UPMC Physician Resources

Children’s Hospital of Pittsburgh of UPMC Lung Researcher Receives Prestigious Scientific Award

PrintPITTSBURGH, May 18, 2015John F. Alcorn, Ph.D., assistant professor of pediatrics in the Division of Pulmonology at Children’s Hospital of Pittsburgh of UPMC, has been selected as the 2015 recipient of the Parker B. Francis Jo Rae Wright Award for Scientific Excellence. The award has been established by the Parker B. Francis Fellowship Program and the Francis Family Foundation to honor Jo Rae Wright, Ph.D.

The award will be presented to Dr. Alcorn today at the Parker B. Francis Fellowship Reception at the American Thoracic Society meeting.

“The Parker B. Francis Fellowship Program and the Francis Family Foundation has been instrumental in my early career development to independence,” said Dr. Alcorn, also assistant professor of pediatrics, University of Pittsburgh School of Medicine. “Receiving this award is exceptionally meaningful to me as I previously completed my Ph.D. training under Jo Rae’s mentorship at Duke University. I am honored to be the recipient Jo Rae Wright Award and I hope to continue on the path toward becoming a leader in pulmonary research.”

Dr. Alcorn’s research focuses on T-cell mediated immunity during influenza infections and secondary bacterial pneumonia, as well as the role of T-cells in severe, steroid-insensitive asthma.

The Parker B. Francis Jo Rae Wright Award for Scientific Excellence is given annually to a recent graduate of the Fellowship Program whose research shows outstanding creativity and promise and who has demonstrated outstanding mentoring and professional leadership qualities. Dr. Alcorn will receive a one-time award of $5,000 to be used to support research costs.

Dr. Jo Rae Wright was a world-renowned scientist, devoted teacher and mentor, and a leader in academia and professional organizations. She served as dean of the Graduate School of Duke University and was president of the American Thoracic Society in 2008. She received the American Physiological Society’s Walter B. Cannon Award for lifetime achievements in research in 2005. She served as a member of the Parker B. Francis Fellowship Program Council of Scientific Advisors from 2004 through 2007 and was a mentor to Parker B. Francis Fellows.

For more information on Dr. Alcorn, visit www.chp.edu.

New Guidelines Aim to Resolve Conflicts in Treating Critically Ill Patients

PITTSBURGH, May 15, 2015 – Who should decide what life-prolonging medical treatments the intensive care patient should receive: the clinician or the patient’s family?  

The answer in almost all circumstances should be “both,” according to the authors of a new policy statement from the American Thoracic Society aimed at providing guidance for crucial decision-making for the care of patients with advanced critical illness while preventing conflicts between medical staff and family caregivers.

“Neither individual clinicians nor families should be given unchecked authority to determine what treatments will be given to a patient,” explained Douglas White, M.D., M.A.S., UPMC Chair for Ethics in Critical Care Medicine, associate professor in the University of Pittsburgh Department of Critical Care Medicine, and co-chair of the committee that produced these guidelines. “Clinicians should neither simply acquiesce to treatment requests that they believe are not in a patient’s best interest, nor should they unilaterally refuse to provide treatment. Instead, if conflicts arise between clinicians and patients’ families, a fair process of dispute resolution should be undertaken, in which neither individual can unilaterally impose his or her will on the other.”

The guidelines, which will appear in the June 1st issue of the American Journal of Respiratory and Critical Care Medicine and are available online Friday at http://www.atsjournals.org/toc/ajrccm/0/ja, are a new resource for an estimated 80,000 health professionals. They are supported by the Society of Critical Care Medicine, the American Association of Critical Care Nurses, the American College of Chest Physicians and the European Society of Intensive Care Medicine.

When a clinician is asked by the family of a critically ill patient to administer invasive interventions that the clinician believes will not benefit the patient, “such disagreements can present particular challenges, since they bring into conflict important interests of patients, clinicians and society,” Dr. White said. “The cases are difficult because there are generally no clear, substantive rules to appeal to and because ICU patients are especially vulnerable because of their overwhelming illness and lack of ability to seek out another doctor if they disagree with the plan.” 

