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June 27, 2013

Research Notes

Big data show promise in breast cancer research

Eight months into its $100 million, five-year enterprise analytics effort, Pitt and UPMC are starting to see the potential of this big-data technology for accelerating scientific discoveries and the promise of personalized medicine.

With the foundational architecture of UPMC’s new enterprise data warehouse in place, Pitt researchers  for the first time were able to electronically integrate clinical and genomic information on 140 patients previously treated for breast cancer.

Said Adrian V. Lee, School of Medicine faculty member in the Department of Pharmacology and Chemical Biology and director of the Women’s Cancer Research Center at the University of Pittsburgh Cancer Institute and Magee-Womens Research Institute: “One of the first questions we asked was, ‘Is there a difference, a unique difference, between pre-menopausal and post-menopausal breast cancer?’ We are interested in this question from a research standpoint because we are moving toward personalized medicine, and personalized medicine is all about finding subgroups of patients who have a specific type of disease for which we could develop novel therapies.”

In this case, the researchers found intriguing molecular differences in the makeup of pre-menopausal vs. post-menopausal breast cancer. While understanding those differences will require more research, the findings eventually could provide a roadmap for developing targeted therapies, noted Lee.

This initial cancer question is just the start of Pitt’s and UPMC’s effort to mine massive amounts of data — clinical, genomic, proteomic, imaging and financial, to name a few — in the pursuit of smarter medicine. Traditionally, these data have resided in separate information systems, making it difficult, if not impossible, to integrate and analyze dozens of variables. “The integration of data, which is the goal of the enterprise data warehouse, allows us to ask questions that we just simply couldn’t ask before,” said Lee.

Having the foundation of the analytics system will make it easier to explore other types of cancer and other diseases, he said. And while the data warehouse started with only two types of breast cancer “omic” data — gene expression and copy number variant data, measuring changes in the amount of DNA — many more will be added.

The breast cancer research was chosen as a test of the enterprise data warehouse because of the rich genomics data available on these 140 patients. Their de-identified information previously had been submitted as part of a federally funded project called The Cancer Genome Atlas, a multicenter effort to produce comprehensive genomic maps of the most common cancers.


Med faculty receive PCORI grants

Two School of Medicine faculty have been selected for research awards by the Patient-Centered Outcomes Research Institute (PCORI), one for $2 million to develop an online tool for the management of sickle cell disease and one for $1 million to improve detection and intervention in cases of child abuse through the use of electronic medical records.

Lakshmanan Krishnamurti, Division of Hematology/Oncology, and Rachel P. Berger, pediatrics, are leading two of 51 projects totaling $88.6 million over three years that PCORI has approved to conduct patient-centered comparative clinical effectiveness research projects.

Krishnamurti is the lead investigator on a project to create an online tool for people with sickle cell disease. SCD is an inherited disorder that affects 90,000 individuals in the United States, largely of minority origin, according to the American Journal of Hematology. SCD is associated with chronic multisystem manifestations as well as substantial morbidity, premature mortality, individual suffering, health-care costs and loss of productivity.

Said Krishnamurti: “Sickle cell disease is a serious disease with multiple treatment options such as a drug called hydroxyurea that modifies the course of the disease, monthly blood transfusions that decrease the proportion of abnormal red blood cells in the circulation, and bone marrow transplantation that replaces the patient’s marrow with that of marrow from a matched healthy donor and essentially eliminates the production of abnormal red blood cells.

“These treatments can prevent complications and improve the lives of patients, but they can be associated with significant side effects. It can be difficult for families to make decisions on the treatment that is best for them, their disease severity and their preferences. This tool will help patients and families make informed decisions about the treatments that are best for their individual situation and in keeping with their values and preferences.”

Berger, a member of the child protection team in the child advocacy center at Children’s Hospital, will lead a project using the hospital’s electronic medical record to help improve outcomes for children of abuse and decrease disparities in screening for child physical abuse.

Said Berger: “Child abuse truly is an under-recognized public health epidemic and is one of the leading causes of death and disability of infants and toddlers. The key to decreasing the morbidity and mortality is early detection and intervention.

