University Times

Grants awarded to researchers

Janet Amico of the School of Pharmacy’s pharmaceutical sciences department received $266,613 from the National Institute of Child Health and Human Development for a study, “Oxytocin Regulation by Neurosteroids and GABA-A Receptor.”

GlaxoSmithKline granted $1,963,084 to Derek Angus of the medical school’s critical care medicine department for research on “Genetic and Inflammatory Markers in Sepsis.”

The U.S. Department of Education granted $259,000 to Robert Hayden of the University Center for International Studies. The funds support Pitt’s Center for Russian and East European Studies.

Lewis Kuller of the Graduate School of Public Health’s epidemiology department received $786,475 from the National Center for Chronic Disease Prevention and Health Promotion for continued funding of Pitt’s Center for Healthy Aging.

The center is part of a larger Pitt initiative to coordinate all of its disease-prevention efforts in teaching, care, research and outreach.

The National Cancer Institute granted $650,840 to George Michalopoulos of the medical school’s pathology department for the project, “Molecular Reclassification of Prostate Cancer,” aimed at improving the classification used for making decisions about prostate cancer treatments.

The chemistry department’s John Yates was awarded $1,155,000 by the Army Research Office for research that seeks to supply the fundamental knowledge base for creating a hybrid coating system capable of detecting and destroying chemical and biological agents.

The coating would be applied to the outer surfaces of military vehicles.

Ellen Frank of the medical school’s psychiatry department was granted $1,336,433 by Forest Research Institute for a study, “Depression: The Search for Treatment Relevant Phenotypes.”

The Air Force Office of Scientific Research awarded $622,193 to Steven Levitan of the engineering school’s Department of Electrical Engineering for “Computer-Aided Design of Multi-Domain Micro Systems.”

The National Institute on Drug Abuse granted $522,518 to Michael Vanyukov of the pharmacy school’s pharmaceutical sciences department for continuing research on the roles of DNA polymorphisms, personality and environmental factors in susceptibility to substance abuse disorders.

PPG Industries has awarded $465,198 to Laura Cassidy-Schall of the Graduate School of Public Health’s biostatistics department for research aimed at developing and maintaining a medical surveillance database of workers employed at PPG plants nationwide.

Jeremy Levy of the physics and astronomy department received a $1.2 million grant from the Defense Advanced Research Projects Agency to develop a novel method for meeting requirements of quantum information processing using ferroelectrically coupled quantum dots.

The University of Wisconsin-Madison granted $2,803,180 to Lauren Resnick of the Learning Research and Development Center to develop and implement a development framework for middle school mathematics. The framework will be tested in the Los Angeles Unified School District.

MPC Corp. awarded $483,698 to Michael Wagner of the School of Medicine’s medicine department for research on using information technology to improve clinical preparedness for bioterrorism.

Bell Yung of the University Center for International Studies received a $432,028 Freeman Foundation grant to promote greater understanding of Asian culture through (among other things) providing opportunities to Pitt students to study Asian languages and enhancing access to electronic media resources about Asia.

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Sex-specific gene found for depression

Pitt researchers have identified variants of a gene that, if inherited by women, may contribute to the development of depression. The same variants do not impact men, the researchers say.

The finding, published in the current issue of the journal Molecular Psychiatry, is the first time scientists have been able to zero in on a specific susceptibility gene for depression.

Depression is the second-leading cause of disability worldwide, affecting nearly 10 percent of the population. And, while scientists have made significant progress developing new drugs to treat it, studies that identify specific risk genes may lead to even more effective drugs designed to target depression in specific individuals.

According to George S. Zubenko, professor of psychiatry at Pitt’s School of Medicine and adjunct professor of biology at Carnegie Mellon University, women are twice as likely as men to develop depression, and genetic differences appear to account for some of that disparity.

These latest results build on research published by Zubenko and his team in October 2002. That research identified a small region of chromosome 2 — equal to 0.01 percent of the human genome — as the potential hiding place for a susceptibility gene for depression in women.

