University Times

Breast cancer proteins studied

Billy W. Day, professor of pharmaceutical sciences, along with co-principal investigator Jean J. Latimer, assistant professor at the UPCI Center for Environmental Oncology, received $742,500 from the Department of Defense for “Quantitative proteomics of nuclear matrix proteins in novel human ductal carcinoma in situ model systems.”

Ductal carcinoma in situ (DCIS) is the earliest identifiable breast cancer lesion. Day and Latimer will determine differential protein expression in epithelial cell lines derived from normal breast tissue, DCIS lines from women whose disease did or did not progress, and lines taken from the non-diseased breasts of the DCIS patients. Because DCIS is a pre-invasive malignancy, the hope is that these studies will provide a better understanding of it and how it may progress to invasive disease, when to treat patients aggressively and when to avoid aggressive procedures.

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Faster precious metal detection discovered

Pitt chemists have found a fast, easy and inexpensive method that could help in the discovery of palladium and platinum deposits and streamline the production of pharmaceuticals. The research was published online Sept. 21 in the Journal of the American Chemical Society.

The new method, developed in the laboratory of chemistry professor Kazunori Koide, relies on a colorless fluorescein-based solution (similar to that used to find blood residue at crime scenes) that glows green under ultraviolet light when it comes in contact with palladium and platinum, which co-exist in nature.

The process takes approximately one hour as opposed to the current method used in mining and pharmaceuticals, which takes days. In addition, the Pitt lab’s method can accommodate hundreds of samples at once whereas the current technology analyzes samples only one at a time.

“Our method can be used on the mining site,” Koide noted.

Palladium and platinum are excellent catalysts and thus important to the chemical, pharmaceutical and automobile industries. Palladium is used most often in the catalytic converters that render car exhaust less toxic.

Koide said a pharmaceutical company is evaluating his method as a way of detecting trace amounts of palladium in drug samples. Although crucial in drug development, residual palladium in pharmaceuticals can be toxic, which means stringent chemical analysis is required to find the metal.

Shortening the analysis to an hour will help get drugs to market faster and, in mining, find viable quantities of these essential metals.

The paper can be found at www.pubs.acs.org/journals/jacsat/.

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See you next year, doc?

While most patients and physicians believe it’s important for adults to have an annual physical examination, there’s growing debate. A study published in the Sept. 24 issue of the Archives of Internal Medicine raises serious questions about the hefty costs and uneven content of these exams.

In the first systematic study to quantify the number, cost and content of preventive health and preventive gynecological exams, researchers found that an estimated 44.4 million adults a year in the United States, or nearly 21 percent, receive a preventive physical exam, while about 19.4 million women, or 18 percent, receive a preventive gynecological exam. The total costs of these exams and associated preventive services are approximately $5.2 billion and $2.6 billion a year, respectively.

The research showed that preventive health and gynecological exams account for one in 12 adult ambulatory visits. Together, they exceed the number of annual visits for either acute respiratory infections or hypertension. The average physical lasted 23 minutes and cost $116, including related laboratory and radiology services.

Lead author Ateev Mehrotra, assistant professor at the School of Medicine and a policy analyst at RAND Corp., said: “Although annual exams are not recommended by any major North American clinical organization, our health system is clearly devoting a great deal of time, money and resources to them.

“Most patients believe they should see a doctor every year for a physical in which the doctor will examine them from head to toe and order lots of tests. There are many doctors who disagree. Physicians need to reach greater consensus on what we should advise patients to do,” he added.

Many of the preventive health exams in the study included lab tests such as complete blood cell counts and urinalysis that do not clearly improve patient outcomes. “More than a third of annual physicals include potentially unnecessary testing at a cost of more than $350 million a year,” Mehrotra estimated. “That’s nearly the amount of money that the state of Massachusetts is spending annually to provide insurance to the uninsured.”

Researchers found that 80 percent of preventive care occurs outside of annual physical exams, and that most patients were seen by physicians for another reason during the same year.

“This finding supports the idea advocated by some that we should use other visits as an opportunity to deliver preventive care,” Mehrotra said.

