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University of Pittsburgh

December 6, 2012

Research Notes

HIV research garners nearly $11.5 million

Researchers at the Schools of the Health Sciences and Magee- Womens Research Institute (MWRI) have been awarded four grants totaling nearly $11.5 million from the Bill & Melinda Gates Foundation.

According to the foundation, more than 22 million new infections will occur by 2015 despite the current decline in infection rates. The foundation’s aims are to stop the spread of HIV by expanding access to successful prevention strategies and to identify and research new ways to prevent HIV transmission.

In a $5 million, three-year project led by Sharon Achilles, faculty member in the Department of Obstetrics, Gynecology and Reproductive Sciences and MWRI investigator, scientists will examine whether hormonal contraceptive methods cause changes in genital tract immune cells, the cells that HIV targets for infection.

“Some studies have indicated that the use of birth control shots, pills or other hormone-based contraception is associated with a higher risk for HIV,” Achilles said. “This presents a challenge because HIV prevention strategies and contraception should work together, rather than in opposition, to maximize the public health benefit.”

In Harare, Zimbabwe, 250 healthy women who are initiating use of one of five commonly used contraceptives will be monitored for six months.

Pitt co-investigator is Sharon Hillier, also of the Department of Obstetrics, Gynecology and Reproductive Sciences.

In the $4.5 million, two-year Options Now (ON) project, researchers will assess the acceptability and safety of injecting rilpivirine, a long-acting HIV drug, into the muscle of HIV-negative people with the aim of preventing infection.

The research team is led by Ian McGowan, faculty member in medicine and obstetrics, gynecology and reproductive sciences, co-principal investigator of the Microbicide Trials Network (MTN) and MWRI investigator. It also includes Beatrice A. Chen and Ross D. Cranston, both of the School of Medicine and MWRI.

“A system of regular injections has been shown to be acceptable, feasible and effective for women worldwide as a method of pregnancy prevention,” McGowan said. “We want to see whether this kind of strategy will be effective at reducing the risk of HIV infection.”

This summer, federal officials approved Truvada, another treatment drug, for use as an HIV prevention agent after two large studies showed it was effective in men who have sex with men and in couples in which one partner is HIV positive and the other is not. Researchers from the MTN are waiting for results from a major clinical trial called VOICE, which will be key to determining whether Truvada is a viable prevention option for women.  In the meantime, researchers are looking at other drug formulations, such as topical gels, vaginal rings and monthly injections that might be preferred over a daily pill and more apt to be used.

A first-of-its-kind collaboration between the Center for Vaccine Research (CVR), the Drug Discovery Institute (DDI) and the Graduate School of Public Health (GSPH) received a $1 million, three-year grant to develop a novel test to detect HIV in its earliest stages.

GSPH Dean and CVR director Donald S. Burke, who also is the UPMC-Jonas Salk Chair of Global Health, is the principal investigator on the project.

Current tests rely on a few proteins made only by the HIV virus itself to detect anti-HIV antibodies in the blood. In new infections, these antibodies typically are at low levels, so it often takes months before a person tests positive for HIV and sometimes years before symptoms develop. The Pitt test is taking a new approach. Instead of looking only at proteins made by the virus, this research will examine a novel class of HIV biomarkers in patient blood samples. This approach utilizes synthetic molecules that resemble proteins and can be produced in millions of different variations. This larger diversity of biomarker targets increases the ability to detect new HIV infections, as well as distinguish between recent and established infections.

Such a test would allow public health workers to determine if a Third World country’s HIV infections are a recent development and how fast the virus is spreading, and physicians could factor in duration of infection to better tailor anti-HIV regimens.

Pitt co-investigators include Ronald Montelaro and Ernesto Marques of the CVR; Lansing Taylor and Mark Schurdak of the DDI, and George Tseng of GSPH.

Lisa Cencia Rohan, a faculty member in the School of Pharmacy and an investigator at MWRI, is leading a 15-month, $758,000 project that will assess the feasibility of thin film dosage forms for vaginal delivery of contraceptive or HIV prevention drugs.

