UPMC Physician Resources

Rhythmic Bursts of Electrical Activity from Cells in Ear Teach Brain How To Hear, Says Pitt Team

PITTSBURGH, May 21, 2014 – A precise rhythm of electrical impulses transmitted from cells in the inner ear coaches the brain how to hear, according to a new study led by researchers at the University of Pittsburgh School of Medicine. They report the first evidence of this developmental process today in the online version of Neuron.

The ear generates spontaneous electrical activity to trigger a response in the brain before hearing actually begins, said senior investigator Karl Kandler, Ph.D., professor of otolaryngology and neurobiology, Pitt School of Medicine. These patterned bursts start at inner hair cells in the cochlea, which is part of the inner ear, and travel along the auditory nerve to the brain.

“It’s long been speculated that these impulses are intended to ‘wire’ the brain auditory centers,” he said. “Until now, however, no one has been able to provide experimental evidence to support this concept.”

To map neural connectivity, Dr. Kandler’s team prepared sections of a mouse brain containing the auditory pathways in a chemical that is inert until UV light hits it. Then, they pulsed laser light at a neuron, making the chemical active, which excites the nerve cells to generate an electrical impulse. They then tracked the spread of the impulse to adjacent cells, allowing them to map the network a neuron at a time.

All mice are born unable to hear, a sense that develops around two weeks after birth. But even before hearing starts, the ear produces rhythmic bursts of electrical activity which causes a broad reaction in the brain’s auditory processing centers. As the beat goes on, the brain organizes itself, pruning unneeded connections and strengthening others. To investigate whether the beat is indeed important for this reorganization, the team used genetically engineered mice that lack a key receptor on the inner hair cells which causes them to change their beat.

“In normal mice, the wiring diagram of the brain gets sharper and more efficient over time and they begin to hear,” Dr. Kandler said. “But this doesn’t happen when the inner ear beats in a different rhythm, which means the brain isn’t getting the instructions it needs to wire itself correctly. We have evidence that these mice can detect sound, but they have problems perceiving the pitch of sounds.”

In humans, such subtle hearing deficits are associated with Central Auditory-Processing Disorders (CAPD), difficulty processing the meaning of sound. About 2 to 3 percent of children are affected with CAPD and these children often have speech and language disorders or delays, and learning disabilities such as dyslexia. In contrast to causes of hearing impairments due to ear deficits, the causes underlying CAPD have remained obscure.

“Our findings suggest that an abnormal rhythm of electrical impulses early in life may be an important contributing factor in the development of CAPD. More research is needed to find out whether this also holds true for humans, but our results point to a new direction that is worth following up,” Dr. Kandler said.

The study team included Amanda Clause, Ph.D., Gunsoo Kim, Ph.D., and Catherine Weisz, Ph.D., all of the University of Pittsburgh School of Medicine; Mandy Sonntag, Ph.D., and Rudolf Rűbsamen, Ph.D., both of the University of Leipzig; and Douglas E. Vetter, Ph.D., of the University of Mississippi Medical Center.

The project was funded by the National Institute on Deafness and Other Communication Disorders grants 04199 and DC011499 and National Institutes of Health grant NS007433; the National Science Foundation; the Pennsylvania Lions Hearing Research Foundation; and Deutsche Forschungsgemeinschaft.

Pennsylvania Recognizes May as Bladder Cancer Awareness Month

PITTSBURGH, May 20, 2014 The month of May has been officially recognized as Bladder Cancer Awareness Month by the State of Pennsylvania. Resolution #699 was sponsored by Representative Robert Freeman, and overwhelmingly passed by the PA House of Representatives. This recognition by the state of PA aligns with the national efforts of the Bladder Cancer Advocacy Network (BCAN). Marge Coffin, the Lehigh Valley-Central PA Chapter President of the BCAN, worked with Representative Freeman’s office to make the recognition official.

“I believe that Resolution #699 is a positive step forward in our efforts to raise awareness and understanding of this disease,” Coffin says.

In the United States, bladder cancer is the sixth most commonly diagnosed form of cancer and approximately 75,000 will be diagnosed this year. There is little public awareness of the disease, despite the fact that more than 500,000 people are currently living it. The signs and symptoms of bladder cancer can be similar to those of other conditions, which has often led to later diagnoses and poor outcomes. Throughout the month, the BCAN will provide educational materials, host events, and will focus on women and bladder cancer.

For more information about Bladder Cancer Awareness Month, please visit BCAN.org.

Jeffrey Gingrich, MD, from the Department of Urology at UPMC discusses the management and treatment of  bladder cancer in the following video: Neoadjuvant Chemotherapy in the Management of Bladder Cancer.