But he notes that there are important exceptions. In concurrence with previous studies, the researchers found that preventive physicals and preventive gynecological exams were the most common venue for evidence-based preventive services like mammograms and Pap smears.

Mehrotra and his colleagues hope that their findings will inform future recommendations about the frequency of preventive exams and the feasibility of providing one to all adults in the United States on an annual basis. If every adult were to receive a preventive physical exam annually, the U.S. health care system would need to provide up to 145 million more visits every year, the researchers estimated. That would account for 41 percent of all time spent on direct patient care by primary care physicians. “This underlines the need to find other means of delivering preventive care beyond annual physicals or to advise some patients they can come in much less frequently,” said Mehrotra.

The study was supported by a National Research Service Award from the Health Resources and Services Administration.

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Neurological surgery research presented

Researchers from Pitt’s Department of Neurological Surgery recently presented findings from more than 15 studies at the Congress of Neurological Surgeons annual meeting.

Selected research findings from Pitt faculty included:

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Better disc treatment found

A study combining the results of 13 centers across the United States found that a minimally invasive percutaneous disc decompression technique is significantly more effective in alleviating pain than nerve root injections alone in patients who experienced severe back and leg pain due to protruding lumbar discs.

Patients who underwent percutaneous disc decompression also reported significantly less disability and improved physical function.

The research was presented by Peter Gerszten.

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Stents safely treat ruptured aneurisms

An analysis of the practical use and outcomes of stents in treating ruptured aneurysms in patients found the approach to be as safe and effective as in patients with unruptured aneurysms. The study of 41 patients represents the largest review of the efficacy and safety of Neuroform stents and the required use of anticoagulants and antiplatelets.

Michael Horowitz presented the research.

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Endoscopic skull base surgery found safe

An analysis of complications in 700 patients who underwent fully endoscopic expanded endonasal skull base surgery over a nine-year period suggests endoscopic surgery is a safe approach to the skull base, particularly when compared to results obtained after standard skull base procedures.

Amin Kassam presented the research.

Other research analyzed the outcomes of 61 young patients who underwent endoscopic endonasal skull base surgery to find that this treatment approach may allow for less trauma compared to conventional treatment approaches, which may disrupt growth centers in the craniofacial skeleton and result in facial asymmetry.

Daniel Prevedello presented the research.

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Gamma knife fights neuromas

An analysis of more than 1,200 patients with acoustic neuromas (benign tumors of the eighth cranial nerve in the brain that can cause hearing loss, ringing in the ears or balance problems) indicated that stereotactic radiosurgery using the gamma knife achieved tumor control in 98 percent of patients and was associated with hearing preservation rates in 75 percent of patients.

L. Dade Lunsford, Lars Leksell Professor of Neurosurgery at the School of Medicine and director of neurological surgery’s Center for Image-Guided Neurosurgery, presented the research.

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Playing after paralysis

A study of transient paralysis following trauma among elite football players reveals new information that may be helpful to those making management, rehabilitation and return-to-play decisions.

The study found that neurologically intact athletes with spinal cord (focal cord) decompression may safely return to football after undergoing decompressive surgery and confirmation of fusion, while there may be an increased chance of repeated disc herniation above or below the fusion.

Joseph Maroon presented the research.

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Pitt researcher nets award

Eva M. Szigethy of psychiatry and pediatrics is among 29 researchers nationwide named as National Institutes of Health New Innovator Award winners.

The awards are reserved for new investigators who have not received an NIH regular research or similar grant. The recipients each will receive $1.5 million in direct costs over five years.

In her project, “Understanding and Treating Neuropsychiatric Symptoms of Pediatric Physical Illness,” Szigethy is studying the neurobiological basis of depression in adolescents with inflammatory bowel disease (IBD) to learn more about the interactions between the brain, gut and immune system in how adolescents cope with chronic illness.

Her research will evaluate the efficacy of a modified cognitive behavioral therapy on emotional well-being, physical health, economic costs and neurobiological outcomes.

Szigethy will use translational neuroscience approaches to examine the brain regions that underlie emotional and cognitive processing by comparing youth with active IBD and depression with youth with IBD and no depression, and with normal controls.

