, call (412) 624-3757.


Cardiovascular Institute part of congestive heart failure study

Researchers at UPMC Health System's Cardiovascular Institute are participating in a phase II/III clinical trial of a genetically engineered protein to treat congestive heart failure.

The protein, called Enbrel, controls a naturally occurring compound, tumor necrosis factor (TNF), that causes inflammation and heart damage.

The trial is based on positive results of an earlier study presented in March at the annual conference of the American College of Cardiology.

"We are encouraged by the initial study of this novel approach to the treatment of congestive heart failure," said Arthur Feldman, Cardiovascular Institute director and principal investigator of the UPMC study. "Enbrel represents the first time that genet ic engineering has been brought to bear on the problem of congestive heart failure. If studies in humans replicate those in animal models, this will truly be a breakthrough in our treatment of heart failure."

Patients in the initial study showed consistent improvement in their heart ejection fraction (the percentage of blood pumped from the heart on each beat) and their overall quality of life.

Research has shown that TNF, an immune system protein, is present in increased amounts in damaged heart tissue. TNF exerts its effects by interacting with specific TNF receptors that are on the surface of the cells. When TNF binds with TNF receptors, it s ets off a chain of events within the cell that may lead to further damage to the heart.

Enbrel is a genetically engineered soluble receptor that works by binding to TNF and preventing it from interacting with cell surface receptors that are on the cells in the heart and circulatory system.

An estimated 4.8 million Americans have congestive heart failure, in which the heart cannot maintain adequate circulation of the blood because it fails to pump blood properly. The failing heart keeps working but becomes inefficient, resulting in fluid ret ention and shortness of breath, fatigue and exercise intolerance. It is the chief cause of about 40,000 deaths in the United States each year and is a major contributing factor in an additional 225,000 deaths.

Patients who may qualify to participate should call 412/647-1666 or 412/647-6882.


Botanical products act like estrogen in animals

A University of Pittsburgh and Pittsburgh VA Medical Center team has provided evidence that certain botanical products act like estrogen in animals.

The findings indicate how these agents may relieve menopausal symptoms but suggest their potential danger for women who should not take estrogen.

The scientists reported their findings last month at the annual meeting of the American Association for Cancer Research.

"Of the plant products we examined, we found that vitex, dang gui, American ginseng and cohosh produced estrogen-like effects in animals," said Patricia Eagon, Pitt associate professor of medicine and principal investigator of the study. "These findings confirm reports that these plants relieve menopausal symptoms, especially hot flashes. However, we still need to conduct further pre-clinical tests with these substances to study their long-term effects and to ensure that they are safe to use.

"Our results should signal a strong note of caution to women who want to relieve menopausal symptoms but who have a family or personal history of breast or uterine cancer," Eagon added. Estrogen is known to fuel the growth of these cancers.

Because the U.S. Food and Drug Administration does not regulate these botanical products, many women who should not take them could end up using them, according to Eagon. Moreover, overuse of these remedies or impurities in the products can lead to liver problems and blood clotting disorders, she said.

The Pittsburgh research team found that extracts of vitex, dang gui, American ginseng and cohosh bound directly to estrogen receptors, just as natural estrogen would. The investigators next tested these compounds in rats whose ovaries were removed so they could not produce significant levels of natural estrogen. After 30 days of treatment, the researchers found that the uterus in each rat grew heavier, an indication that this organ had an estrogen-like response to the extracts. In addition, the scientists found that blood levels of luteinizing hormone (LH) decreased in these animals. Produced by the pituitary, LH triggers other organs to make estrogen. Naturally high levels of estrogen turn off LH production. In the treated animals, the plant extracts sim ilarly reduced LH production, according to the investigators.

Herbal remedies have been used for centuries to relieve various gynecological symptoms, including absent periods, painful periods and symptoms of menopause.

Eagon's research is supported by a grant from the U.S. Army.


UPCI team is first to uncover role of faulty DNA repair in breast cancer

A research team at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Hospital has uncovered a pivotal role for problems with DNA repair in breast cancer, which could help explain why most early-stage breast cancers respond to available treatments and why advanced tumors thrive despite aggressive therapy.

The report provides the first evidence that cells from early-stage breast cancers fail to repair DNA like normal cells through nucleotide excision repair (NER). The details were reported at a scientific mini-symposium last month at the annual meeting of t he American Association for Cancer Research.

The research team looked at breast tissues from 30 early-stage breast cancer patients and 12 controls. In 85 percent of the patients, the investigators also found that non-cancerous cells surrounding a breast tumor had poor NER activity, suggesting that a breakdown in this safety mechanism may initiate the cancer in most women affected by the disease.