Review of Presentations from Children’s Hospital Liver Transplantation Conference Published in Molecular Genetics Journal

PITTSBURGH, May 20, 2014 – Presentations from Challenging the Paradigms: Liver Transplantation Metabolic Disease at Children’s Hospital of Pittsburgh of UPMC were summarized in Molecular Genetics and Metabolism. The conference, which focused on metabolic liver transplantation, featured presentations on the evolution of liver transplantation as a viable treatment approach for an increasing number of metabolic diseases in a variety of clinical situations.

The review, Liver Transplantation for Pediatric Metabolic Disease, focuses on metabolic diseases that can be cured and improved by liver transplantation, as well as metabolic diseases that should be further considered for treatment by liver transplantation. Current indications and outcomes of transplantation and organ allocation issues are also addressed.

Authors include George Mazariegos, MD, Sara McIntire, MD, Jerry Vockley, MD, PhD, Ira J. Fox, MD, and Benjamin Shneider, MD, of Children’s Hospital of Pittsburgh of UPMC; Barbara Burtone, MD, of Ann & Robert Lurie Children’s Hospital of Chicago; Nedim Hadzic, MD, PhD, of King’s College Hospital in London; Priya Kishnani, MD, of Duke University; D. Holmes Morton, MD, of the Clinic for Special Children; Ronald J. Sokol, MD, of Children’s Hospital Colorado; Marshall Summar, MD Children’s National Medical Center; Desiree White, PhD, of Washington University; and Vincent Chavanon of Mount Sinai Hospital.

Children’s Hospital Physician Authors Paper on LMTK2 Facilitation of CFTR Endocytosis

PITTSBURGH, May 20, 2014 – A physician from Children’s Hospital of Pittsburgh of UPMC was part of a team that wrote a paper on the link between Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Lemur Tyrosine Kinase 2 (LMTK2) for the treatment of cystic fibrosis patients who are taking medication. The paper was published in The Journal of Biological Chemistry.

Agnieszka Swiatecka-Urban, MD, assistant professor of nephrology at Children’s Hospital, and assistant professor in the Department of Cell Biology and Physiology at the University of Pittsburgh School of Medicine, was one of the authors of the paper, LMTK2 Mediated Phosphorylation Regulates CFTR Endocytosis in Human Airway Epithelial Cell. The data in the paper indicates that targeting the protein LMTK2 may increase the cell surface density of CFTR Cl- channels and improve the stability of pharmacologically rescued ΔF508-CFTR in patients with cystic fibrosis. Their finding may also be applicable to the mechanisms of decreased CFTR function in smoking-related lung diseases.

Additional authors include Kristine M. Cihil, University of Pittsburgh School of Medicine; Simão Luz, PhD, Margarida D. Amaral, PhD, and Carlos M. Farinha, PhD, all of the University of Lisboa in Portugal; and David L. Brautigan, PhD, of the University of Virginia School of Medicine.

Maryland Patients Can Now Access UPMC CancerCenter Resources Under New Affiliation with Meritus Health’s John R. Marsh Cancer Center in Hagerstown

PITTSBURGH, May 20, 2014 – Cancer patients in Hagerstown, Md., now have access to UPMC CancerCenter’s world-class clinical care and the latest research under a new affiliation agreement with Meritus Health’s John R. Marsh Cancer Center.

The agreement, effective May 1, allows patients to access the vast resources of the UPMC CancerCenter, including its treatment protocols, clinical trials, provider-to-provider consultations, genetic counseling support services and collaboration in research and survivorship programs.

“We are excited to be able to work with Meritus Health’s John R. Marsh Cancer Center and to offer patients in Maryland access to our vast cancer network. We are proud to be able to offer patients the best in care right in their own communities and this affiliation affirms our commitment to do just that,” said Stanley Marks, M.D., chairman of UPMC CancerCenter, partner with the University of Pittsburgh Cancer Institute.

Clinical and professional staff at Meritus Health’s John R. Marsh Cancer Center also can participate in training and education programs offered through UPMC CancerCenter, the only National Cancer Institute-designated comprehensive cancer center in western Pennsylvania.

“Meritus Health is proud of our John R. Marsh Cancer Center’s affiliation with the UPMC CancerCenter network. Access to UPMC’s international experts and resources affords us the opportunity to offer our patients enhanced cancer care services close to home,” said Joseph P. Ross, Meritus Health’s president and CEO. “Service improvements, access to research studies, genetic counseling, support programs and educational resources are valuable assets for our patients, providers and staff.”