“These findings confirm our earlier research suggesting the existence of susceptibility genes that have sex-limited effects on the vulnerability of women to developing severe depression,” said Zubenko.

“More than 80 percent of women in our study who inherited a particular variant of CREB1 developed depressive disorders, while a second version of this gene appeared to have protective effects.”

CREB1 is a gene that encodes a regulatory protein called CREB that orchestrates the expression of large numbers of other genes that play important roles in the brain and the rest of the body as well.

The widespread importance of CREB as a genetic regulator throughout the body suggests that the newly identified CREB1 variants may influence the development of additional psychiatric disorders related to depression, such as alcohol and other substance use disorders, as well as medical conditions that are associated with depression.

The identification of CREB1 leads Zubenko’s team to believe that genes for other components of cell signaling pathways that operate through CREB may be involved in mood disorders.

Alterations in CREB1 expression have been reported in the brains of patients who died with major depression, those of animal models of major depression and related disorders, and in the brains of animals treated with antidepressant drugs.

CREB also has been implicated in neuronal plasticity, cognition and long-term memory, abnormalities of which commonly occur in patients with major depression, may predispose patients to the onset or recurrence of major depression, and may be related to the eventual development of irreversible dementias like Alzheimer’s disease in some patients. Interactions of CREB with estrogen receptors might explain how inherited variants of CREB1 could affect the susceptibility of major depression only in women.

According to Zubenko, further progress in diagnosis and treatment of clinical depression that result from these findings will likely take some time, but research such as this will likely change the way doctors diagnose and treat major depression.

Zubenko said, “Genotyping markers in chromosomal regions that harbor susceptibility genes may provide more immediate advances in the treatment of major depression. For example, individuals with particular genetic markers in these regions may respond better to particular current treatments than others. This strategy may enable clinicians to use genetic markers to better match individual patients to treatments to which they will optimally respond, while minimizing side effects.”

The study received funding from the National Institute of Mental Health.

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Findings reported at AOSSM meeting

Amnesia, confusion may signal concussion

Loss of consciousness may not be the main indicator of a concussion, according to research released July 21 at the annual meeting of the American Orthopaedic Society for Sports Medicine (AOSSM).

“Athletes may sustain a severe concussion without losing consciousness,” said lead author Mark R. Lovell, director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine concussion program. “Amnesia and confusion on the field after injury may be as important, if not more important, in making a return-to-play decision.”

More than 300,000 sports-related concussions occur annually in the United States with at least 62,000 resulting from high school contact sports. Approximately 34 percent of college football players have one concussion and 20 percent have multiple concussions. Contact sports have a 19 percent annualized risk of concussion.

Lovell’s study appears in the July issue of The American Journal of Sports Medicine. He and colleagues James P. Bradley, Michael W. Collins and Charles J. Burke, all from UPMC’s Department of Orthopaedic Surgery, evaluated 181 high school and college athletes with sports-related concussions to analyze the role of loss of consciousness in predicting neurocognitive recovery. Of the athletes studied, 30 had loss of consciousness and 151 had no documented loss of consciousness.

“We recommend that anyone who is thought to have had a concussion not be put back into athletic contest until he or she has been thoroughly evaluated by a physician and undergone neuropsychological testing. This is especially important with athletes 18 years of age and younger because their brains are still developing,” Lovell said.

Concussion grading systems recently have come under scrutiny because of the lack of evidence-based support. Grading scales assign a number based on suspected concussion severity. In the grading systems, loss of consciousness is typically considered to be sole or primary indicator of serious injury. Consequently, athletes exhibiting other symptoms of concussion — including amnesia and confusion — often return to regular activities earlier than those who lost consciousness.

A recent consensus conference on concussion management questioned the role of loss of consciousness and found existing guidelines to be inadequate. Conference recommendations emphasized the value of individualized evaluation and neuropsychological testing.