Rohan is co-principal investigator with Sharon Hillier on a recently launched, early-stage clinical trial to test the safety of a vaginal film preparation containing a microbicide called dapivirine to ward off HIV infection. But before safety and efficacy trials can be expanded, Rohan noted, “it must be determined whether such a product can be successfully manufactured and distributed to resource-poor locations and what traits it must have to be acceptable to large numbers of users in a variety of settings.”

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NIH funds Biomedical Technology Research Ctr.

Pitt’s School of Medicine, Carnegie Mellon University (CMU) and the Pittsburgh Supercomputing Center (PSC) have been awarded a five-year, $9.3 million grant from the National Institutes of Health (NIH) to establish the Biomedical Technology Research Center (BTRC), which will develop computational tools for modeling and simulating biological systems from the tissue level down to the molecular level.

By filling in the missing pieces between modeling efforts at disparate scales of structural biology, cell modeling and large-scale image analysis, this initiative seeks to identify the molecular and cellular mechanisms that control neurotransmission and signaling events, which in turn could lead to the development of novel treatments for nervous system disorders.

Principal investigator Ivet Bahar, the John K. Vries Chair of the Department of Computational and Systems Biology in the School of Medicine, said: “With these tools, our goal is to better understand and appreciate the impact of defective proteins and interactions at the cellular level, and their effects on the central nervous system behavior. We hope to bridge the gaps between molecular-, cellular- and tissue-level information to build integrated models of cell signaling and regulation.”

Robert F. Murphy, director of the Lane Center for Computational Biology in Carnegie Mellon’s School of Computer Science, will lead CMU’s participation. The PSC’s long-established National Resource for Biomedical Supercomputing (NRBSC), headed by Markus Dittrich, is the third major partner. The collaboration includes the Salk Institute for Biological Studies in La Jolla, Calif.

A supplementary award of $1.1 million provides two years of additional support for the Anton supercomputer, which the NRBSC  has  made  available to U.S. biomedical scientists since 2010. The special-purpose computing system from D.E. Shaw Research has achieved exceptional results in the simulation of proteins and other biomolecules.

Bahar’s team will tailor computational models for five biomedical research projects including neurotransmitter signaling, immune cell regulation and neuronal circuit reconstruction that are underway at Pitt, Caltech, Allen Brain Institute (Seattle), and UT Southwestern Medical Center.

Bahar noted: “Until now, experimental scientists have been collecting data that are not testable by computational methods, while the computational scientists have been building models and making predictions that can’t be verified experimentally. We aim to bridge this communication gap, too, so that we can solve relevant problems computationally while generating new hypotheses that can be tested in the lab.”

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Light shed on virus linked to developmental delays, deafness

A School of Medicine study published online in PLOS ONE reveals that primitive human stem cells are resistant to human cytomegalovirus (HCMV), one of the leading prenatal causes of congenital intellectual disability, deafness and deformities worldwide.

Researchers found that as stem cells and other primitive cells mature into neurons, they become more susceptible to HCMV, which could allow them to find effective treatments for the virus and to prevent its potentially devastating consequences.

Senior author Vishwajit Nimgaonkar, faculty member in psychiatry, said, “This study is the first of its kind, and the first to discover that primitive stem cells are actually resistant to HCMV.”

Access to cultured human neurons, necessary to understand the pathogenic effects of HCMV, has been limited by difficulties in growing the brain cells in the laboratory. Yet through human-induced pluripotent stem (iPS) cells, researchers were able to overcome this hurdle.

The study authors derived live iPS cells by reprogramming cells called fibroblasts obtained from human skin biopsies. The iPS cells then were induced to mature through several stages into neurons, the primary cells in the brain. The researchers were able to evaluate the patterns of damage caused by HCMV on all these cells.

The research findings suggest:

• Human iPS cells do not permit a full viral replication cycle, suggesting for the first time that these cells can resist CMV infection.

• CMV infection distorts iPS cell differentiation into neurons, and that may be a mechanism by which infected babies develop impairments of brain maturation and intellectual ability.

• iPS-derived mature neurons are more susceptible to CMV infection and once infected show effects including defective function that have been shown in other animal studies and in other human tissues. The neurons die a few days after infection lab studies, possibly reflecting the impact of CMV on the human brain.

