UPMC Physician Resources

Tinnitus Caused by Too Little Inhibition of Brain Auditory Circuits, Pitt-led Study Says

PITTSBURGH, April 18, 2011 - Tinnitus, a relentless and often life-changing ringing in the ears known to disable soldiers exposed to blasts, unwary listeners of too-loud music and millions of others, is the result of under-inhibition of key neural pathways in the brain’s auditory center, according to scientists at the University of Pittsburgh School of Medicine in this week’s early online edition of the Proceedings of the National Academy of Sciences. The discovery, which used a new technique to image auditory circuits using slices of brain tissue in the lab, points the way to drug development and effective treatment for a condition that currently has no cure.

Prior research has shown that auditory circuits in the brain are more excitable in tinnitus sufferers, but until now it has not been clear whether that is due to hyperactivity of excitatory neural pathways, reduced activity of inhibitory ones, or a bit of both, explained senior investigator Thanos Tzounopoulos, Ph.D., assistant professor of otolaryngology and neurobiology, Pitt School of Medicine.

“This auditory imbalance leaves the patient hearing a constant ringing, buzzing or other irritating noise even when there is no actual sound,” he said. “Tinnitus drowns out music, television, co-workers, friends and family, and it profoundly changes how the patient perceives and interacts with the world.”

According to the American Tinnitus Association, tinnitus is the most common service-connected disability among veterans of the Iraq and Afghanistan conflicts. Of the 50 million who have experienced it, 16 million have symptoms severe enough to seek medical attention and 2 million tinnitus sufferers are unable to carry out day-to-day activities.

To identify what goes wrong in the brain’s auditory circuits, Dr. Tzounopoulos’ team created tinnitus in a mouse model. While the rodent was sedated, one ear was exposed to 45 minutes of 116 decibel (dB)-sound, equivalent to an ambulance siren. Intense noise exposure is thought to lead to damage in the cochlea, an inner ear structure critical to the neural transmission of sound waves, and clinically undetectable hearing loss.

Several weeks later, the scientists confirmed the exposed mice had tinnitus by conducting startle experiments in which a continuous, 70dB tone was played for a period, then stopped briefly and then resumed before being interrupted with a much louder pulse.

Mice with normal hearing could perceive the gap and, because they were aware something had changed, were less startled than mice with tinnitus, whose ear ringing masked the moment of silence in between the background tones.

The scientists then sought to determine what had gone wrong in the balance of excitation and inhibition of the auditory circuits in the affected mice. They established that an imaging technique called flavoprotein autofluorescence (FA) could be used to reveal tinnitus-related hyperactivity in slices of the brain. Experiments were performed in the dorsal cochlear nucleus (DCN), a specialized auditory brain center that is crucial in the triggering of tinnitus. FA imaging showed that the tinnitus group had, as expected, a greater response than the control group to electrical stimulation. Most importantly, despite local stimulation, DCN responses spread farther in the affected mice.

Dr. Tzounopoulos’ new experimental approach has resolved why tinnitus-affected auditory centers show increased responsiveness. After administering a variety of agents that block specific excitatory and inhibitory receptors and seeing how the brain center responded, his team determined that blocking an inhibitory pathway that produces GABA, an inhibitory neurotransmitter, enhanced the response in the region surrounding the DCN in the control brain slices more so than it did in the tinnitus slices.

“That means the DCN circuits are already ‘disinhibited,’ or blocked, in tinnitus,” Dr. Tzounopoulos explained. “We couldn’t block inhibition anymore to elevate the evoked response, like we could in the normal brain. And, when we blocked another inhibitory circuit mediated by the neurotransmitter glycine, or when we blocked excitatory pathways, there was no difference in the responses between the groups.”

This means that agents that increase GABA-mediated inhibition might be effective treatments for tinnitus, he added. Dr. Tzounopoulos’ team is now trying to identify such drugs.

Co-authors of the paper include Jason W. Middleton, Ph.D., and Courtney Pedersen, of the University of Pittsburgh; Taro Kiritani and Gordon M.G. Shepherd, M.D., Ph.D., of Northwestern University; and Jeremy Turner, Ph.D., of Southern Illinois University.