Szigethy also will compare the efficacy of a combined cognitive behavioral therapy-physical illness narrative intervention targeting emotional and cognitive processing with supportive non-directive therapy in terms of improving emotional well-being, alleviating physical symptoms and reducing health care costs.

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Bone, mineral research presented

Pitt researchers presented results of their investigations recently at the annual meeting of the American Society for Bone and Mineral Research.

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Hip fractures, low D linked

Women with low levels of vitamin D have an increased risk of hip fracture, according to a study led by the Graduate School of Public Health.

Pitt epidemiology professor Jane A. Cauley and colleagues evaluated patient data on 400 women enrolled in the Women’s Health Initiative observational study cohort who had experienced hip fracture to find that the risk of hip fractures climbed as vitamin D concentrations in their blood decreased.

“The risk of hip fractures was 77 percent higher among women whose 25 hydroxyvitamin D levels were at the lowest concentrations,” said Cauley, who has spent much of the past 15 years investigating the physical changes that take place in postmenopausal women. “This effect persisted even when we adjusted for other risk factors such as body mass index, family history of hip fracture, smoking, alcohol use and calcium and vitamin D intake.”

Though the exact daily requirement of vitamin D has not been determined, most experts think that people need at least 800 to 1,000 international units a day. Many experts believe the current recommended levels of 400 IUs daily should be increased.

The vitamin is manufactured in the skin after sun exposure, and is not available naturally in many foods other than fish liver oils. Some foods are fortified with the vitamin.

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Actonel cuts cancer patients’ bone loss

Breast cancer survivors who took a weekly dose of risedronate, sold as Actonel, lost significantly less bone than those who did not take the drug, according to a two-year study from the School of Medicine.

Director of UPMC’s osteoporosis prevention and treatment center and bone health program Susan Greenspan and colleagues evaluated 87 women in the prevention of osteoporosis in postmenopausal women with breast cancer following chemotherapy study.

All participants in the randomized, double-blind trial received calcium and vitamin D supplements, but half took 35 milligrams of risedronate once a week while others took a placebo.

“Chemotherapy drugs and other medical treatments for breast cancer are known to induce menopause, which can kick-start bone loss, putting survivors at risk for osteoporotic fractures,” said Greenspan, professor of medicine. “This study also looked at changes in spine and hip bone mineral density, as well as evidence of bone breakdown.”

Ninety-seven percent of study participants had normal or low bone mass at enrollment. At baseline, many were taking tamoxifen, a breast cancer drug aimed at estrogen-sensitive tumors that also is sometimes used as a preventive therapy by women at high risk for breast cancer.

While tamoxifen can have a positive impact on bone in postmenopausal women, a small percentage of women were taking aromatase inhibitors (also used for prevention), which can have a negative effect on bone. During the second year of the study, about half the women began taking aromatase inhibitors and stopped taking tamoxifen.

“After 24 months, women in the placebo group had significant bone loss in the spine and hip that we didn’t see in women taking risedronate,” noted Greenspan. “In fact, women taking risedronate had a bone density much higher in the spine and hip than women in the placebo group.” The researchers also observed that the greatest bone loss was found in women on aromatase inhibitors. Even so, risedronate continued to be successful in preventing bone loss.

Other authors from the School of Medicine were Karen T. Vujevich, Adam Brufsky, Barry C. Lembersky, Subashan Perera and Victor Vogel.

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Brugia malayi parasite sequenced

An international team of researchers has revealed the genetic secrets of one of the world’s most debilitating human parasites. Brugia malayi, a roundworm that causes elephantiasis, is estimated by the World Health Organization to have seriously incapacitated and disfigured more than 40 million people worldwide.

According to first author Elodie Ghedin of infectious diseases in Pitt’s School of Medicine, having a complete genetic blueprint of the organism undoubtedly will lead to the development of much better therapies. “The genomic information gives us a better understanding of what genes are important for different processes in the parasite’s life cycle. So, it will now be possible to target these genes more specifically and interrupt its life cycle,” she said.

The study appears in the Sept. 21 issue of the journal Science.

Ghedin led a worldwide team of scientists in the sequencing project while at the Institute for Genome Research, which is now part of the J. Craig Venter Institute, a not-for-profit research organization in Bethesda. The study was funded by the National Institute of Allergy and Infectious Diseases.