“The goal of our study is to determine whether we can improve and standardize the way in which physicians and other health-care professionals screen for physical abuse in infants and toddlers. By standardizing screening, we hope to decrease or even eliminate the racial disparities that currently exist in which infants and toddlers receive the recommended screening.”


Extra-porous materials may aid gas storage & drug delivery

Researchers in the Dietrich School of Arts and Sciences have designed a family of materials that could make drug delivery, gas storage and gas transport more efficient and economical.

The recent work builds upon chemistry faculty member Nathaniel Rosi’s research published in 2012 in Nature Communications detailing a new class of metal-organic frameworks: crystalline compounds consisting of metal vertices and organic linkers that form porous structures. Last year, Rosi and his team created one of the most porous materials known at the time by changing the size of the vertex (the metal cluster) rather than the length of the organic linkers. Now, he and his team have extended those linkers, demonstrating a family of materials even more porous — a property necessary for more efficient gas storage.

Rosi, principal investigator of the project, likens his work to that of a builder remodeling a child’s chair. As the child grows taller, the legs of the chair become too short. Because the owner likes the structure and integrity of the chair, the owner decides to lengthen its legs instead of purchasing a new one. This is what Rosi and his team have done with their frameworks: they have used one material as a structural blueprint and replaced another element (the organic linkers) to prepare more porous materials.

In addition to their utility for gas storage, these porous materials could be critical for low-cost industrial separations, when one molecule is separated from another batch of molecules for purification purposes. The petrochemical industry has numerous high-value (and high-cost) separations used to isolate important chemicals involved with oil refining. Some of these separations could benefit from the use of porous materials as filters, said Rosi. Likewise, he notes that the pore size for his class of materials would be particularly useful for separating nanoparticles. Porosity also can affect the efficiency of pharmaceutical delivery into the human body.

An important metric for evaluating the porosity of a material is its pore volume. In Rosi’s demonstration, three of these materials have pore volumes exceeding 4 cubic centimeters per gram (cc/g). Only one other metal-organic framework has a pore volume above this amount, with most others having volumes below 3 cc/g.

Said Rosi: “Pore volume is a measure of how empty or vacant a material is — how much space in the material isn’t filled. When the pore openings are large, and the pore volume is large, it opens up the possibility of using the material as a scaffold to precisely organize and position biomolecules or nanoparticles in space.”

Rosi and his team currently are investigating high-porous and low-density materials to be used as scaffolds for organizing large molecules and nanoparticles into functional materials. His team members include Tao Li, a Pitt graduate student studying chemistry and the lead researcher on the project, along with Pitt undergraduate chemistry students Mark T. Kozlowski and Evan A. Doud and a Chatham University student.

A portion of the work was performed with funding from the National Energy Technology Laboratory’s Regional University Alliance, using instruments from the Petersen Institute for Nanoscience and Engineering and the Swanson School of Engineering’s Department of Mechanical Engineering and Materials Science.

The findings were reported in the latest issue of the Journal of the American Chemical Society and first published online May 20 in JACS.


IS professor wins Army research award

Peter Brusilovsky, chair of the graduate information science and technology program and faculty member in the School of Information Sciences, has been awarded a $623,005 contract from the U.S. Army Contracting Command to study technological architecture, algorithms and interfaces that support a new Advanced Distributed Learning Initiative project exploring a variety of approaches that enable educational software to adapt to the goals, knowledge and personal traits of individual learners. This initiative provides state-of-the-art education and training for workers in the U.S. Department of Defense and other units of the federal government.

The three-year-contract will support Brusilovsky’s work with the initiative’s “Personal Assistant for Learning,” an architecture model for personalized learning to be used across platforms and devices, including mobile phones. Brusilovsky will help to build the software needed to improve the ways in which computers support humans.


Engineering prof’s paper named one of top 25 most influential

Alex Jones, faculty member in electrical and computer engineering and director of the computer engineering program in the Swanson School of Engineering, has been recognized for writing one of the top 25 most influential papers in the 20-year history of the annual symposium on field-programmable custom computing machines.

The  paper,  “A  MATLAB Compiler for Distributed, Heterogeneous, Reconfigurable Computing Systems,” examines how to simplify the process of reconfigurable computer coding using MATLAB software, which is employed by engineers, scientists and others to analyze data, create algorithms and produce models and applications.


fluSick leave may reduce spread of flu

Allowing all employees access to paid sick days would reduce influenza infections in the workplace, according to an analysis by Graduate School of Public Health modeling experts.