Lovell said that, given the proper amount of time to heal, young athletes’ brains should completely recover from concussion. Should a young athlete sustain a second concussion before the brain recovers from a previous concussion, the effects of the injuries may become cumulative or lingering.

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Concussion healing may take 10 days

In a second study released at the AOSSM annual meeting, researchers tested a simple, data-based approach to measure the severity of a concussion.

The field of concussion management seems to be evolving beyond non-evidence based numeric grading systems to a data-driven approach, said Michael W. Collins, assistant director of the UPMC sports concussion program within the orthopaedic surgery department and the Center for Sports Medicine. “We have developed a 20-minute computerized test battery that is sensitive to the effects of concussion.”

The Immediate Post-concussion Assessment and Cognitive Test (ImPACT) evaluates different areas of the brain that are sensitive to concussion by measuring reaction time, processing speed, cognitive ability and memory. Numerous national and international professional athletic organizations, as well as 70 colleges and universities, use ImPACT. More than 10,000 athletes have been tested with the system, resulting in a large database of normative values.

For this study, Collins, Mark R. Lovell and Freddie H. Fu compared ImPACT results from 231 concussed high school and college athletes with those of 50 non-concussed age- and gender-matched control subjects. They found that ImPACT accurately identified the concussed athletes.

In addition, they found that recovery time from a concussion could take 10 days, despite the fact that many athletes report improved symptoms by the fifth day following injury. “We are finding memory deficits and neurocognitive functioning deficits that last up until day 10 post injury,” Collins said.

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Manners award winners named

Pitt’s University Center for Social and Urban Research (UCSUR) has awarded the third annual Steven D. Manners Faculty Development Awards, established in memory of the center’s assistant director, who died in 2000 at age 49.

The awards, according to UCSUR director Richard Schulz, are intended to “continue the trend begun by Steve Manners, which was to support faculty members and their research and to improve the research infrastructure at the University.”

Prior to this year, UCSUR offered annually two awards of up to $10,000 each. In 2003, however, because of the large number of applications, UCSUR decided to fund six awards totaling $38,500.

The awardees and descriptions of their projects follow.

• Pamela Peele, associate professor of health economics in the Graduate School of Public Health, for “Health Services Writing Workshop Series.”

Peele intends to create an ongoing resource to help health services researchers produce peer-reviewed publications for broad, multidisciplinary audiences.

• William Klein, assistant professor in the Department of Psychology, for “Communication of Risk Factor Information to Individuals High in Colorectal Cancer Risk.” This study will seek to decrease the incidence of colorectal cancer by exploring the impact of providing targeted risk factor information to individuals at high risk for the disease and adopting health promoting and self-affirming lifestyle activities.

• Daniel Rosen, assistant professor in the School of Social Work, for “An Examination of Informal Social Supports Used by Older Methadone Clients.” Rosen’s goal is to examine the extent of formal and informal social support systems across the life span of older opiate-addicted individuals. services researchers produce peer-reviewed publications for broad, multidisciplinary audience

• Lisa Brush, associate professor in the sociology department, for “Battering, Work and Welfare.”

This project will use data to explore connections among violence against women, poverty and welfare-to-work transition.

• Audrey Murrell, associate professor in the Joseph M. Katz Graduate School of Business, for “The Old Boys’ Network Revisited.”

Because the competitive bidding system used in the construction industry means that primary contractors must rely on a number of subcontractors, Murrell will look at social networks within the industry in Allegheny County and where minorities and women face exclusion.

• Jeannette Trauth, assistant professor in the Graduate School of Public Health, for “Use of Dietary Supplements Among Individuals Enrolled in Clinical Trials for the Treatment of Cancer.”

Studies have shown that patients with cancer who use dietary supplements in addition to conventional medical treatment frequently do not report this to their physicians. This project will document the use of dietary supplements among patients with breast, prostate and colorectal cancer who are enrolled in clinical trials to evaluate the perceptions of oncologists regarding their patients’ use of dietary supplements and to evaluate the design of cancer clinical trials to determine if they specifically address this use.

