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University of Pittsburgh

September 11, 1997

RESEARCH NOTES

UPMC study shows immune globulin improves heart function

Cardiac researchers at the University of Pittsburgh Medical Center (UPMC) have found that patients with acute cardiomyopathy who were treated with high doses of intravenous immune globulin, human antibodies, showed a significant improvement in heart function to the extent that they were removed from the heart transplant waiting list.

Dennis McNamara, assistant professor of medicine and director of UPMC's cardiomyopathy clinic, led the study.

"Immune globulin is frequently used to treat other autoimmune diseases but has never been looked at in adults with inflammatory heart disease," McNamara said. "We wanted to determine if patients with recent onset acute primary dilated cardiomyopathy, who were sick enough to need a heart transplant, might improve with therapy sufficiently to delay or prevent the need for heart transplantation." The study followed 10 patients, one of whom died before the therapy could be completed. The remaining nine patients received intravenous immune globulin for up to four days and were discharged from the hospital. Patients ranged in age from 18 to 60. All were awaiting heart transplants. After one year, all nine showed an improved left ventricular ejection fraction, the percentage of blood ejected from the heart during each beat.

"The immune globulin essentially reset the body's immune system and allowed the body to heal itself," McNamara said. "The average increase in ejection fractions was twice what had been reported using other treatments. All had a marked improvement in their exercise capacity and quality of life. All were working and none of them, two years after treatment, have been readmitted to the hospital with heart failure." In contrast, during the same study period, 72 other patients were treated conventionally; 31 percent had died or received transplants after one year.

"We are now in the middle of a multi-center trial which will include 60 patients nationwide," McNamara said. "We are excited by the results of this initial study, but we need a controlled trial in a large group before we know what role immune globulin will play in the treatment of this illness." Heart failure due to dilated cardiomyopathy affects more than 100,000 Americans and is a major reason for heart transplants in young adults. Studies suggest that the condition results from a common viral infection which, in some patients, causes an autoimmune response in which the body attacks itself.

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UPJ professor gets grant

Stephen Kilpatrick, assistant professor of biology at the Johnstown campus, has received a $10,429 University of Pittsburgh Research Council grant to research his proposed project, "Molecular Population Genetics of Drosophila Melanogaster.

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DOE awards Pitt $5 million for radiation science training center

The U.S. Department of Energy (DOE) has awarded Pitt $5 million to establish the first comprehensive training program for post-doctoral fellows in radiation research.

Designated a University Center for Excellence for Training in Radiation Science by the DOE, Pitt will recruit highly qualified candidates with scientific or medical doctoral degrees for an intensive education program. The program will include in-depth coursework and independent research in health physics, radiobiology, radiation epidemiology, toxicology of radiation, occupational and environmental medicine and health risk assessment. The program is devised to be flexible and individualized and offers a competitive stipend.

Pitt's program will be based in the Department of Environmental and Occupational Health in the Graduate School of Public Health. Program leaders say they hope to train 30 fellows over five years.

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New treatment improves survival for non-small cell lung cancer

A novel treatment using combination chemoradiation for regionally advanced, surgically unremovable non-small cell lung cancer (NSCLC) appears to be promising and could lead to a new standard of care for the disease, according to a Pitt researcher.

The treatment uses the drugs Taxol (paclitaxel) and Paraplatin (carboplatin for injection) in conjunction with thoracic radiotherapy.

An ongoing Pitt study of 38 NSCLC patients projects that 54 percent of them will remain alive after three years. That percentage is compared with an average 19 percent survival rate at the three-year mark for those patients receiving conventional chemotherapy and radiation treatment.

"The message here is that this early, aggressive, well tolerated treatment appears to save a significant number of lives," said study leader Chandra Belani, a Pitt associate professor of medicine and co-director of experimental therapeutics at the University of Pittsburgh Cancer Institute.

Lung cancer is the largest single cause of cancer death in the United States, according to statistics provided by the National Cancer Institute.

The disease is hard to detect and difficult to treat, resulting in it being responsible for one of every four cancer deaths in the nation.

The five-year survival rate for lung cancer victims has remained low — 12 percent in 1973 and 13 percent in 1992. n colleagues from two other centers participating in the National Institute of Allergy and Infectious Diseases MACS project.

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UPMC using new heart drug

Cardiologists at the University of Pittsburgh Medical Center are using a new drug, recently approved by the U.S. Food and Drug Administration, for treating congestive heart failure.

The drug, Coreg (Carvedilol), is the first new drug for the treatment of heart failure in 14 years.

It is the first of its type to be available in the United States for heart failure. "Coreg reduces the heart rate by blocking beta receptors on the cells of the heart. This reduces the work the heart has to do to pump blood," said Srinivas Murali, a Pitt associate professor of medicine and director of transplant cardiology at UPMC.

"In the multi-center trials in which the UPMC participated, Coreg significantly reduced the combined risk of mortality and cardiovascular morbidity. In three other studies, it reduced death from congestive heart failure and total hospitalizations by up to 49 percent," Murali said.