The researchers simulated an influenza epidemic in Pittsburgh and surrounding Allegheny County and found that universal access to paid sick days would reduce flu cases in the workplace by nearly 6 percent and estimated it to be more effective for smaller workplaces.

Said lead author Supriya Kumar, a post-doctoral associate in the Department of Epidemiology: “Our simulations show that allowing all workers access to paid sick days would reduce illness because fewer workers get the flu over the course of the season if employees are able to stay home and keep the virus from being transmitted to their co-workers.”

In addition to investigating the impact of universal access to paid sick days, Kumar and her colleagues looked at an alternative intervention they termed “flu days,” in which all employees had access to one or two paid days to stay home from work and recover from the flu. Giving employees one flu day resulted in more than a 25 percent decrease in influenza infections due to workplace transmission. A two flu-day policy resulted in a nearly 40 percent decrease. The researchers found that flu days were more effective for larger workplaces, defined as having 500 or more employees.

Other study authors included public health faculty John J. Grefenstette, David Galloway and Steven M. Albert.

The work was supported by the National Institute of General Medical Science and reported in the online version of the American Journal of Public Health. It will be printed in the August issue.


Concussion, Alzheimer’s patients’ brain abnormalities similar

The distribution of white matter brain abnormalities in some patients after mild traumatic brain injury (mTBI) closely resembles that found in early Alzheimer’s, according to School of Medicine investigators.

White matter in the brain is made up of long, finger-like fibers projecting from nerve cells and is covered by a whitish fatty material. While gray matter, the part of our brain without the fatty covering, holds our knowledge, white matter is what connects different regions of gray matter, allowing different parts of the brain to communicate with one another.

The study suggests that the initial traumatic event that causes mTBI, or concussion, acts as a trigger for a sequence of degenerative changes in the brain, which result in patient symptoms and are very similar to the degenerative changes seen in early Alzheimer’s. Saeed Fakhran, faculty member in radiology, and his research team wanted to see if there was a relationship between white matter injury patterns and severity of post-concussion symptoms in mTBI patients with normal findings on conventional magnetic resonance imaging (MRI) exams. The researchers studied data from imaging exams performed on 64 mTBI patients and 15 control patients utilizing an advanced MRI technique called diffusion tensor imaging (DTI), which identifies microscopic changes in the brain’s white matter.

Said Fakhran: “In the past, we believed that patients with mTBI have symptoms because of abnormalities secondary to the initial injury. Our preliminary findings suggest that the initial event causing the concussion is like lighting a fuse, acting as a trigger for a sequence of degenerative changes resulting in patient symptoms that could potentially be prevented.”

According to Fakhran, sleep-wake disturbances (SWD) are among the most debilitating post-concussive symptoms, affecting patients’ quality of life and productivity and magnifying post-concussion memory and social dysfunction. Such disturbances are among the earliest symptoms in Alzheimer’s patients, and also are seen in many mTBI patients. In addition, many mTBI patients have difficulty filtering out white noise and concentrating on important sounds, making it difficult for them to understand the world around them. Hearing problems are an independent risk factor for developing Alzheimer’s disease, and the same type of problem in mTBI patients has predicted which patients with memory problems eventually will develop Alzheimer’s disease.

“For this study, we looked back, analyzing images of injuries. In further research, we hope to recruit patients immediately after their injury and watch brain changes as they occur over time. The first step in developing a treatment for any disease is understanding what causes it, and if we can prove a link, or even a common pathway, between mTBI and Alzheimer’s it could potentially lead to effective treatment strategies for both diseases,” said Fakhran.

The study was published in the June issue of Radiology.


Oldest sign of lead pollution by humans found

Humans began contributing to environmental lead pollution as early as 8,000 years ago, according to research under lead author David Pompeani, PhD candidate in the Department of Geology and Planetary Science in the Dietrich school.

The research team detected the oldest discovered remains of human-derived lead pollution in the world in the northernmost region of Michigan, suggesting metal pollution from mining and other human activities appeared far earlier in North America than in Europe, Asia and South America.