The research was funded by the National Institutes of Health, the U.S. Department of Defense, the American Tinnitus Association, and the Albert and Ellen Grass Faculty Award.

Transplant Guardian Angels at UPMC provide comfort and patient- and family-centered care

Pittsburgh, PA, April 18, 2011–The first time Holly Rute was called in to UPMC Presbyterian for a possible double-lung transplant she was put in a room and, when her family needed food or a drink, she was left nervous and alone.

The second time, on April 11, when her husband and 11-year-old daughter went out to dinner, Mrs. Rute had the company of Kate Fitzpatrick, 21, a junior nursing student at the University of Pittsburgh and one of UPMC’s new Transplant Guardian Angels.

Read full article: http://www.post-gazette.com/pg/11108/1139826-114-0.stm?cmpid=healthscience.xml

Pitt Researchers Find Higher Rates of Suicidality and Depression Among Gay Teens

PITTSBURGH, April 5, 2011 - A University of Pittsburgh School of Medicine study finds that gay and lesbian teens reported higher rates of suicidality and depression than did heterosexual youth. The findings are reported online in the Journal of Adolescent Health, the official publication of the Society for Adolescent Health and Medicine (SAHM). The Pitt study provides the first systematic review and analysis of suicidality and depression symptoms in this teen population.

“We conducted a meta-analysis, which means we combined the results of 18 studies involving more than 100 different comparisons and over 100,000 teenage participants, and we were surprised by the overwhelming consistency of the results,” said Michael P. Marshal, Ph.D., lead author and assistant professor of psychiatry and pediatrics at Pitt’s School of Medicine. “No matter how we looked at it, gay teens reported higher levels of suicidality than straight teens. Overall, gay teens were almost three times more likely to report a history of suicidality.”

According to the Centers for Disease Control, suicide is the third leading cause of death among adolescents and young adults in the United States, with the rate of suicide attempts during the lifetime of this population ranging from 1 to 10 percent. Teen suicide results in approximately 4,500 lives lost each year. The overwhelming majority of teens who make suicide attempts demonstrate mood psychopathology, with depression being the most prevalent disorder.

This study found that, on average, 28 percent of gay teens reported a history of suicidality compared to 12 percent of heterosexual teens. The studies also showed that even after controlling for variables such as depression, low self-esteem, substance use and conflict with family, gay and lesbian youth were still more than twice as likely to report a history of suicidality as heterosexual youth.

“These results suggest that it is extremely important that health professionals create a clinical environment that makes it easy for gay and lesbian youth to discuss their sexual orientation with their doctors,” adds Dr. Marshal. “Doctors and clinics need to emphasize their privacy policies and assure teens that they will not discuss their sexual orientation with parents or caregivers. It also is critical that primary care physicians are trained to screen youth for suicidal thoughts and behaviors and be prepared to help them seek the appropriate treatment services.”

Dr. Marshal and his colleagues now are trying to  understand why being  a member of a sexual minority puts a teen at increased risk for suicidal thoughts and behavior so that  the proper interventions can be provided. “The vast majority of gay and lesbian teens do not report suicidality and depression. We need to learn more about how gay and lesbian youth manage to stay healthy in the face of a persistent and pervasive homophobic culture.”

Co-authors of the study include Laura J. Dietz, Ph.D., David A. Brent, M.D., and Helen A. Smith, Ph.D., University of Pittsburgh School of Medicine; Mark S. Friedman, Ph.D., and Ron Stall, Ph.D., University of Pittsburgh Graduate School of Public Health; James McGinley, B.A., University of North Carolina; Brian C. Thoma, B.A., University of Utah; Pamela J. Murray, M.D., M.P.H., West Virginia University; and Anthony R. D’Augelli, Ph.D., Pennsylvania State University.

Cocaine is Direct Cause of Cognitive Deficits, Says University of Pittsburgh Team

PITTSBURGH, March 30, 2011 - Cocaine use directly contributes to the development of cognitive deficits such as impairments of visual working memory and difficulty adapting to rule changes in reward tasks, according to researchers at the University of Pittsburgh School of Medicine in the March 30 issue of The Journal of Neuroscience.