An estimated 4.8 million Americans have congestive heart failure, in which the heart fails to maintain adequate circulation of the blood because of a dysfunction in the pumping action of the heart. Heart failure 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. It also is the leading cause of hospitalization among Americans age 65 and older and, consequently, consumes a significant portion of the Medicare budget.

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Researchers study blood substitute in trauma patients

University of Pittsburgh Medical Center researchers are participating in a study to determine the effectiveness of a new blood substitute in treating trauma patients with severe blood loss. About 40 sites nationwide are participating in the study.

A patented, experimental blood substitute will be given to trauma patients to treat the harmful side effects of severe blood loss and possibly prevent death. The study is made possible by guidelines recently adopted by the U.S. Food and Drug Administration that allow consent to be waived in studies of emergency therapies for patients in life-threatening situations.

Due to the nature of this study, patient consent may not be possible. Obtaining advance consent from family members also will be difficult because the blood substitute must be given within one hour of hospital arrival. Patients or their families will be notified as soon as possible about the study and given the option of whether or not to continue.

About 20 patients will be enrolled in the study at UPMC. Half will receive the blood substitute and half will receive a saline solution. Patients also will be given all current standard treatments.

The blood substitute, developed by Baxter Healthcare Corp., is derived from human red blood cells. A specialized filtration and heating process makes the finished product safe from viruses. The solution carries oxygen and therefore has significant potential in trauma situations where large amounts of blood loss can result in a lack of oxygen to vital tissues. It is easily stored in emergency departments and can be immediately transfused in trauma patients.

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'Triggers' prompt obese to lose weight

In the largest study of its kind, a majority of formerly obese men and women, who lost significant amounts of weight and kept it off, reported that a specific event or incident prompted them to do so.

Nearly 77 percent of the 629 women and 155 men recruited for the National Weight Control Registry study reported that a trigger event preceded their loss of large amounts of weight. About 32 percent of the participants described either a medical trigger (sleep apnea, lower back pain, fatigue, aching legs or varicose veins) or an emotional trigger (for example, one woman reported that her husband left her and her lawyer told her it was because she was too fat).

Women were more likely than men to report an emotional trigger. For over 11 percent of the subjects, the trigger event was seeing themselves in a mirror or photograph.

Mary L. Klem, senior research fellow in the Pitt medical school's psychiatry department, was lead author of the study results, which were published in the August issue of the American Journal of Clinical Nutrition.

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Pitt scientists find clue to why ex-smokers develop lung cancer long after quitting

Smoking for at least 25 years appears to trigger a biological switch that drives the growth of lung cells. Once set in motion, this process could lead to cancer, according to researchers at the University of Pittsburgh Cancer Institute (UPCI) in a report published in the August issue of the Journal of Respiratory and Critical Care Medicine.

"We believe that this switch is a smoking-related indicator of lung cancer risk because we see it activated in most individuals with a long history of smoking, regardless of whether they already have developed cancer," said Jill Siegfried, associate professor of pharmacology at Pitt's medical school and director of basic science at UPCI's Lung Cancer Center.

"Once this switch is turned on, it appears to be permanent, which may explain in part why long-term ex-smokers who have not had a cigarette in over 25 years are still at high risk for getting lung cancer. Knowing when this switch appears in someone's lung could help clinicians administer chemopreventive drugs to avert the final transformation of these cells into cancer. Better still, if we can turn off this switch, we might significantly reduce the odds that an ex-smoker will ever get lung cancer," Siegfried said.

The "switch" is gastrin-releasing peptide (GRP) receptor, a protein that appears on the surface of lung cells in people who have smoked a pack or more of cigarettes for at least 25 years. GRP receptors capture nearby circulating hormones (bombesin-like peptides, or BLPs) which are normally important for maturation of fetal lungs and which spur lung cells to divide in the mature organ. After the GRP receptor appears in an ex-smoker's lung, new clusters of lung cells form. These new cells, in turn, may continue to express GRP receptors which capture more BLPs in a self-perpetuating cycle leading to unrestrained growth of lung tissue.

"Our study is an important first step," Siegfried said. "We are currently conducting a large-scale study of smokers and nonsmokers to confirm these findings and expand our understanding of the steps between smoking and the development of lung cancer, which is a very complex process." Minimally invasive heart bypass more cost effective, better for patients than traditional surgery, UPMC study finds Minimally invasive heart bypass surgery, called MIDCAB, results in significant cost saving and greater benefits to patients when compared to traditional bypass surgery (CABG), according to a study by a University of Pittsburgh Medical Center (UPMC) surgeon in the July issue of the Annals of Thoracic Surgery.

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In MIDCAB, surgeons operate on the heart through a single, three-inch incision, making the stressful procedure of cutting through the breastbone unnecessary. They also operate on the blocked artery while the heart continues to beat, unlike CABG in which the patient is put on a heart-lung bypass machine and the heart is stopped.

"We found that MIDCAB was associated with significantly reduced hospital resource utilization and morbidity," said Marco Zenati, a UPMC cardiothoracic surgeon and principal investigator of the study.

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UPMC to study prevention, treatment of pain associated with amputation and spinal cord injury

For the first time, amputees and people with spinal cord injuries who suffer from chronic pain resulting from their conditions and from prolonged use of manual wheelchairs will be studied to find ways to prevent and minimize that pain, and to find the best combination of treatments for it.