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Protein genetically engineered to measure, display glucose levels

Two Pitt researchers have created a protein that can not only measure glucose concentrations but also transmit information about those levels.

The research, reported July 15 in the journal Analytical Chemistry, could lead to a safer, less invasive procedure for diabetics to monitor their blood sugar levels than the finger-prick method currently used.

One application of the research would be to embed the protein in a tiny porous capsule implanted just below the patient’s skin. The patient would be able to monitor the glucose level with an optical device that would “read” the color of the protein.

Research assistant professor Kaiming Ye and Distinguished Professor of Engineering Jerome Schultz, both of the Department of Bioengineering in Pitt’s School of Engineering, genetically engineered a glucose indicator protein — a living biosensor — by fusing green fluorescent proteins from a genus of jellyfish to both ends of a glucose binding protein from the bacteria E. coli.

“Our work is on the front line of developing new generation of biosensors called living biosensors that can be used to sense intracellular molecules by microscopy, in real time,” Ye said.

“Typically, biosensors are composed of two elements: a component like an enzyme or antibody that recognizes the presence of another material like glucose and a transducing component that gives a signal that can be measured, such as a colored product from an enzyme reaction or fluorescent molecule,” said Schultz, who directs Pitt’s Center for Biotechnology and Bioengineering.

“In this research, we have genetically engineered a hybrid protein that combines both functions: recognition and transduction,” Schultz explained. “Thus, when this protein is exposed to glucose, the amount of fluorescence changes that can be easily picked up by a photocell, like those in a digital camera, providing a continuous method of measuring glucose in body fluids.”

Since the molecule is entirely a protein, with no synthetic chemical dyes involved, it can be produced directly within, and by, living cells.

Thus, by placing the gene for this protein into cells in which knowing the glucose concentration is important, scientists will be able to measure the fluorescence coming from these cells under different conditions, e.g. in the pancreas when exposed to insulin, or in contracting heart cells, or in the brain to understand how cells are involved in different functions.

The protein has applications beyond simply measuring glucose, according to Schultz. It can be used to understand the metabolism and control in different cell types in various research studies with animals.

Also, this type of protein sensor may become a powerful new tool to understand behavior and the effects of drugs on normal and abnormal cells. The researchers have tested the protein in vitro in mammalian cells and have made a prototype biosensor with the protein.

One of the technical issues yet to be overcome is that the protein is not sensitive to glucose changes in the range of glucose concentrations normally found in blood.

“Our protein works at much lower glucose concentrations than those found in blood,” said Schultz. “So we are working to ‘dumb down’ the response of the protein.”

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Alterations of genes may increase lung cancer risk

Researchers have long sought to explain why some smokers get lung cancer and others do not.

In one of the first studies to suggest that the interaction of two genes may play a role, researchers at the University of Pittsburgh Cancer Institute (UPCI) have found that inheriting alterations in both a DNA repair gene and a cyclin D1 gene may increase the risk of lung cancer in those exposed to tobacco carcinogens.

The preliminary findings were presented July 13 at the annual meeting of the American Association for Cancer Research. 

“We found a strong correlation between genetic polymorphisms in two genes and lung cancer risk,” said Marjorie Romkes, the study’s co-investigator, who is an associate professor in the Pitt medical school’s Department of Medicine and director of the University’s General Clinical Research Center Pharmacogenetics Care Laboratory.

“Our findings, while preliminary, suggest that the co-inheritance of mutations in a DNA repair gene called XPD and the cyclin D1 gene may be linked to increased risk of lung cancer in those exposed to tobacco smoke. While we have known that these genes are linked to lung cancer on their own, this is the first time we have observed that they may interact to increase lung cancer risk.”