“The findings were quite surprising, but this is only the first in a series of studies on HCMV,” added Nimgaonkar. “There is a lot of interest in what we can do to treat the infection, and current work is already underway to screen for new drugs that could be used to fight these viruses.”

In the United States, 50-80 percent of people have been infected with HCMV by the time they reach 40. Infections rarely are serious, but the virus does not leave the body. CMV also is the most common congenital infection in the United States, occurring when a woman contracts CMV during pregnancy and passes the virus to her fetus. According to the U.S. Centers for Disease Control and Prevention, one of every 150 children is born with CMV infection and one in five of them develops permanent problems, such as intellectual disability, vision and hearing loss, and seizures.

Pitt researchers are collaborating with the Drug Discovery Institute to further understand the cellular system and determine which agents are most effective against HCMV and similar viruses, and which treatments would be safe for human use.

The lead author was Leonardo D’Aiuto. Other Pitt collaborators were Roberto Di Maio; Brianna Heath, Annie M. Watson and Mikhil Bamne of GSPH; Giorgio Raimondi, Jadranka Milosevic, Lei Yang, Bo Lin, Jocelyn Danielle Mich-Basso, and Etienne Sibille of the School of Medicine; W. Tony Parks, and Toshio Miki.

This work was supported by the Stanley Medical Research Institute, the National Institute of Mental Health, the National Center for Research Resources, the NIH Roadmap for Medical Research and Pitt’s Department of Psychiatry.

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Ultrasound for breast cancer screening?

Ultrasound screening could be a more affordable and convenient way to detect early breast cancers in women, especially where there is little access to mammograms, according to School of Medicine researchers. The results, part of a multinational study that looked at ultrasound as an adjunct to screening mammography, were presented last week at the annual meeting of the Radiological Society of North America.

Researchers, led by Wendie Berg, faculty member in radiology and a radiologist at Magee-Womens Hospital, reviewed data from the ACRIN 6666 study, which found that the addition of a screening ultrasound or magnetic resonance imaging test to annual mammograms was associated with a breast cancer detection benefit for women. Berg’s team evaluated the data from the perspective of using ultrasound as the primary screening method, taking into consideration cancer detection, patient recalls, the number of biopsies performed and whether those biopsies showed breast cancer.

“We found that breast cancer detection with ultrasound alone compares quite favorably to mammography alone, and was actually better at detecting early invasive breast cancers,” said Berg. “Ultrasound screening could be a viable option, particularly in countries where ultrasound is readily available but access to mammography is limited.”

In the study, 2,662 participants enrolled at 21 sites in the United States, Canada and Argentina completed three annual rounds of mammography screening followed by whole breast ultrasound screening, with a 12-month clinical follow-up in the fourth year. Ultrasound screening picked up 53 percent of all breast cancers, as did mammography screening. More importantly, invasive breast cancers constituted the vast majority of cancers detected by ultrasound. Screening ultrasound, however, did result in more false positive results than mammography.

The research was funded by the Avon Foundation for Women and the National Cancer Institute.

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Timing crucial for spinal cord patients

Timing is everything when it comes to inducing plasticity, or adaptation, in the spinal cord to improve voluntary movement, according to researchers at the School of Medicine.

In a study published online in Current Biology, they demonstrated that the temporal order at which impulses from the brain and a peripheral nerve arrived at the spinal cord is critical to improving hand strength and dexterity among patients with a chronic, incomplete spinal cord injury.

The number of survivors after spinal cord injury has risen dramatically over the past few decades. More than 50 percent of all spinal cord injury survivors experienced cervical lesions, which often result in impairments in hand and arm motor function, explained senior author Monica A. Perez, faculty member in the Department of Physical Medicine and Rehabilitation and the Systems Neuroscience Institute in the School of Medicine.

“We are using noninvasive electrophysiological measures to understand the mechanisms of recovery and to determine how we can best enhance transmission of remaining descending pathways to muscles in patients with incomplete spinal cord injuries,” she said. “The ultimate aim is to improve the patient’s ability to execute daily functions, such as eating and grasping, as independently as possible.”