Students Swayed by ‘Relaxing, Fun’ Image of Hookah Smoking Ignore Health Harms

PITTSBURGH, May 20, 2014 – Educational campaigns meant to dissuade college students from initiating hookah tobacco smoking may be more successful if they combat positive perceptions of hookah use as attractive and romantic, rather than focusing solely on the harmful components of hookah tobacco smoke, a new University of Pittsburgh School of Medicine study found.

The research, supported by the National Cancer Institute, examined the sequence of events around which university students first smoke tobacco from a hookah, also known as a water pipe, in an effort to determine the driving factors behind the decision. It will be published in the June issue of the journal Nicotine & Tobacco Research and is online now. Because hookah tobacco smoking exposes the user to substantial amounts of toxicants such as carbon monoxide, nicotine, carcinogens and tar, initiation of this behavior is of concern.

“It was surprising to learn that college students, even when they were aware of the health dangers associated with hookah tobacco smoking at baseline, still went on to use a hookah for the first time,” said lead author Jaime Sidani, Ph.D., M.P.H., senior research specialist in the Program for Research on Media and Health (PROMH) at Pitt. “However, students who had less positive attitudes toward hookah smoking were significantly less likely to initiate. This suggests that countering positive attitudes may be at least as effective as emphasizing harm in preventing initiation of hookah tobacco smoking.”

Dr. Sidani and her colleagues analyzed a sample of 569 first- and second-year University of Florida college students who were surveyed twice over a seven-month period about their attitudes, knowledge and behaviors regarding hookah smoking. During that time, 13 percent of the students initiated hookah tobacco use.

The students were more likely to initiate hookah use if they had positive attitudes toward hookah smoking — which is frequently promoted as relaxing, pleasurable, fun and sexual — and if they thought it was a socially acceptable practice among their peers.

“Hookah tobacco smoking does not seem to be hampered by many of the negative social stigmas of cigarette smoking,” said Dr. Sidani. “If educational programs can help students to cut through the positive portrayals and marketing of hookah smoking, it may be possible to make hookah smoking less attractive and socially acceptable, resulting in less initiation.”

Senior author Brian Primack, M.D., Ph.D., director of PROMH, added that regulation of hookah tobacco smoking and marketing in the United States is confusing and less rigorous than laws meant to prevent cigarette smoking, which may contribute to misperceptions around hookah smoking.

“Clear policy measures addressing the sale and marketing of hookah products and regulation of hookah bars and cafes may be another way to counteract the positive attitudes young adults hold toward hookah smoking,” Dr. Primack said.

Additional authors of this research are Ariel Shensa, M.A., of Pitt; and Tracey E. Barnett, Ph.D., and Robert L. Cook, M.D., M.P.H., both of the University of Florida.

This research was supported by National Cancer Institute grant no. R01-CA140150 and the Steven Manners Memorial Fund at Pitt’s University Center for Social & Urban Research.

Pitt Study Shows for First Time How Huntington’s Disease Protein Could Cause Death of Neurons

PITTSBURGH, May 18, 2014 – Scientists at the University of Pittsburgh School of Medicine have identified for the first time a key molecular mechanism by which the abnormal protein found in Huntington’s disease can cause brain cell death. The results of these studies, published today in Nature Neuroscience, could one day lead to ways to prevent the progressive neurological deterioration that characterizes the condition.

Huntington’s disease patients inherit from a parent a gene that contains too many repeats of a certain DNA sequence, which results in the production of an abnormal form of a protein called huntingtin (HTT), explained senior investigator Robert Friedlander, M.D., UPMC Professor of Neurosurgery and Neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But until now, studies have not suggested how HTT could cause disease.

“This study connects the dots for the first time and shows how huntingtin can cause problems for the mitochondria that lead to the death of neurons,” Dr. Friedlander said. “If we can disrupt the pathway, we may be able to identify new treatments for this devastating disease.”

Examination of brain tissue samples from both mice and human patients affected by Huntington’s disease showed that mutant HTT collects in the mitochondria, which are the energy suppliers of the cell. Using several biochemical approaches in follow-up mouse studies, the research team identified the mitochondrial proteins that bind to mutant HTT, noting its particular affinity for TIM23, a protein complex that transports other proteins from the rest of the cell into the mitochondria.

Further investigation revealed that mutant HTT inhibited TIM23’s ability to transport proteins across the mitochondrial membrane, slowing metabolic activity and ultimately triggering cell-suicide pathways. The team also found that mutant HTT-induced mitochondrial dysfunction occurred more often near the synapses, or junctions, of neurons, likely impairing the neuron’s ability to communicate or signal its neighbors.

