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January 10, 2002


Pitt, VA get $8 million to study alcohol-HIV interactions

Alcohol is the drug most commonly abused by people infected with HIV, researchers say. To study how alcohol use and abuse interacts with HIV infection and treatment, Pitt and the Pittsburgh Veterans Administration Medical Center have received an $8 million grant from the National Institute on Alcohol Abuse and Alcoholism.

"We know that alcohol and unprotected sex are common bedfellows. Alcohol use and abuse may be an important risk factor for HIV infection," said the study's principal investigator, Amy Justice, of Pitt and the Pittsburgh VA. "Overuse of alcohol likely aggravates common related medical and psychiatric diseases such as hepatitis C and depression. Alcohol use may also decrease the benefit of HIV treatment by causing people to miss taking their medication and increasing the risk of treatment toxicity."

An expansion of the ongoing Veterans Aging Cohort Study (VACS), the current study will identify the role of alcohol use and abuse in determining health and quality of life among aging veterans with and without HIV. The study also will examine the effect alcohol has on susceptibility to drug toxicity and the progression of related diseases.

Justice and co-principal investigator Joseph Conigliaro, also of Pitt and the Pittsburgh VA, will lead the study of 2,000 HIV-infected veterans and 2,000 non-HIV-infected, matched controls from VA facilities in Manhattan/Brooklyn, Bronx, Atlanta, Los Angeles and Houston. At these sites, researchers will examine the impact of alcohol use and abuse on related diseases, drug toxicity, death, quality of life, treatment success, use of health care services and prescription drug use and adherence.

The VA's national electronic medical records system, which includes laboratory and pharmacy data and can track patient status over time, offers unique advantages for such a long-term study.

"Because the VA pays for all currently approved antiretroviral medications and can track patients among several clinical sites, we expect to achieve excellent follow-up on these patients," Conigliaro said. "In addition, patients with HIV infection in the VA system are predominantly members of important and understudied minority groups."

The national VA hospital system is the largest single provider of HIV services in the United States, and in 2000 it treated some 18,000 HIV-infected veterans.

Justice is a Robert Wood Johnson Generalist Faculty Scholar and associate professor in the School of Medicine, and associate professor of health services research at the Graduate School of Public Health. Conigliaro is associate professor in the medical school. Both are staff physicians at the Pittsburgh VA Medical Center.


Prof gets grant for innovative research on brain tumor treatment

William Chambers, associate professor of pathology at Pitt's School of Medicine, has received a $450,000 award from the James S. McDonnell Foundation through its 21st Century Science Initiative.

The award program annually funds researchers pursuing challenging and important projects that will likely advance the current state of scientific knowledge in treating brain cancer. Chambers, a member of the University of Pittsburgh Cancer Institute (UPCI)'s Immunology Program and Brain Tumor Center, was one of three researchers nationally who received the award in 2001.

Chambers's research focuses on the treatment of gliomas, which are highly lethal, primary brain tumors. Currently, these tumors are very difficult to treat successfully. Malignant gliomas make up the majority of primary brain tumors and are expected to kill approximately 13,000 brain cancer patients this year.

Gliomas tend to aggressively invade the folds and creases of the brain around the tumor, making them difficult or impossible to completely remove surgically. Similarly, with standard treatment such as chemotherapy and radiation, it is difficult to treat the tumor successfully without damaging the surrounding healthy tissues. Because of the limitations of standard therapies, Chambers is exploring gene therapy-based, immunological approaches that activate and maintain the function of the anti-tumor immune response.

"While there is evidence that immune cells, such as lymphocytes, infiltrate gliomas, they are generally ineffective in fighting the tumor's growth and development," said Chambers. "Many analyses have indicated that the function of lymphocytes is suppressed in gliomas, as is the function of the immune system throughout the body in patients with gliomas. Our hope is that we can correct and improve the function of the immune response to these tumors and use this to target the infiltrative areas of gliomas that are difficult to eliminate using standard therapies."

Chambers will combine two therapeutic approaches that individually have produced promising, but limited, results. He proposes that coupling the therapies will create an advantage to either approach as a single therapy. The combined approach, called RICS therapy, or the reversal of immunosuppression coupled with cytotoxic cell stimulation, attempts to induce an effective immune response by blocking the function of tumor-derived transforming growth factor-b (TGFb). TGFb is a protein produced by gliomas that is responsible for much of the immune suppression associated with these tumors. The approach also seeks to stimulate cytotoxic lymphocytes, which include natural killer (NK) cells and T cells, to destroy the gliomas.

Chambers will be working with hormones produced by the immune system called cytokines to stimulate these cells. One in particular, interleukin-12, activates the anti-tumor effects of both NK cells and T cells and has been shown to promote anti-glioma immunity.



Pitt doctors to perform implant on patients with rare eye disease

Pitt ophthalmologists will participate in a clinical trial using INTACS corneal implants to correct a rare condition called keratoconus. Pitt's ophthalmology department is one of four centers participating in the trial.

Keratoconus is a degenerative disease in which thinning of the corneal tissue causes the cornea to swell and bulge forward. The disease strikes patients in their late teens to early 20s and progresses until the 30s or 40s. Patients with keratoconus experience a progressive loss and distortion of vision, which in the early stages can be treated with eyeglasses. Later stages are corrected with rigid contact lenses and, in severe cases, a corneal transplant.

"By using INTACS to treat keratoconus, we hope to provide our patients a restorative option where we can help improve corneal shape," said Deepinder Dhaliwal, chief of refractive surgery at UPMC Eye & Ear Institute.