Said Pompeani: “Humanity’s environmental legacy spans thousands of years, back to times traditionally associated with hunter-gatherers. Our records indicate that the influence of early Native Americans on the environment can be detected using lake sediments. These findings have important implications for interpreting both the archeological record and environmental history of the upper Great Lakes.”

The research team — including Mark Abbott and Daniel Bain from geology and planetary science and alumnus Byron A. Steinman — examined Michigan’s Keweenaw Peninsula because it is the largest source of pure native copper in North America. Surveys in the 1800s identified evidence for prehistoric human mining activity such as hammerstones, ladders and pit mines.

The team investigated the timing, location and magnitude of ancient copper mining pollution. Sediments were collected in June 2010 from three lakes located near ancient mine pits. They analyzed the concentration of lead, titanium, magnesium, iron and organic matter in the collected sediment cores, finding distinct decade- to century-scale increases in lead pollution preserved from thousands of years ago.

Reconstructions of metal pollution from other parts of the world only provide evidence for lead pollution during the last 3,000 years, said Pompeani. The team currently is investigating places near other prehistoric copper mines surrounding Lake Superior.

The work was funded by a Henry Leighton Memorial Fund grant, the Geological Society of America and the National Science Foundation (NSF).

The paper was first published online May 14 in Environmental Science and Technology.


pill bottlesDrug use varies between Medicare, VA patients

Medicare beneficiaries with diabetes are two-three times more likely to use expensive brand-name drugs than a comparable group of patients treated within the VA Healthcare System, according to a nationwide study by researchers from Pitt, VA Pittsburgh Healthcare System and Dartmouth.

Spending in Medicare Part D would have been an estimated $1.4 billion less in 2008 if brand-name and generic drug use matched that of the VA for the medications studied.

Said lead author Walid Gellad, faculty member in GSPH’s Department of Health Policy and Management and the School of Medicine: “Our study shows that we can make a big dent in Medicare spending simply by changing the kinds of medications people are using — and physicians are prescribing — without worrying about whether the government should or should not negotiate drug prices. The levels of generic use found in the VA are attainable, and they are compatible with high quality care.”

Gellad and his colleagues analyzed 2008 data for more than 1 million Medicare beneficiaries and 500,000 veterans to compare prescription use between Medicare and the VA, focusing on diabetes, cholesterol and blood pressure medications.

Medicare and the VA have a significantly different approach to drug prescribing. Medicare contracts with more than 1,000 private insurance companies, each using a distinct formulary and cost-sharing arrangement for prescribing drugs. The VA uses a single formulary and all veterans have the same cost-sharing arrangement.

Brand-name drugs cost considerably more than generic medications because the distributors of generics generally are not paying the cost of drug development, brand protection and marketing. In a chronic condition like diabetes, there is a broad range of available therapies with widely diverging costs, some of which can be lessened by using a generic medication rather than its brand-name counterpart.

Of the four medication groups commonly used by patients with diabetes, the researchers found that Medicare beneficiaries were more than twice as likely as VA patients to use brand-name drugs in almost every region of the country.

“We’re not suggesting that Medicare turn into a VA system, nor do we believe that brand-name drugs have no role in improving health,” said Gellad, who is also a primary care physician. “This study is about how we can manage our limited resources while maintaining high-quality care. The VA shows us that it can be done for prescription drugs. Going forward, we need to understand whether these differences in prescription use have changed, if at all, from 2008 to present.”

Other Pitt authors on this study were  Julie Donohue, Xinhua Zhao, Maria K. Mor, Carolyn T. Thorpe, Chester B. Good and Michael J. Fine.

This research was supported by VA Health Services Research & Development, VA VISN 4 Competitive Pilot Project Fund, RAND-University of Pittsburgh Health Institute, Agency for Healthcare Research and Quality and the Robert Wood Johnson Foundation Dartmouth Atlas Project.

The report is online and will be published in the July 16 edition of the Annals of Internal Medicine.


Mathematicians devise formula to analyze medical, environmental conditions

A 350-year-old mathematical mystery could lead toward a better understanding of medical conditions like epilepsy or even the behavior of predator-prey systems in the wild, report researchers in the Dietrich school’s Department of Mathematics.