A wide range of cognitive difficulties are seen among cocaine users, but it hasn’t been clear whether that reflects pre-existing traits that made them more susceptible to drug abuse or to the drug itself, said senior investigator Charles W. Bradberry, Ph.D., associate professor of psychiatry at Pitt School of Medicine.

“It’s well known that the level of cognitive deficit can predict how successful treatment is likely to be,” he said. “If we understand what the problems are and whether the drug itself was the cause, then we might be able to design treatments that have a better chance of working.”

For the study, the researchers assessed cognitive skills in 14 rhesus monkeys that learned to touch an abstract shape on a touch screen to receive either a sip of water or a cocaine infusion via a special access port into a blood vessel. Within a week, the cocaine group was regularly self-administering the maximum of six doses daily from Tuesdays to Fridays.

On Mondays, after three days without receiving drugs, the monkeys’ associative learning skills were assessed. Each animal was presented with two consistent stimuli on the touch screen with a correct answer recorded for touching the one associated with a higher volume of water reward. But once a threshold number of correct answers was achieved, the rules were reversed, with the high stimulus becoming low and the low becoming high.

The researchers found that the cocaine group learned the initial rules as quickly and at first responded as accurately as the water-only group, but only five of the eight achieved the threshold of correct responses. The researchers then increased the difference between high and low rewards, which allowed the remaining three monkeys in the cocaine group to get to threshold.

“That tells us the cocaine users have a hard time maintaining focus and attention,” Dr. Bradberry said. “But if we increase the reward value of these things they’re trying to learn, we can overcome that cognitive deficit.”

He added that once the stimuli were reversed, the cocaine group had much greater difficulty learning and adapting to the change in rules, indicating a deficit in cognitive control processes or executive brain functions that require focus and  guide volitional, goal-directed behavior.

In another task, the animals saw a single image that when touched resulted in a supplemental water reward. Then they were shown the same image along with a random one, and if they chose the correct one after a delay of up to 40 seconds they got the reward. The cocaine group’s performance was less accurate as the delay increased.

“This experiment reveals that cocaine use causes impairments of visual working memory,” Dr. Bradberry said. “Like the inability to maintain consistent levels of accuracy in the other task, this could reflect problems with attention in addition to the impairment in cognitive control.”

His team now is using imaging tools to see how the brain’s structure might change due to cocaine exposure.

Co-authors of the paper include Jessica N. Porter, Ph.D. candidate, Adam S. Olsen, Kate Gurnsey, Brian P. Dugan, and Hank P. Jedema, Ph.D., all of the University of Pittsburgh.

The study was funded by the National Institute on Drug Abuse, part of the National Institutes of Health; and the Veterans Affairs Medical Research Service.

UPMC leads nation in number of lung transplants

Pittsburgh, PA, March 30, 2011–Increased referrals from around the country and surgeons’ ability to use donor lungs once considered unsuitable contributed to a record 131 lung transplants at University of Pittsburgh Medical Center last year, officials said Tuesday.

The 2010 total was the most among the nation’s 66 lung transplant centers. The centers performed a total of 1,771 lung transplants, according to the United Network for Organ Sharing, a nonprofit organization that tracks organ transplants for the federal government.

The growth of UPMC’s program is due, in part, to increased transplants among patients with more complicated conditions, said Dr. Joseph Pilewski, transplant pulmonologist and medical director of the UPMC Lung Transplantation Program.

UPMC Physician and International Expert in Women’s Mental Health to Receive Prestigious 2011 Women in Science Award

PITTSBURGH, March 29 - The American Medical Women’s Association has named Katherine L. Wisner, M.D., M.S., as the recipient of the 2011 Women in Science Award, which is given to a female physician who has made exceptional contributions to medical science, especially in women’s health, through her basic and/or clinical research, her publications and through leadership in her field.

“I was delighted to hear about the award,” noted Dr. Wisner. “I am honored to have contributed to research in perinatal mental health over the last 25 years, as it has gone from being essentially unknown in the U.S. to a field of great interest among investigators and clinicians. I accept the award in honor of the many women who have participated in research studies so that our knowledge about perinatal mental disorders and treatments could advance.”  