Understanding how this particular parasite has adapted to humans may yield medical benefits far beyond treating elephantiasis, said collaborator Alan L. Scott of Johns Hopkins University. “Parasitic worms are a lot like foreign tissue that has been transplanted into the human body. But unlike baboon hearts or pig kidneys, which the immune system quickly recognizes as foreign and rejects, worms can survive for years in the body. Discovering how they do so may someday benefit transplant surgery,” explained Scott.

Donald Burke, dean of Pitt’s Graduate School of Public Health, said, “Insights into the gene activation pathways of B. malayi will undoubtedly speed the pace of discovery of new treatments. And any new interventions to reduce the burden of disfiguring elephantiasis around the world will indeed be welcome.”

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Necrosis studied

A new study led by investigators from the School of Medicine demonstrates that the process of necrosis, thought to be an irreversible pathway to cell death, actually may be triggered as part of a regulated response to stress by the protein SRP-6.

Further, the research team realized that this protein might be harnessed to direct some cells — those in cancerous tumors, for instance — to die, while saving others, such as degenerating neural cells responsible for Alzheimer’s and Parkinson’s diseases. The work appears on the Sept. 21 cover of the journal Cell.

SRP-6 is a serine protease inhibitor (or serpin) that targets the cell’s digestive center, the lysosome. The authors report that the family of intracellular serpins may help cells survive in the face of stressors by protecting against lysosomal injury and its cellular consequences.

Senior author Gary A. Silverman, chief of newborn medicine in the Department of Pediatrics, said: “For years, we believed that cell death related to a catastrophic insult such as a stroke or heart attack that deprives tissue of oxygen couldn’t really be treated, so we focused on strategies to prevent further damage by restoring blood flow as quickly as possible with clot busters and surgery. But our research indicates that necrosis can be interrupted and possibly repaired, even after the injury process is well underway. This insight has exciting implications for the management of heart disease, stroke and neurological illnesses.”

With further investigation, it may be possible to learn to deprive cancer cells of their serpin protectors and target them for death. Alternatively, physicians might be able to boost serpin activity to stop cells from dying — for example, intestinal cells affected by the bacterial infection necrotizing enterocolitis (NEC), a major cause of death and illness in fragile, premature infants.

Primary author Cliff J. Luke, assistant professor of pediatrics at Pitt and an investigator at Magee-Womens Research Institute, said, “There are a lot of diseases associated with cell necrosis, such as stroke, neurodegenerative diseases and NEC, and now we know that the pathway to necrosis is much more systematic than we once thought it was. With further study, we may be able to identify targets of intervention to halt the necrotic progression in some of these diseases and possibly even prevent them.”

The study was funded by the National Cancer Institute, the National Human Genome Research Institute, the Mario Lemieux Foundation and the Twenty-Five Club of Magee-Womens Hospital.

Other Pitt authors were Stephen C. Pak, Yuko S. Askew, Terra L. Naviglia, David J. Askew, Shila M. Nobar, Anne C. Vetica, Olivia S. Long, Simon C. Watkins and Donna B. Stolz, all of the School of Medicine.

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Contraceptive advice lacking

Although prescription medications that may increase the risk of birth defects commonly are used by women in their childbearing years, only about half receive contraceptive counseling from their health care providers, according to a School of Medicine study reported in the Sept. 18 issue of the Annals of Internal Medicine.

First author Eleanor Bimla Schwarz of the departments of medicine and obstetrics, gynecology and reproductive medicine at the School of Medicine, said: “We found that over the course of a year, one in six women of reproductive age filled a prescription for a medication labeled by the Food and Drug Administration as increasing the risk of fetal abnormalities. Unfortunately, many women filling prescriptions that can increase risk of birth defects remain at risk of pregnancy.”

Schwarz and colleagues studied patient data related to all prescriptions filled by more than 488,000 reproductive-aged women during 2001. When they compared medications labeled as increasing the risk of birth defects to safer medications, the researchers found little difference in rates of contraceptive counseling, use of contraception or subsequent pregnancy test results.