To verify the findings, the researchers showed that producing more TIM23 could overcome the protein transport deficiency and prevent cell death.

“We learned also that these events occur very early in the disease process, not as the result of some other mutant HTT-induced changes,” Dr. Friedlander said. “This means that if we can find ways to intervene at this point, we may be able to prevent neurological damage.”

The team’s next steps include identifying exact binding sites and agents that can influence the interactions of HTT and TIM23.

Co-authors of the paper include other scientists from the University of Pittsburgh School of Medicine and Washington University School of Medicine.

The project was funded by National Institutes of Health grants NS039324, NS077748 and AG033724; the Brain & Behavior Research Foundation; the DSF Charitable Foundation; and the Huntington’s Disease Society of America.

Breakthrough in HIV/AIDS Research Gives Hope for Improved Drug Therapy

PITTSBURGH, May 16, 2014 – The first direct proof of a long-suspected cause of multiple HIV-related health complications was recently obtained by a team led by the University of Pittsburgh Center for Vaccine Research (CVR). The finding supports complementary therapies to antiretroviral drugs to significantly slow HIV progression.

The study, which will be published in the June issue of the Journal of Clinical Investigation and is available online, found that a drug commonly given to patients receiving kidney dialysis significantly diminishes the levels of bacteria that escape from the gut and reduces health complications in non-human primates infected with the simian form of HIV. The study was funded by the National Institutes of Health (NIH).

“We now have direct evidence of a major culprit in poor outcomes for some HIV-infected people, which is an important breakthrough in the fight against AIDS,” said Ivona Pandrea, M.D., Ph.D., professor of pathology at Pitt’s CVR. “Researchers and doctors can now better test potential therapies to slow or stop a key cause of death and heart disease in people with HIV.”

Chronic activation of the immune system and inflammation are major determinants of progression of HIV infection to AIDS, and also play an important role in inducing excessive blood clotting and heart disease in HIV patients. Doctors believed this was due to microbial translocation, which occurs when bacteria in the gut gets out into the body through intestinal lining damaged by HIV.  However, no direct proof of this mechanism existed.

Dr. Pandrea and her colleagues showed blocking the bacteria from leaving the intestine reduces the chronic immune activation and inflammation. They did this by giving the drug Sevelamer, also known by the brand names Renvela and Renagel, to monkeys newly infected with simian immunodeficiency virus, or SIV, the primate-form of HIV.

Sevelamer is an oral drug approved by the U.S. Food and Drug Administration to treat elevated levels of phosphate in the blood of patients with chronic kidney disease.

The gut bacteria bind to Sevelamer, making it much more difficult for the bacteria to escape into the body and cause serious problems, such as heart disease, while further weakening the immune system and allowing HIV to progress to full-blown AIDS.

In SIV-infected monkeys treated with Sevelamer, levels of a protein that indicates microbial translocation remained low. However, in the untreated monkeys the levels increased nearly four-fold a week after SIV infection.

The treated monkeys with the lower rates of microbial translocation also had lower levels of a biomarker associated with excessive blood clotting, showing that heart attacks and stroke in HIV patients are more likely associated with chronic immune system activation and inflammation, rather than HIV drugs.

“These findings clearly demonstrate that stopping bacteria from leaving the gut reduces the rates of many HIV comorbidities,” said Dr. Pandrea.

Because most interventions in people infected with HIV begin after the person has reached chronic stages of infection when the gut is already severely damaged, Dr. Pandrea notes, “These treatments may not be as effective later in the infection. Clinical trials in HIV-infected patients were not yet successful in reducing microbial translocation in chronically infected patients. Our study points to the importance of early and sustained drug treatment in people infected with HIV.”

Other approaches, such as coupling Sevelamer with antibiotics, anti-inflammatory drugs, probiotics or supplementation of existing HIV/AIDS drugs could further reduce the likelihood of microbial translocation. Clinical trials are underway to assess these strategies.

Additional researchers on this study are Jan Kristoff, B.A., M.S., George Haret-Richter, Ph.D., Dongzhu Ma, Ph.D., Cuiling Xu, Ph.D., Jennifer L. Stock, B.S., Tianyu He, B.S., Adam D. Mobley, B.S., Samantha Ross, B.A., M.S., Anita Trichel, D.V.M., Ph.D., Cristian Apetrei, M.D. Ph.D., all of Pitt; Alan Landay, Ph.D., Rush University; Ruy M. Ribeiro, Ph.D., Los Alamos National Laboratory; Elaine Cornell, technician, and Russell Tracy, Ph.D., both of the University of Vermont; and Cara Wilson, M.D., of the University of Colorado.