Dr. Wisner is a professor of psychiatry, obstetrics, gynecology and reproductive sciences and epidemiology at the University of Pittsburgh School of Medicine, and director of the Women’s Behavioral HealthCARE program at the Western Psychiatric Institute and Clinic of UPMC. She also serves as an investigator at the Magee-Womens Research Institute. Her research focuses on the psychiatric treatment of women of childbearing age, and she is internationally recognized as an expert in the treatment of depression during pregnancy and the postpartum period.

Dr. Wisner has received funding from the National Institute of Mental Health as the principal investigator since 1988. She studies the impact of both exposure to major depression during pregnancy, as well as treatment with a class of antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) on maternal and infant outcomes. Dr. Wisner also is studying pregnancy outcomes for women with bipolar disorder and the pharmacokinetics of treatment with lithium during pregnancy.   

She currently is conducting a clinical trial for postpartum depression that includes treatment with an estradiol skin patch, the antidepressant sertraline or placebo to increase treatment options for women with postpartum depression. Her team has screened over 10,000 new mothers from Magee-Womens Hospital of UPMC for depression, and found a 14 percent positive rate.

Dr. Wisner will receive her award during a presentation that will take place at the American Medical Women’s Association annual meeting in Washington D.C., on April 2.

The American Medical Women’s Association (AMWA) is an organization of women physicians, medical students and other persons dedicated to serving as the unique voice for women’s health and the advancement of women in medicine. The organization was founded by Dr. Bertha VanHoosen in 1915 in Chicago, at a time when women physicians were an under-represented minority. As women in medicine increase in numbers, new problems and issues arise that were not anticipated. AMWA has been addressing these issues for 94 years. For more information, visit www.amwa-doc.org.

Experimental Radioprotective Drug Safe for Lung Cancer Patients, Says University of Pittsburgh Cancer Institute Study

PITTSBURGH, March 22, 2011 – Patients with advanced non-small cell lung cancer can safely take an experimental oral drug intended to protect healthy tissue from the effects of radiation, according to a study led by researchers at the University of Pittsburgh Cancer Institute (UPCI) and published in this month’s issue of Human Gene Therapy.

The findings support further clinical testing of the agent, called manganese superoxide dismutase (MnSOD) plasmid liposome, to determine if giving it alongside chemotherapy and radiation will prevent damage to normal cells that is the typical cause of side effects in cancer treatment, said senior investigator Joel S. Greenberger, M.D., professor and chair, Department of Radiation Oncology, Pitt School of Medicine, and co-director of the lung and esophageal cancer program at UPCI.

“If we can sufficiently protect tissues that are normal, we should be able to deliver our cancer treatments more effectively and perhaps even at higher doses,” he explained. “Our aim is to improve the quality of life of patients by minimizing side effects while providing the best treatment for their cancers.”

For the safety study, 10 patients with inoperable stage III non-small cell lung cancer took oral doses of MnSOD plasmid liposome twice weekly for a total of 14 doses during seven weeks of conventional chemotherapy and radiation treatment. The agent, which boosts levels of an antioxidant the body makes naturally, is made of fat droplets containing the gene that produces MnSOD. When swallowed, it is absorbed by cells in the esophagus, which is a common site for severe side effects during radiation treatment for lung cancer.

One patient experienced mild heartburn and a slight rash and another had mild constipation and a fluctuation in blood sodium, problems that might be associated with MnSOD treatment. No other toxicities were thought to be due to the experimental drug.

“The results of this initial trial indicate that MnSOD plasmid liposome can be safely administered,” Dr. Greenberger said. “It did not linger in normal cells after treatment, nor did it protect cancer cells from radiation treatment. The next study, which is underway at UPCI, is to determine whether it protects normal tissue, particularly the esophagus, from radiation exposure.”

A common toxicity of lung cancer radiation therapy is esophagitis, or inflammation of the esophagus, he explained. Within a few weeks of treatment, patients typically experience painful swallowing that over time can become so severe that narcotics or a break from radiotherapy may be necessary for patient comfort.

Preclinical testing has shown that generating higher levels of MnSOD in healthy cells can suppress the production of inflammatory molecules and reduce cell death, micro-ulceration and esophagitis. Because the agent is delivered to healthy tissue, it does not protect tumor cells from radiation treatment. In fact, Dr. Greenberger noted, experiments hint that when it is given to cancer cells, it actually encourages cell death because of abnormalities in their cellular metabolism.