In the study, lead author Karen L. Bunday, a postdoctoral research scholar in Perez’s lab, paired transcranial magnetic stimulation of the hand area of the brain’s motor cortex and electrical stimulation of a peripheral nerve in the wrist that innervates hand muscles in 19 participants with chronic cervical spinal cord injury and 14 uninjured participants. The paired pulses, which are noninvasive and painless, were given 100 times over approximately 17 minutes.

Unlike other stimulation techniques currently used in clinical studies, the researchers targeted the synapse, or junction, between corticospinal fibers and spinal motor neurons.

The researchers found that when impulses from the motor cortex were timed to arrive at the spinal cord precisely 1-2 milliseconds before impulses from a peripheral nerve in the wrist reached spinal motor neurons, there were improvements in hand muscle activity, strength and manual dexterity in a precision grip task in spinal cord injured patients. Researchers also observed an increase in corticospinal transmission in both injured and uninjured individuals that lasted for up to 80 minutes.

“We learned that we can noninvasively stimulate the brain and the peripheral nerve in a more efficient way,” Bunday said. “The timing between brain and peripheral nerve stimulation has to be precisely set in order to effectively improve voluntary movement. We customized the paired stimulation protocol to each person, which allowed us to take into account individual differences and conduction delays which are present after spinal cord injury.”

“We are now further examining the mechanisms of this plasticity and ways to make these changes more persistent,” Perez said.
The project was funded by the National Institute of Neurological Disorders and Stroke and the Paralyzed Veterans of America.

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E-visits = more antibiotics

Researchers at the School of Medicine and UPMC found that patients who contacted their doctors electronically via an e-visit for sinusitis and urinary tract infections (UTIs) were no more likely to need follow-up care than those who saw doctors in person.

However, e-visit patients were more likely to receive antibiotics, and those with UTIs in particular were less likely to have relevant testing ordered by their physicians before receiving medication.

The findings, available online in the Archives of Internal Medicine and appearing in the Jan. 14 print edition, covered four primary care practices at UPMC. The researchers examined data from 5,165 visits for sinusitis and 2,954 visits for UTIs from Jan. 1, 2010, to May 1, 2011.

Nine percent of the visits for sinusitis and 3 percent for UTIs occurred through the Internet.

In a UPMC e-visit, patients log in to a secure personal health record portal and answer a series of questions about their conditions. Doctors typically reply through the portal within a couple of hours, have full access to the patient’s electronic medical record, and can prescribe drugs electronically.

“The main concern about e-visits, now offered in various forms by numerous health systems, has centered on quality issues — specifically about whether physicians can make accurate diagnoses without a physical exam, whether the use of tests and follow-up visits is appropriate and whether antibiotics might be overprescribed,” said lead author Ateev Mehrotra, faculty member in internal medicine at the School of Medicine and a researcher at the non-profit RAND Corp. “Our findings refute some of these concerns and support others.”

The researchers found that for each condition, there was no difference in how many patients had a follow-up visit either for that condition or for any other reason.

“Follow-up rates are a rough proxy for misdiagnosis or treatment failure, so the lack of difference should be reassuring to patients and physicians,” said Mehrotra.

However, physicians were more likely to prescribe an antibiotic at an e-visit for either condition.

“When physicians cannot directly examine the patient, they may be more likely to take a ‘conservative’ route and order antibiotics,” Mehrotra said. This is a concern because misuse of antibiotics is leading to an increase in drug-resistant germs.

For UTIs, the researchers found that physicians were less likely to order a urinalysis or urine culture, which can confirm a bacterial infection, after an e-visit (8 percent compared with 51 percent of office visits).

Few sinusitis-relevant tests were ordered for either type of visit.

While Mehrotra and his team did not directly measure costs, Medicare reimbursement data and other studies provide some evidence that e-visits have the potential to decrease health spending.

For UTI visits, Medicare reimbursement for an e-visit was $40 compared with $69 for an office visit. Additionally, the lower rate of testing at e-visits outweighed the increase in prescriptions. In total, the estimated cost of UTI care was $74 for an e-visit compared to $93 for office visits.