The mystery dates back to 1665, when Dutch mathematician, astronomer and physicist Christiaan Huygens first observed that two pendulum clocks mounted together could swing in opposite directions. The source was tiny vibrations in the beam caused by both clocks, affecting their motions.

The effect, now referred to by scientists as “indirect coupling,” was not analyzed mathematically until nearly 350 years later, and deriving a formula that explains it remains a challenge to mathematicians still. Now, the researchers have applied this principle to measure the interaction of units — such as neurons, for example — that turn “off” and “on” repeatedly.

Said co-author Jonathan E. Rubin, a mathematics faculty member: “We have developed a mathematical approach to better understanding the ‘ingredients’ in a system that affect synchrony in a number of medical and ecological conditions. Researchers can use our ideas to generate predictions that can be tested through experiments.”

More specifically, the researchers believe the formula could lead toward a better understanding of conditions like epilepsy, in which neurons become overly active and fail to turn off, ultimately leading to seizures. Likewise, it could have applications in other areas of biology, such as understanding how bacteria use external cues to synchronize growth.

The study examined these forms of indirect communication that are not typically included in most mathematical studies owing to their complicated elements. In addition to studying neurons, the researchers applied their methods to a model of artificial gene networks in bacteria, which are used to better understand how genes function.

“In the model we studied, the genes turn off and on rhythmically,” said Rubin. “While on, they lead to production of proteins and a substance called an autoinducer, which promotes the genes turning on. Past research claimed that this rhythm would occur simultaneously in all the cells. But we show that, depending on the speed of communication, the cells will either go together or become completely out of synch with each other.”

To apply their formula to an epilepsy model, the team assumed that neurons oscillate, or turn off and on in a regular fashion. Mathematics faculty member G. Bard Ermentrout, who worked with Rubin, compares this to Southeast Asian fireflies that flash rhythmically, encouraging synchronization.

“For neurons, we have shown that the slow nature of these interactions encouraged ‘asynchrony,’ or firing at different parts of the cycle,” he said. “In these seizure-like states, the slow dynamics that couple the neurons together are such that they encourage the neurons to fire all out of phase with each other.”

The researchers believe this approach may extend beyond medical applications into ecology — for example, a situation in which two independent animal groups in a common environment communicate indirectly. Rubin illustrates the idea by using a predator-prey system, such as rabbits and foxes.

“With an increase in rabbits will come an increase in foxes, as they’ll have plenty of prey,” he said. “More rabbits will get eaten, but eventually the foxes won’t have enough to eat and will die off, allowing the rabbit numbers to surge again. Voila, it’s an oscillation.

“So, if we have a fox-rabbit oscillation and a wolf-sheep oscillation in the same field, the two oscillations could affect each other indirectly because now rabbits and sheep are both competing for the same grass to eat.”

Undergraduate mathematics major Jonathan J. Rubin also contributed to the research.

The paper was published online May 13 in Physical Review Letters. The research was supported in part by an NSF grant.


depressionTreating depression helps decrease mortality

Evidence-based treatment of depression reduces mortality rates by nearly 25 percent, relative to those under more traditional care, among older adults with major depression, researchers have found. Thus, treating depression can extend life expectancy and mitigate the mortality that is associated with depression.

Co-authored by Charles Reynolds, the study looked at 20 primary care practices involving 1,226 participants. In the study, a depression care manager worked with primary care physicians to offer psychotherapy and an increased antidepressant dose (if warranted) and monitored symptoms, adverse drug effects and treatment adherence.

The research concluded that older adults with major depression in practices provided with additional resources to intensively manage depression had a mortality risk lower than that observed in the usual care, and an outcome similar to older adults without depression.

Said Reynolds: “Our observation shows that evidence-based treatment of depression reduces eight- to nine-year rates of mortality by 24 percent, relative to usual care, among older adults with major depression treated in primary care clinics.”


Chemistry, physics profs win accolades

Chemistry faculty member Haitao Liu received an Air Force Office of Scientific Research 2013 award through the young investigator research program for work on “DNA-Templated Fabrication of Arbitrary-Structured Porous Carbon Materials.” The program will split approximately $15 million among 40 scientists and engineers over a three-five year period.

Physics and astronomy faculty member Andrew Daley received an NSF CAREER Award, which will support his research and related teaching initiatives over the next five years. The NSF program recognizes junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organizations.