He and his team plan to investigate the use of MnSOD plasmid liposome for other cancers, such as protecting the rectum from radiotherapy for prostate cancer and protecting the bladder during ovarian or endometrial cancer treatment.

The research team includes co-lead author Ahmad A. Tarhini, M.D., James D. Luketich, M.D., and others from UPCI; co-lead author Chandra P. Belani, M.D., of Penn State Hershey Cancer Institute; and others from Emory University, University of Washington School of Medicine, and PharmaReg Consultants, of San Leandro, Calif.

The study was funded by the UPCI Specialized Program of Research Excellence (SPORE) in lung cancer.

UPMC Uses New Technology to Treat Aortic Heart Valve Disease without Open Heart Surgery

PITTSBURGH, March 22, 2011 – UPMC has performed its first patient implants in the Medtronic CoreValve® U.S. Clinical Trial to evaluate a non-surgical, less-invasive procedure as a treatment alternative to open-heart surgery for patients who suffer from a serious narrowing of the heart’s aortic valve.

UPMC is one of 40 hospitals across the U.S. to participate in the trial for patients with severe aortic stenosis, which prevents the heart’s aortic valve from opening completely and in turn hampers healthy blood flow from the aorta to the rest of the body. Untreated, it can lead to serious heart problems.

A 66-year-old man, from New Alexandria, Pa., was one of the first patients at UPMC to receive the CoreValve implant. He suffered shortness of breath, which worsened when climbing stairs, and required oxygen nearly around-the-clock because of his aortic stenosis.

In January, physicians channeled a catheter through a small opening in his femoral artery to reach the heart. The physician then guided the CoreValve System to the aortic valve, where the valve self-expanded to replace the diseased aortic valve; the procedure was completed without open-heart surgery or surgical removal of the aortic valve.

“Now I’m practically not using oxygen at all,” the patient said.

His procedure was performed by William Anderson, M.D., director of Interventional Cardiology at UPMC, and Thomas Gleason, M.D., director of the Center for Thoracic Aortic Disease of the UPMC Department of Cardiothoracic Surgery.

“Aortic stenosis frequently occurs in elderly patients who have a higher risk of complications from standard valve-replacement surgery. This growing patient population may then have the most to gain from new, less invasive, catheter-based approaches to the implantation of a new aortic valve. The trial will allow us to explore this possibility,” Dr. Anderson said.

Worldwide, approximately 300,000 people have been diagnosed with this condition (100,000 in the U.S.), and approximately one-third of these patients are deemed at too high a risk for open-heart surgery, the only therapy with significant clinical effect that currently is available in the United States.

“Because open-heart surgery is currently the only available treatment option for these patients, and because the risks of surgery can be significant for many patients, the medical community is enthusiastic about the less-invasive option,” Dr. Gleason said.

In the U.S., the CoreValve System will not be commercially available until the successful completion of this clinical trial and approval by the U.S. Food and Drug Administration. The CoreValve System received CE (Conformité Européenne) Mark in Europe in 2007.

For more information about the Medtronic CoreValve U.S. Clinical Trial, visit www.aorticstenosistrial.com.

Physicians are available for interviews to discuss the clinical trial. Broadcast quality animation also is available.

Information about the clinical trial is available at www.clinicaltrials.gov.

Children’s Hospital of Pittsburgh of UPMC Receives Official LEED Certification

PITTSBURGH, March 17, 2011 Children’s Hospital of Pittsburgh of UPMC has become one of the first LEED®-certified pediatric hospital campuses in the United States.

On the Children’s campus, the hospital and mid-campus parking garage recently received official LEED (Leadership in Energy and Environmental Design) certification, which was established by the U.S. Green Building Council (USGBC) and verified by the Green Building Certification Institute. Children’s Hospital’s John G. Rangos Sr. Research Center has received LEED Silver certification, the third-highest designation attainable.

The new Children’s Hospital campus, located on 10 acres in the Lawrenceville neighborhood of Pittsburgh, opened in May 2009 and includes more than 1.5 million square feet of usable space.