The researchers found that internists and family practitioners prescribed the largest proportion (48 percent) of riskier medications to women of childbearing age. Psychiatrists prescribed 15 percent of these drugs; dermatologists, 12 percent; obstetrician/gynecologists, 6 percent, and pediatricians, 3 percent, according to the study.

“Many women — and perhaps their physicians — may be unaware of the risks associated with the use of some medications, the chance that women may become pregnant, or both,” said Schwarz, who also is an assistant investigator at Magee-Womens Research Institute.

While about half of the women in this study had received contraceptive counseling, other studies have shown that nationwide, only about 20 percent of women are advised to use birth control when they receive potentially dangerous medications.

“The scary thing is that we know women in other primary care health care settings are even less likely to get information about birth control,” she said.

“While efforts are needed to ensure that women get information about birth control and the risk of medication-induced birth defects, it also is important to realize that different birth control methods are not equally effective,” she said. “Women who were using the most effective methods of contraception, such as the intrauterine device, or IUD, were least likely to have a positive pregnancy test after filling a prescription for a potentially dangerous medication,” Schwarz said.

“Women should not avoid using prescription medications, but clinicians need to remember that sometimes birth control is needed until a woman is ready to have a healthy pregnancy and a healthy baby,” she added.

This study was funded by the National Institute of Child Health and Human Development and Duramed Pharmaceuticals.

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Antiretrovirals could slow spread of HIV

Giving a daily antiretroviral pill to people to prevent HIV could profoundly slow the spread of the infection in sub-Saharan Africa, where it is a full-blown epidemic, School of Medicine researchers report.

Published by the Public Library of Science in the Sept. 19 issue of PLoS ONE, the findings are based on a mathematical model developed by the researchers to predict the public health impact of pre-exposure chemoprophylaxis (PrEP) — an HIV prevention strategy that uses antiretroviral drugs, currently given in combination to treat HIV-positive individuals, to stop the infection from occurring in the first place.

The model predicts that PrEP, targeted to those at highest behavioral risk, could potentially prevent 3.2 million cases of HIV in southern sub-Saharan Africa alone in 10 years. The region is the epicenter of the global HIV/AIDS epidemic with almost 63 percent of the world’s HIV-infected population, totaling about 22.4 million adults.

Data from animal studies suggest that PrEP is an effective method of preventing HIV infection and it is now under study in human populations. The strategy has its detractors, however, who suggest that the availability and use of PrEP could cause sexual disinhibition in which individuals feel as though they no longer need to practice traditional methods of safe sex, including abstinence, using condoms and limiting sexual partners.

Lead author Ume Abbas of Pitt’s School of Medicine said, “We know that antiretroviral drugs given at or shortly after exposure can reduce the risk of HIV infection. While the ongoing PrEP studies in humans are extremely important, they are not designed to look at the potential public health impact of PrEP. What we hoped to answer with our study is whether there is a potential population-level benefit from PrEP in reducing rates of HIV transmission. We found a substantial benefit can be gained from PrEP, indicating it may play an important role in our arsenal of HIV-prevention strategies.”

The researchers studied three scenarios within the model: an optimistic scenario in which they assumed PrEP was effective 90 percent of the time and used by 75 percent of the sexually active population; a neutral scenario in which PrEP was effective 60 percent of the time and used by 50 percent of the sexually active population, and a pessimistic scenario in which PrEP was effective 30 percent of the time and used by 25 percent of the sexually active population.

The optimistic scenario showed new HIV infections cut by 74 percent if used consistently for 10 years. The benefits in the neutral and pessimistic scenarios were lower — a 24.9 percent reduction in the neutral scenario and a 3.3 percent reduction in the pessimistic scenario.

To address the issue of sexual disinhibition, the researchers assumed a 100 percent increase in risky sexual behavior and observed that while the beneficial effect of PrEP in the optimistic scenario declined when an individual became sexually disinhibited, there was still a notable reduction of HIV infections in the range of 23.4 to 62.7 percent.

The researchers also looked at the cost-benefit of distributing PrEP and found that targeting it to individuals who were the most sexually active and thus at the highest risk for HIV infection produced a significant decline — 28.8 percent — in infections at a much lower cost than distributing PrEP to the general population.