Latimer's results could explain why chemotherapy and radiation therapy are so effective against early-stage breast cancer. "Standard chemotherapy drugs like 5-fluoruracil and cyclophosphamide and radiation therapy all work by damaging DNA. If a breast tum or has a poor capacity to repair this damage, it will die," Latimer said.

Variations in NER activity among the breast cancer patients studied also suggest that therapies could be custom tailored, according to Latimer. "If a breast cancer biopsy indicates better, though still abnormal levels of NER activity, it's possible that t he patient may not respond optimally to chemotherapy or radiation therapy. In this case, a clinician might want to use biological therapies, which do not operate by damaging DNA directly."

Unfortunately, later-stage breast cancers appear to regain NER activity.

"Advanced-stage tumors may compensate for the lack of one NER enzyme by increasing the production of another NER enzyme that performs the same function," Latimer said. "In this way, the tumor can effectively repair treatment-related DNA damage."

Latimer's team used fresh tissues taken within five hours of surgery and grown in culture. A patent is pending on this culture method, which is the only one available to grow normal breast tissue for up to three months.


Hearing aids can reduce problems for at-home Alzheimer's patients and caregivers

Problem behavior and hearing handicaps in patients with Alzheimer's disease and hearing loss were significantly reduced after the patients had begun wearing properly fitted hearing aids as part of an in-home study, conducted by audiologists at the UPMC Eye & Ear Institute's Center for Audiology and Pitt's communication science and disorders program.

The research, published in the April Journal of Speech, Language and Hearing Research, showed that hearing aid treatment for Alzheimer's patients living at home with caregivers may actually benefit the caregiver as much as the patient.

Although previous studies have shown that more than 60 percent of aging individuals with organic mental syndromes (such as Alzheimer's) also had impaired hearing, hearing deficits may be the most frequently unrecognized condition in Alzheimer's patients. The impairment often is masked by other behavioral symptoms and patients may communicate adequately in ideal quiet conditions, according to Catherine Palmer, Pitt assistant professor of communication science and disorders, director of the Center for Audi ology and principal investigator for the study.

In addition, Alzheimer's patients traditionally have been considered difficult to test for hearing loss and difficult to manage because of anticipated patient non-compliance.

"Diseases can interact to make a pair of diseases much more disabling than either one alone and this may be the relationship between Alzheimer's and hearing impairment associated with aging," Palmer said.

Palmer's research was supported by a grant from the National Association for Alzheimer's Disease.


Bone marrow infusion helps to reduce organ rejection

Organ rejection occurs less often and is less severe in patients who receive infusions of bone marrow from the same donor, researchers from Pitt's Thomas E. Starzl Transplantation Institute report.

Their findings, which represent six years of studying patients who received the extra boost of donor immune system cells, indicate the procedure augments the cellular environment that the research team believes is necessary for long-term acceptance of a t ransplanted organ.

Results of the study — the largest of its kind — are particularly encouraging for recipients of hearts, lungs and combined kidney and pancreas, said Abdul Rao, assistant professor of surgery and pathology and director, section of cellular transplantatio n. In addition, the outcomes for liver transplant patients suggest that some patients can be weaned from the drugs that control organ rejection, he said.

Controlling rejection is the key to organ transplantation. Surgeons mainly rely on drugs that suppress the patient's immune response as their main defense against an immune system attack. But organ rejection can occur even years later. Even if the drugs c ontrol rejection, they can produce serious medical complications and make the patient more susceptible to cancers and infections.

The study included 268 patients who received donor bone marrow along with transplants of livers, pancreases, pancreatic islet cells, kidneys, intestines, hearts and lungs.


Guidelines may mean more CF patients will die waiting for transplants, study predicts

The number of patients with cystic fibrosis (CF) who die waiting for lung transplants will likely increase if surgeons follow new international wait-listing guidelines and current geographic disparities in waiting times persist, a UPMC Health System surgeon reports.

Robert J. Keenan, who heads UPMC's lung transplant program, said his study, which examined outcomes of 164 CF patients evaluated for transplantation, indicates that the medical criteria adopted last year by the transplant community are too restrictive. In the United States, where organs are allocated in a local-first system, this would limit the window of opportunity in which donor organs can be found.

"At our center, and at others that tend to have longer waiting times, we expect there to be substantial mortality on the waiting list. If geographic disparities in waiting times were minimized, these guidelines might be more reasonable for medical practic e," said Keenan.

More than 25 percent of patients needing lungs die waiting, according to the United Network for Organ Sharing; these rates vary from region to region.

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