Mehrotra cautioned that the study has some limitations, including that it captured only follow-up visits, not outcomes, such as resolution of symptoms. The team also did not compare phone care, which is commonly provided in primary care practices, to electronic or office visits.

“Our initial findings emphasize the need to continue assessing the clinical impact of e-visits as their popularity grows,” said Mehrotra.

Also author on the paper were Steven M. Albert of GSPH  and Suzanne Paone, G. Daniel Martich  and Grant J. Shevchik, all of UPMC.

The study was funded by UPMC and NIH.

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Seniors’ sleep habits better than commonly thought

More than half of retired people aged 65 and over report sleeping at least 7.5 hours per night, and between the hours of 11 p.m. and 7:30 a.m., contrary to commonly held assumptions that most elderly go to bed early and have trouble sleeping through the night.

Those findings came from a study by researchers at Pitt’s Sleep and Chronobiology Center (SCC) and University Center for Social and Urban Research (UCSUR).

The study, supported by the National Institute on Aging, was conducted over five years and provided empirical self-reported data on the timing, quality and duration of sleep, as well as levels of daytime sleepiness in a large sample of retired older adults.

“Our findings suggest that in matters regarding sleep and sleepiness, as in many other aspects of life, most seniors today are doing better than is generally thought,” said Timothy H. Monk, the study’s lead author and faculty member in psychiatry. “The stereotype of most seniors going to bed at 8 p.m., sleeping very lightly and being unduly sleepy during the day may be quite inaccurate, suggesting that 60 really is the new 40.”

Researchers based the study, published in the journal Healthy Aging and Clinical Care in the Elderly, on extensive telephone interviews with nearly 1,200 retired seniors in western Pennsylvania.

About 25 percent said they slept fewer than 6.7 hours per night and experienced problems with nocturnal sleep and daytime sleepiness. The remaining 75 percent reported sleeping more than 6.75 hours, on average.

According to the authors, previous studies have highlighted the chronic sleep disruption often experienced by older adults, but few of these reviews were supported by strong empirical data and many concentrated on illness, thereby furthering stereotypical beliefs that older adults sleep for shorter periods of time, go to bed and rise very early, and experience daytime sleepiness.

Additional observations include:

• Age-related sleep problems in older adults may depend largely on the health of the individual, rather than on the age of that individual.

• Most seniors do not have reliably earlier bedtimes than younger adults and report sleeping at least 7.5 hours per night.

• Daytime sleepiness in older adults often can be associated with medications, illnesses and poor nocturnal sleep, and may not be necessarily associated with age.

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Patient-centered outcomes research funded

The Patient-Centered Outcomes Research Institute (PCORI) has awarded $678,000 to Paul A. Pilkonis, faculty member in psychiatry and psychology.

PCORI is an independent, non-profit organization authorized by Congress under the Affordable Health Care Act. Its mission is to fund research that will provide patients, their caregivers and clinicians with the evidence-based information needed to make better-informed health-care decisions.

The goal of the Pitt project, entitled “Evaluating PROMIS Instruments and Methods for Patient-Centered Outcome Research: Substance Use Treatment,” is to implement and assess measures of health status administered by computer during treatment programs for substance abuse.

The study will combine work from the Pittsburgh research site of the Patient-Reported Outcomes Measurement Information System (PROMIS), supported by NIH, with the PCORI agenda.

The study will use newly developed measures for alcohol use as well as measures from other domains of health, including pain, fatigue, physical functioning, emotional distress, sleep disturbance and social participation.

The computerized reports of patients will be translated into visual displays that summarize, at a glance, an entire profile of health status.

Given the usual focus on abstinence in the treatment of substance abuse, comprehensive assessment of other aspects of physical and mental health often receives less attention.

The purpose of the newly funded work is to improve the partnership between patients, their providers, managers of treatment programs and clinical researchers by implementing a brief and efficient tool to assess health status, thereby bringing increasingly personalized treatment to the substance use setting.

The research activities will take place in the outpatient clinics of UPMC’s Addiction Medicine Services.

Co-investigators are Lan Yu of the Department of Medicine and Dennis Daley of the Department of Psychiatry.

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The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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