The INTACS procedure involves the implantation of two arc-shaped plastic inserts between layers of the cornea. Previously used in patients with myopia (near-sightedness), the procedure flattens the cornea, making the cornea closer to its natural shape.

An estimated 272,000 Americans suffer from the potentially blinding disease of keratoconus. This study, an FDA-approved clinical feasibility study, will involve patients nationwide.



Pitt faculty report findings at national cell biology meeting

Clinical and basic science research findings of nearly 50 studies were presented by Pitt School of Medicine researchers at the annual meeting of the American Society for Cell Biology last month.

Findings included the following:

* Johnny Huard, associate professor of orthopedic surgery, molecular genetics, biochemistry and bioengineering, and his colleagues reported that adult cells, also called somatic muscle stem cells, that are derived from skeletal muscle also may be coaxed to form blood-cell precursors.

Working with a strain of "mdx" mice, a rodent model for Duchenne muscular dystrophy, Huard's group also found reason to believe genetically engineered stem cells may be used to deliver the essential missing protein dystrophin to musculature wasted by the congenital disease.

Experiments injecting these cultured skeletal muscle cells into mdx mice revealed that while some cells migrated to the muscles, others found their way into bone marrow. Those in the bone marrow showed evidence of being able to produce new blood cells.

* Gerard Apodaca, associate professor of medicine and cell biology and physiology, and his colleagues have taken a closer look at the epithelial cells that line the inner surface of the bladder.

By mounting pieces of bladder tissue in "stretch chambers" and observing their behavior at the cellular level during simulated bladder filling, the researchers found that the bladder surface area is able to modulate to accommodate increased pressure in a unique way. Microscopic compartments called vesicles both expand to increase surface area and contract — perhaps to remove old membrane that has been damaged by exposure to the toxic components of urine.

A key role in this process is played by a molecule called cyclic adenosine monophospate, which can regulate surface area — in some cases without even stretching the tissue. The researchers believe the findings may provide insight into how other cell types respond to external mechanical stimuli.

* Jean Latimer, assistant professor of obstetrics, gynecology, women's health, biochemistry and molecular genetics, and Victor Vogel, professor of medicine and epidemiology, and their colleagues are trying to identify ways to predict which early-stage breast tumors are most likely to recur using live-cell imaging.

They have developed an in vitro culture system for mammary epithelial cells that come from both normal and malignant tissues. Using this system, the cells can be propagated for three months or longer by maintaining primary cultures. Through imaging data collected by using time-lapse digital movie techniques, the researchers compared the behavior and "construction methods" of normal and malignant tissues. Preliminary results from this data support the possibility of a novel new indicator for breast tumor recurrence.

* Researchers led by William Saunders, associate professor of biological sciences, and Susanne Gollin, associate professor of human genetics, have shown that toxic chemicals in cigarette smoke directly interfere with the way certain cells prepare for division.

These epithelial cells line the inside of the mouth and are called squamous cells. Cigarette smoke appears to negatively impact the cells when they separate their chromosomes. Researchers hypothesize that this may lead to a change in chromosome structure and contribute to the types of division defects seen in cancer cells.

Saunders and his colleagues targeted the anaphase stage of cell division, when cellular chromosomes copy themselves and move in identical sets to opposite poles in preparation for division into two sister cells. By exposing these cells to cigarette smoke condensate (CSC) in the laboratory, the researchers observed serious errors in cell division. Sometimes a single chromosome was pulled in two different directions at once to form a bridge. These anaphase bridges may be an early precursor to malignancy.



Ventilator weaning to be studied here

For patients with restrictive lung diseases, lung infections, or neuromuscular injuries that impair breathing, long-term mechanical ventilation (LTMV) can be a lifesaver. Yet for all its benefits, LTMV is invasive, expensive and frequently associated with a higher risk of serious complications such as nosocomial infections, weight loss and delirium. And in some cases, LTMV has been linked with increased mortality.

While a superior weaning technique or ventilator mode for LTMV has not been identified, the manner or process in which a particular mode of weaning is applied may actually have a greater impact on weaning success than the mode itself. A new study by Mary Beth Happ, assistant professor at Pitt's School of Nursing, could identify better applications of care for nurses, physicians and respiratory therapists who are weaning patients with LTMV.

Happ, who received $800,000 from the National Institute for Nursing Research (NINR) for her "Ventilator Weaning: Processes of Care and Communication" study, will focus on interpersonal interactions, therapeutic strategies and environmental factors that contribute to weaning success or are associated with inconsistent/plateau weaning from LTMV. Happ said her study will capitalize on a unique 'natural laboratory' to fill important gaps in the current understanding of advanced specialty clinician practice in ventilator weaning.

"During a two-and-a-half year period, we will work with approximately 30 patients, family visitors and clinician caregivers in a medical intensive care unit (MICU) and step-down medical intensive care unit," said Happ, who is the principal investigator for the study. "Because the MICU is the environment where weaning from long-term mechanical ventilation actually occurs, the real barriers and successful strategies that are encountered by patients and clinicians will be more evident."

Happ hopes to find a therapeutic approach that can be utilized by various members of the health care team. "Nurses, physicians, respiratory therapists, and others work together to achieve successful weaning from LTMV," Happ explained. "Since ventilator weaning is a multidisciplinary process, knowledge from this study may help those disciplines work together more effectively to achieve successful outcomes in patients weaning from long-term mechanical ventilation."

Study co-investigators in-clude nursing school professor Leslie Hoffman and assistant professor Valerie Swigart, plus medical school professor Robert Arnold and associate professor Michael Donahoe.

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