This work was supported by NIH grants R01 HL117715, R01 RR025781, 5P01 AI076174 and P30 AI082151.

Magee Hosts Russian Physicians to Study Women’s Health

PITTSBURGH, May 15, 2014 – A delegation of five Russian obstetric gynecologists will visit Magee-Womens Hospital of UPMC and Magee-Womens Research Institute (MWRI) for a comprehensive program exploring advanced care practices and scientific research for a wide range of women’s health issues.

The delegation will spend May 23 to 31 in Pittsburgh learning best practices in gynecological care, obstetrics, neonatology, mid-wifery, maternal/fetal care and prenatal care. They also will learn about significant research advances in ovarian cancer, breast cancer, fertility, reproductive biology and uterine prolapse. Members of the delegation will shadow physicians and nurses in Magee’s neonatal intensive care unit, birth center and breast imaging center, and spend time in MWRI’s laboratories observing current research projects and technology.

“The visit from this delegation is an exciting opportunity to share medical and research advances happening in Pittsburgh that could have an impact nationally and internationally,” said Leslie Davis, president, Magee-Womens Hospital of UPMC. “It also is a wonderful chance for our researchers and physicians to learn from their Russian counterparts.”

The delegation is hosted by Magee Womancare International (MWI), a nonprofit organization that serves as the international humanitarian outreach arm of Magee.

“While our organization now brings health education programs and technical assistance to the international communities of Pittsburgh, we were first established to improve health care conditions for women and infants in the former Soviet Union,” said Nicole Travis, the administrative director of MWI. “The arrival of this delegation brings our work full circle, and we are greatly looking forward to sharing our resources here in Pittsburgh.”

This visit is managed by the Open World Leadership Center, a support agency of the United States Congress. The Open World program enhances understanding and capabilities for cooperation between the United States and the countries of Eurasia by developing a network of leaders in the region who have gained significant, firsthand exposure to American democracy and the free-market system.

For more information, please contact Nicole Travis at 412-641-8996 or travisn@mwri.magee.edu or Maura Sheldon, Open World Public Affairs Officer, at 202-707-6197.

Children’s Hospital of Pittsburgh of UPMC Study Shows Rise in Emergency Department Visits for Traumatic Brain Injury

PITTSBURGH, May 13, 2014 – There was a nearly 30 percent increase in the rate of visits to United States’ emergency departments (ED) for traumatic brain injury (TBI) from 2006 to 2010, according to a study led by a Children’s Hospital of Pittsburgh of UPMC physician. The rise might be attributable to a number of factors, including increased awareness and diagnoses.

Results of the study, led by Jennifer R. Marin, M.D., M.Sc., an emergency medicine physician at Children’s Hospital, are published in the recent issue of the Journal of the American Medical Association.

The team used data from the Nationwide Emergency Department Sample (NEDS) database to determine national trends in ED visits for TBI from 2006 through 2010. NEDS is a nationally representative database and includes 25 to 50 million visits from more than 950 hospitals each year. Additionally, the authors used U.S. census data in order to determine incidence rates and the burden of traumatic brain injury on the U.S. population.

“The reason for this increase may be because more people are sustaining head injuries, patients are more aware of TBI and more likely to seek emergency care, health care professionals are more vigilant about making these diagnoses, or a combination of these,” said Dr. Marin, also assistant professor of pediatrics and emergency medicine at University of Pittsburgh School of Medicine. “The findings underscore the need for more evaluation into why and how to reverse these trends so that we can minimize the incidence of traumatic brain injury and the consequences associated with these injuries.”

The team found that in 2010 there were an estimated 2.5 million ED visits for TBI, representing a 29 percent increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6 percent. The majority of the increase in the incidence of TBI occurred in visits coded as concussion or unspecified head injury. Children younger than 3 years and adults older than 60 years had the largest increase in TBI rates. The majority of visits were for minor injuries and most patients were discharged from the ED.

“Traumatic brain injury is an important cause of morbidity and mortality each year,” Dr. Marin said. “There has been widespread attention to traumatic brain injury, specifically in terms of prevention, in the last decade by policy makers and health professionals. Large-scale studies that assess national statistics and trends are one of the few ways we have to understand the scope of the problem.”

The authors suggest that the increase in TBI among the very young and very old may indicate these age groups do not benefit as much from public health interventions, such as concussion and helmet laws and safer sports’ practices.

For more information on Dr. Marin and Children’s Hospital of Pittsburgh of UPMC, visit www.chp.edu.

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