The award will support Daley’s research on non-equilibrium dynamics in systems of cold atoms and molecules.


Breathalyzer for diabetes?

Diabetes patients often receive their diagnosis after a series of glucose-related blood tests in hospital settings, then have to monitor their condition daily through expensive, invasive methods. But what if diabetes could be diagnosed and monitored through cheaper, noninvasive methods?

Chemistry faculty members have demonstrated a sensor technology that could simplify the diagnosis and monitoring of diabetes through breath analysis alone.

Even before blood tests are administered, those with diabetes often recognize the condition’s symptoms through their breath acetone — a characteristic “fruity” odor that increases significantly during periods of glucose deficiency. The Pitt team was interested in this biomarker as a possible diagnostic tool.

Said Alexander Star, principal investigator of the project and chemistry faculty member: “Once patients are diagnosed with diabetes, they have to monitor their condition for the rest of their lives. Current monitoring devices are mostly based on blood glucose analysis, so the development of alternative devices that are noninvasive, inexpensive and provide easy-to-use breath analysis could completely change the paradigm of self-monitoring diabetes.”

Together with his colleagues Mengning Ding, a Pitt graduate student studying chemistry, and  another researcher at the National Energy Technology Laboratory (NETL), Star used a sol-gel approach, which is a method for using small molecules (often on a nanoscale level) to produce solid materials.

The team combined titanium dioxide, an inorganic compound widely used in body-care products such as makeup, with carbon nanotubes, which acted as “skewers” to hold the particles together. These nanotubes were used because they are stronger than steel and smaller than any element of silicon-based electronics.

This method, which the researchers playfully call “titanium dioxide on a stick,” effectively combined the electrical properties of the tubes with the light-illuminating powers of the titanium dioxide. They then created the sensor device by using these materials as an electrical semiconductor, measuring its electrical resistance (the sensor’s signal).

The researchers found the sensor could be activated with light to produce an electrical charge. This prompted them to “cook” the “skewers” in the sensor under ultraviolet light to measure acetone vapors, which they found were lower than previously reported sensitivities.

Star said, “If such a sensor could be developed and commercialized, it could transform the way patients with diabetes monitor their glucose levels.”

The team is working on a prototype of the sensor, with plans to test it on human breath samples soon.

The paper was first published in the Journal of the American Chemical Society online June 5. The work was performed in support of ongoing research at the NETL.


Immune cells associated with inflammation in HIV/AIDS

Depleted numbers of a specific type of white blood cell in the immune systems of people infected with HIV/AIDS appear to be associated with increased levels of unchecked and often damaging inflammation in the body, School of Medicine researchers have discovered.

The low numbers of white blood cells, known as CD4+CD73+ T cells  —  named for the expression of certain proteins and enzymes on their surface — persist even when HIV is well-controlled with medications.

Said corresponding author Bernard J.C. Macatangay, medicine faculty member in the Division of Infectious Diseases/HIV/AIDS program: “People with well-controlled HIV have been shown to have higher rates of chronic, non-AIDS-related diseases, such as cardiovascular disease. This is believed to be related to the persistent immune activation and inflammation associated with chronic HIV infection. We believe that the depleted CD4+CD73+ T cells play an important role in this inflammation.”

The study analyzed blood samples from 36 men positive for HIV, some who had consistently taken a medication regimen to suppress the virus and some who had not, along with 10 HIV-negative controls.

The body has ways to decrease and control inflammation through different regulatory mechanisms. One of these is through the production of adenosine, a biochemical compound that may have anti-inflammatory properties.

CD73 is an enzyme that is important in the production of adenosine. In the HIV-positive men, the study found that the CD4+CD73+ T cells are depleted and, despite treatment, do not increase to levels seen in uninfected individuals. The Pitt researchers found an association between the low levels of CD4+CD73+ T cells and higher levels of immune activation and inflammation in the study participants.

Co-author Theresa Whiteside, medicine faculty member in pathology, immunology and otolaryngology and a member of Pitt’s Cancer Institute, said: “The suppression pathways we explore in this study have similarities to those that we have recently linked to immune suppression in cancer.”