“We’re proud to receive our official certification because it means we’ve achieved our goal of designing and building a world-class pediatric hospital that also is an extremely healthy, transformative and environmentally sustainable environment for our patients and families, staff and community,” said Eric Hess, vice president, operations, who also served as project executive for the new Lawrenceville campus. “From the early design stages, Children’s Hospital planned to develop a green campus that would meet the criteria for LEED certification. Even more impressive than being one of the first hospitals to achieve this status is the fact that we achieved this certification on two buildings, which comprise more than 80 percent of the total campus square footage.”

Children’s received LEED certification for energy use, lighting, water and material use, as well as for incorporating a variety of other sustainable strategies. By using less energy and water, LEED-certified buildings save money for families, businesses and taxpayers; reduce greenhouse gas emissions; and contribute to a healthier environment for employees, residents and the larger community, according to the USGBC.

Children’s commitment to employ green practices extends well beyond its bricks and mortar to operating policies and procedures regarding facility maintenance, housekeeping, food service and waste management. Children’s also fosters its green philosophy by working with clinicians, academicians and the community to conduct research on the subject of sustainability and its health effects on children. Additional environmentally sustainable initiatives include:

  • water-efficient landscaping with drip irrigation systems
  • use of building materials with recycled content (including recycled post-consumer structural steel)
  • use of regional construction materials to reduce transportation issues
  • use of low VOC materials such as sealants, adhesives, paints and carpets
  • installation of air filtration systems that increase indoor air quality
  • installation of water fixtures that reduce water use
  • maximum use of daylight and views and automatic shade systems to reduce cooling costs
  • access to a rooftop healing garden
  • continued use of recycled content and local materials whenever possible
  • access to public transportation
  • availability of bike racks and showers
  • employing a “green” education program for staff, patients and guests
  • utilization of 9.2 percent renewable electricity generation
  • energy optimization systems and heating and cooling recovery systems
  • plant materials with low water needs
  • fragrance-free cleaning products in most locations
  • low mercury lighting and no mercury equipment in the health care environment
  • waste reduction including recycling of batteries, paper, cardboard and kitchen grease
  • utilization of reusable sharps containers to minimize medical waste
  • development of a continuing medical education-accredited lecture series for residents that focuses on environmental health issues
  • implementation of a paperless information management system that allows physicians to place nearly all inpatient care orders electronically, eliminating handwritten and verbal orders

“Children’s Hospital’s LEED certification demonstrates tremendous green building leadership,” said Rick Fedrizzi, president, CEO, and founding chair, USGBC. “The urgency of our mission has challenged the industry to move faster and reach further than ever before, and Children’s Hospital serves as a prime example of just how much we can accomplish.”

Follow this hyperlink for more information about the new Children’s Hospital campus.

UPMC Presbyterian Shadyside President and UPMC Kidney Specialist to be Honored by National Kidney Foundation

PITTSBURGH, March 9, 2011 - UPMC Presbyterian Shadyside President John Innocenti has been named this year’s Corporate Gift of Life Awardee and Thomas Kleyman, M.D., chief of the University of Pittsburgh Renal-Electrolyte Division, has been named Medical Gift of Life Awardee by the National Kidney Foundation (NKF) Serving the Alleghenies.

Innocenti and Dr. Kleyman will receive their awards at the foundation’s annual Kidney Gift of Life Gala on Saturday, March 19 at the Circuit Center & Ballroom on the South Side.  “With World Kidney Day on March 10, we are honored to have outstanding individuals as our Gift of Life Awardees,” said Kevin Ho, M.D., a nephrologist at UPMC and the event chair.

“In addition to Mr. Innocenti’s leadership within the UPMC hospital system, he served as our NKF Corporate Walk Chairman in 2009 and 2010, making public appearances and attracting both sponsorship and contributions,” Dr. Ho said.

Dr. Kleyman is being honored for his contributions to kidney research. Dr. Kleyman is the director of the Pittsburgh Center for Kidney Research.

“Dr. Kleyman has contributed to our general understanding of how the kidneys process sodium and continues to advance nephrology research on multiple fronts,” Dr. Ho said.

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