John Mellors, senior author of the study and professor in the School of Medicine and Graduate School of Public Health, said, “Our data highlight the enormous potential public health benefit of pre-exposure chemoprophylaxis against HIV, provided the regimen is efficacious and used consistently daily for a number of years.”

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

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NSF funds CORP project

The National Science Foundation has awarded School of Education professor Margaret Smith $2.1 million to support Pitt’s Cases of Reasoning and Proving in Secondary Mathematics (CORP) project.

The award is a continuing grant that has been approved on scientific/technical merit for approximately five years.

“The goal of this new program is to help high school math teachers better understand what they are teaching and how children understand math,” said Alan Lesgold, dean of Pitt’s School of Education.

According to Smith, the co-principal investigator of CORP, the project’s curriculum will provide opportunities for teachers to improve their own skills related to reasoning and proving and to develop strategies for helping their students engage in these critical mathematical processes.

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NIH funding for mentoring renewed

Michael R. Pinsky of critical care medicine, anesthesiology and bioengineering was awarded a five-year renewal of his Mid-Career Investigator Award from the National Heart Blood and Lung Institute of the National Institutes of Health for his proposal entitled “Clinical applications of heart-lung interactions.”

The award will allow Pinsky the time to continue mentoring young clinical investigators in the fields of clinical and translational research.

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Social marketing aids future docs

A School of Medicine program in which first-year Pitt medical students designed health-related brochures found that the students became more comfortable interacting with patients after being taught marketing principles.

The study appears in this month’s Patient Education and Counseling.

The medical school’s pilot program adopted commercial marketing principles for positive social purposes, also known as “social marketing.” The goal was to help train future doctors to interact with patients who have differing cultural perspectives and limited health literacy, or the ability to obtain and understand basic health information.

According to the Institute of Medicine, nearly 90 million people in the United States are considered to have limited health literacy.

Senior study author Brian A. Primack of medicine and pediatrics in the School of Medicine said, “We have found that social marketing may provide an innovative and compelling framework for teaching medical students to be sensitive to the needs of patients with different degrees of health literacy and diverse backgrounds.”

All 147 students enrolled in Pitt’s first-year medical school class participated. Several student-produced brochures were selected for professional production and distribution in local hospitals and doctors’ offices. Brochures tackled health issues as varied as motorcycle helmet safety, facing the diagnosis of cancer and tattoo and piercing safety.

“After a brief and inexpensive intervention, medical students showed measurable improvement in their understanding of social marketing and health literacy,” said Primack.

“Furthermore, their self-reported comfort interacting with patients of diverse backgrounds after the study was independently associated with their knowledge of health literacy and their experience developing the brochures.”

Co-authors included Thuy Bui, medical director for the program for health care to underserved populations at the School of Medicine, and Carl I. Fertman of health and physical activity in the School of Education.

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UPJ nursing funding awarded

The Pennsylvania Higher Education Foundation has awarded an $18,000 Nursing Education Grant to Nancy Grove, who recently retired as associate professor of nursing and director of the RN-to-BSN program at Pitt-Johnstown.

PHEF provides educational grants and scholarships to nursing students who complete the nursing program during the 2007-08 academic year.

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NSF grant given for engineering ed

The National Science Foundation has awarded $728,875 for a project directed by Larry Shuman, associate dean for academic affairs in the School of Engineering.

“Collaborative Research: Improving Engineering Students’ Learning Strategies Through Models and Modeling” builds upon model-eliciting activities (MEAs) — a methodology that teaches by having small teams of students address open-ended case studies that simulate real-world problems.

The MEA methodology was developed in mathematics education research but recently has been introduced in engineering education.

Investigators are deepening the implementation of MEAs and related student and faculty assessment in undergraduate curricula across six partner institutions. They are broadening the libraries of usable MEAs to different engineering disciplines and extending the MEA approach to misconceptions, innovation and ethical decision-making in engineering.

Pitt co-principal investigators of the study were industrial engineering professor Mary Besterfield-Sacre and visiting research assistant professor Renee Clark.

The other institutions involved are the California Polytechnic State University, Colorado School of Mines, Purdue University, United States Air Force Academy and the University of Minnesota-Twin Cities.

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