Said Macatangay: “Significant damage occurs very early in infection, while they are still asymptomatic and do not even know they have the virus. This is why it is important that we continue to examine the role of CD4+CD73+ T cells and adenosine in increased inflammation among HIV/AIDS patients and look for ways to repair the damage to the natural pathways by which these cells act.”

Additional medical faculty study co-authors included Zenichiro Saze, Edwin K. Jackson, Sharon A. Riddler, Benedict B. Hilldorfer and John W. Mellors; William G. Buchanan and Charles R. Rinaldo of the Graduate School of Public Health, and a researcher from the University of Ulm.

The results of the study, funded by NIH and available online, will be reported in the journal AIDS.


loud noise 3Cause, possible preventive for tinnitus found

An epilepsy drug shows promise in an animal model for preventing tinnitus from developing after exposure to loud noise, according to a new School of Medicine study. The findings reveal the reason the chronic and sometimes debilitating condition occurs.

Some 5-15 percent of Americans hear whistling, clicking, roaring and other phantom sounds of tinnitus, which typically is induced by exposure to very loud noise.

Senior investigator Thanos Tzounopoulos, medicine faculty member and member of the auditory research group in the Department of Otolaryngology, said: “There is no cure for it, and current therapies such as hearing aids don’t provide relief for many patients.”

The team focused on an area of the brain that is home to an auditory center called the dorsal cochlear nucleus (DCN). Tinnitus is associated with hyperactivity of DCN cells, which fire impulses even when there is no actual sound to perceive. So the researchers looked closely at the biophysical properties of KCNQ channels, through which potassium ions travel in and out of the cell.

“We found that mice with tinnitus have hyperactive DCN cells because of a reduction in KCNQ potassium channel activity,” Tzounopoulos said. “These KCNQ channels act as effective ‘brakes’ that reduce excitability or activity of neuronal cells.”

In the model, sedated mice were exposed in one ear to a 116-decibel sound, about the loudness of an ambulance siren, for 45 minutes, which was shown in previous work to lead to the development of tinnitus in 50 percent of exposed mice. Tzounopoulos and his team tested whether an FDA-approved epilepsy drug called retigabine, which specifically enhances KCNQ channel activity, could prevent the development of tinnitus. Thirty minutes into the noise exposure and twice daily for the next five days, half of the exposed group was given injections of retigabine.

Seven days after noise exposure, the team determined whether the mice had developed tinnitus by conducting startle experiments in which a continuous 70 dB tone is played for a period, stopped briefly and then resumed before being interrupted with a much louder pulse.

Mice with normal hearing perceive the gap in sounds and are aware something had changed, so they are less startled by the loud pulse than mice with tinnitus, which hear phantom noise that masks the moment of silence in between the background tones.

The researchers found that mice treated with retigabine immediately after noise exposure did not develop tinnitus. Consistent with previous studies, 50 percent of noise-exposed mice that were not treated with the drug exhibited behavioral signs of the condition.

“This is an important finding that links the biophysical properties of a potassium channel with the perception of a phantom sound,” Tzounopoulos said. “Tinnitus is a channelopathy, and these KCNQ channels represent a novel target for developing drugs that block the induction of tinnitus in humans.”

The KCNQ family is comprised of five different subunits, four of which are sensitive to retigabine. The researchers aim to develop a drug that is specific for the two KCNQ subunits involved in tinnitus to minimize the potential for side effects.

“Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely,” Tzounopoulos said. “It might also be useful for other conditions of phantom perceptions, such as pain in a limb that has been amputated.”

Co-authors were Shuang Li and Veronica Choi, otolaryngology.

The project was funded by the U.S. Department of Defense, NIH/National Institute on Deafness and Other Communication Disorders, UPMC and The Eye and Ear Foundation of Pittsburgh.

It was reported online in the Proceedings of the National Academy of Sciences.


Civil engineer wins award

Piervincenzo Rizzo, faculty member in civil and environmental engineering at the Swanson School of Engineering, is the co-recipient of the 2013 Outstanding Paper Award from the American Society for Nondestructive Testing (ASNT).

Rizzo and graduate research assistant Xianglei Ni were recognized for their article “Use of Highly Nonlinear Solitary Waves in Nondestructive Testing” by the ASNT Journal, Materials Evaluation from May 2012.


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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