The study compared 173 patients with lung cancer to a control group of 184 healthy individuals and found that mutations in both XPD and cyclin D1 (CCND1) occurred more often in the lung cancer patients.

In addition, a strong increase in lung cancer risk was observed among individuals with a smoking history and a combination of mutations in both the XPD and CCND1 genes.

“These findings are important because they have the potential to help us identify those smokers who have a greater likelihood of developing lung cancer,” said Romkes.

“If we can identify individuals at high risk and screen them early, we could have a real impact on morbidity and mortality from lung cancer.”

She added that for the first time these results suggest an interaction between damage to the DNA repair pathway and the cell cycle control pathway, exposure to carcinogens present in cigarette smoke and resultant lung cancer risk.

Cancer is caused when damage in cells results in unregulated cellular growth. When DNA repair genes (whose job is to ensure that genetic information is accurately copied when cells divide) are damaged or mutated, they increase the frequency of other genetic mutations that also can lead to cancer. CCND1, one of the key cell cycle regulators, is important in cell cycle control and is central to the repair of DNA damage before cell division.

Difficult cancer to treat due to its advanced stage at diagnosis, lung cancer is expected to be diagnosed in more than 170,000 people in the United States this year.

The study is funded by a grant from the National Cancer Institute.

Co-investigators on the project include Pitt’s Shama Buch, Bing Zhu, S. Lerdtragool, A. Gaither Davis, Dominic Odom, Jill Siegfried and Jennifer Grandis.

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Common gynecologic complaint linked to herpes risk

Investigators at the Magee-Womens Research Institute have found an apparent link between a common gynecological disorder called bacterial vaginosis (BV) and an increased risk for the acquisition of herpes.

The Pitt-affiliated researchers report their findings in the August issue of Clinical Infectious Diseases, which is the journal of the Infectious Diseases Society of America.

“We found that women with BV were nearly twice as likely to get herpes as women who did not have BV,” said Thomas L. Cherpes, an infectious disease fellow at Pitt and the study’s first author. “The presence of BV seems to increase susceptibility to herpes infection in women.”

Worldwide, herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted diseases. At least 45 million people are estimated to have genital herpes in the United States alone, according to Sharon Hillier, professor in the departments of obstetrics, gynecology and reproductive sciences and molecular genetics and biochemistry at Pitt’s School of Medicine and senior author of the study.

BV also is a frequently diagnosed condition.

“Symptoms of discharge are one of the most common reasons women visit a gynecologist,” said Hillier, adding that BV rates in some populations are estimated to be as high as 50 percent.

“Other studies, too, have shown that women who have BV are more likely to get other sexually transmitted diseases such as gonorrhea and HIV,” she added.

The Pittsburgh study also noted that risk appears to be higher among African-American women.

BV is characterized by an increase in vaginal alkalinity and substitution of certain beneficial bacteria, particularly those that produce hydrogen peroxide, with more toxic bacteria. This depletion of hydrogen peroxide-producing bacteria is believed to result in diminished defense against sexually transmitted diseases.

The Pitt study involved 1,248 sexually active women 18 to 30 years of age. After initial screening for BV and HSV-2 status, the women were asked to return three more times at four-month intervals for follow-up testing. At each visit, vaginal swabs and blood samples were collected for subsequent evaluation.

Of the 670 women who were negative for HSV-2 at enrollment, 32 acquired antibodies to HSV-2 during the study period. When adjusted for other variables, it became clear that the presence of BV was a significant indicator of risk for subsequent HSV-2 infection when compared with women who had normal vaginal flora.

“It seems likely that more comprehensive screening and appropriate treatment could reduce susceptibility to HSV-2,” Hillier said.

Unlike HSV-2, which typically has a life-long duration of infection, BV can often be effectively treated with a short course of antibiotics.

Other study authors include Leslie Meyn, Marijane Krohn and Joel Lurie, all of the Magee-Womens Research Institute.

The research was funded by the National Institute of Allergy and Infectious Diseases.