The University of Pittsburgh Medical Center is recruiting subjects for a three-part, $3.5 million study sponsored by the National Institutes of Health.

"People with amputations or spinal cord injuries and persistent pain are a neglected population when it comes to treatment and research," said Thomas Rudy, the study's overall principal investigator. Rudy is a Pitt associate professor of anesthesiology, psychiatry and biostatistics and director of UPMC's Pain Evaluation and Treatment Institute.

"The three projects of this major research program are long overdue steps aimed at minimizing the preventable suffering of people already living with disability," he said. "Among the unique features of this project are the multidisciplinary emphasis, the effort to prevent as well as treat pain, and the integration of sophisticated biomechanical engineering, rehabilitation science, and biometic analyses with clinical activities." The three projects are: "Wheelchair Ergonomic and Chronic Pain Intervention," "Treating Chronic Pain Following Spinal Cord Amputation" and "Measuring Outcomes in Pain Treatment of Spinal Cord Injury and Amputation." Engineering faculty awarded grants David I. Cleland has received a $20,000 grant from the Project Management Institute (PMI) to develop a Project Management/Team Management Sourcebook. The publication will be an annotated comprehensive bibliography dealing with principal contributions featured in the national and international literature on project management. Cleland also has been appointed to the search committee for a new PMI executive director.

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The Ben Franklin Technology Center has awarded $100,000 to Ronald D. Neufeld for a project, "Belt Filter Processing System," to be conducted in conjunction with Roediger Pittsburgh.

Roediger, a major manufacturer of belt filtration equipment, wants to develop a system approach to handling sludge from source generation to final disposal. Pitt is evaluating the linkage between "pre-treating" sludges and filtration characteristics. In addition, the University is developing a proposed standard technique for evaluating pressure filtration applications that is comparable to the standard "buchner funnel" approach for vacuum filters.

The Electric Power Research Institute also has awarded $40,000 to Neufeld for evaluation of an Arizona electric utility fly ash as potential feedstock material for making autoclaved cellular concrete (ACC). ACC is an environmentally benign construction material that uses about 70 percent by weight recycled fly ash as a silica source for the making of low density pre-cast building materials.

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Scientists discover how genes work together to control neural development

Scientists have discovered how three genes work together to regulate the development of nerve cells — fundamental new knowledge that could boost efforts in other areas, including cancer research.

In the Aug. 8 issue of the journal Cell, two research teams reported that they independently made the same discovery. One team is led by Zhi-Chun Lai, assistant professor of biology, biochemistry and molecular biology at Penn State, and Richard W. Carthew, a Pitt assistant professor of biology. Gerald M. Rubin, of the University of California at Berkeley, leads the other research team.

The research is expected to contribute to understanding of the nervous system and the brain.

To make their discovery, Lai and Carthew's team studied fruit-fly eyes to figure out which genes regulate the development of photoreceptor neurons — cells that convert light signals into chemical signals the brain can understand. The team used both genetic studies and cell-culture studies to complement and confirm their findings. "The fly genes we are studying are amazingly similar to their corresponding human genes and, at the very fundamental cellular level, there is no difference between the human cell and the fly cell," Lai said.

During the fourth day of a fly's life, certain proto-eye cells receive instructions from the fly's genes to become either light-filtering cone cells or photoreceptor neurons. "That's when we dissect the eyes to look at them under the microscope," Lai said.

External signals tell the developing cells what kind of cell to become by initiating a cascade of internal molecular reactions called "signal-transduction pathway." "Cancer can result if errors occur in the signal-transduction pathway, giving a cell the signal to divide instead of the signal to become a neuron," Carthew explained.

Last year, Lai discovered an important clue about how a component of the signal-transduction pathway — a special kind of cell-growth regulator known as a neural inhibitor — works genetically. He found that proto-eye cells could become neurons only when the gene for making a protein known as Tramtrack was inactivated.

"Tramtrack is a kind of 'gatekeeper' protein that prevents the cell from differentiating into a neuron," Carthew said. "When the cell receives a signal to become a neuron, the signal-transduction pathway is activated, which induces the production of proteins that somehow get rid of Tramtrack." With that discovery pointing the way, Lai, Carthew and their team began a search to discover exactly which proteins destroy Tramtrack.

The researchers narrowed the list to two proteins, Phyllopod and Sina, and demonstrated that they team up to target the Tramtrack protein for destruction. "We are pretty confident that together Phyllopod and Sina bind to the gatekeeper protein, Tramtrack, which is the kiss of death that marks it for destruction by the cell's garbage-disposal enzymes," Carthew said. "Once the gatekeeper Tramtrack protein is removed, the cell is free to become a neuron. Up until a few years ago, everyone thought developing cells always received positive signals, but now evidence is building at a rapid rate that the message often carried by the signal-transduction pathway is 'kill the gatekeeper.'" Lai added, "Many vertebrate proteins, some known to be involved in cancers, carry a structural feature similar to the Tramtrack protein. We are now searching for other biological systems where genes for Tramtrack-like proteins prevent cell development."


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