The guidelines emphasize that conflicts in the ICU can and should be prevented through early and intensive communication between the patient’s family and the health care team. When conflicts cannot be resolved with ongoing dialogue, the policy statement recommends early involvement of expert consultants, such as palliative care and ethics consultants, to help find a negotiated agreement. If a dispute remains unresolvable despite intensive communication and negotiation, the committee recommends a fair process of dispute resolution, involving a review of the case by a multidisciplinary ethics committee within the hospital, ongoing mediation, a second medical opinion, offering family the option to seek to transfer the patient to an alternate institution, and informing the family of their right to appeal to the courts.

“Families need to be given a voice regarding what treatments are consistent with the patient’s values and preferences, and physicians’ professional integrity also needs to be respected, meaning that they should not be compelled to administer treatments that violate good medical practice,” Dr. White said.

The policy statement also outlines innovative procedures for two additional situations. When families request treatment that is truly futile, meaning that it simply cannot accomplish its physiologic aims, the clinician should refuse to administer the treatment and should clearly explain the rationale behind the treatment decision. In addition, for situations in which medical urgency does not allow compliance with the longer dispute resolution process, the committee has provided expedited steps that, nevertheless, ensure a fair process.

“These guidelines provide clinicians with a framework to manage treatment disputes with an emphasis on procedural fairness, frequent communication, expert consultation and timeliness,” said co-chair Gabriel T. Bosslet, M.D., assistant professor of clinical medicine at the Charles Warren Fairbanks Center for Medical Ethics at Indiana University. “We hope that states will adopt laws similar to these guidelines, so that all sides in a particular dispute can have the resources they need to come to a resolution.”

Co-authors of the guidelines include Thaddeus M. Pope, Hamline University Law School; Gordon Rubenfeld, M.D., Sunnybrook Health Sciences Center; Bernard Lo, M.D., University of California, San Francisco; Robert Truog, M.D., Harvard Medical School; Cynthia Rushton, Ph.D., R.N., Johns Hopkins University; J. Randall Curtis, M.D., University of Washington; Dee W. Ford, M.D., Medical University of South Carolina; Molly Osborne, M.D., Portland VA Medical Center, Oregon Health Sciences University; Cheryl Misak, M.A., University of Toronto; David H. Au, M.D., VA Puget Sound Health Care System, University of Washington; Elie Azoulay, M.D., Ph.D., Saint Louis Teaching Hospital and Paris 7 University; Baruch Brody, Ph.D., Baylor College of Medicine; Brenda Fahy, M.D., University of Florida; Jesse Hall, M.D., University of Chicago; Jozef Kesecioglu, M.D., Ph.D., University Medical Center-Utrecht, the Netherlands; Alexander A. Kon, M.D., University of San Diego; and Kathleen Lindell, Ph.D., R.N., University of Pittsburgh.

Pitt Physician Researchers Determine Elevated Peptide Level Associated With Mortality in HIV-Infected Women

PITTSBURGH, May 15, 2015 – Pulmonary medicine experts from the University of Pittsburgh have identified an elevated NT-pro-brain natriuretic peptide (NT-proBNP) level as being independently associated with all-cause mortality in HIV-infected women. NT-proBNP is a marker of cardiac ventricular strain and systolic dysfunction.

The authors, led by Matthew Gingo, MD, associate professor of medicine in the Division of Pulmonary, Allergy, and critical Care Medicine at the University of Pittsburgh, measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early, and 1082 HIV-infected and 448 HIV-uninfected women late in the highly active antiretroviral therapy (HAART) periods in the Women’s Interagency HIV Study.

They found that a NT-proBNP level above the 75th percentile was more likely in HIV-infected persons, but was only statistically significant in the late period. In HIV-infected participants, a NT-proBNP level greater than the 75th percentile was independently associated with worse five-year survival in the early HAART period and remained a predictor of mortality in the late HAART period, independent of other established risk covariates, such as age, race/ethnicity, body mass index, smoking, hepatitis C serostatus, hypertension, renal function, and hemoglobin. NT-proBNP level was not associated with mortality in HIV-uninfected women.

The authors concluded, “NT-proBNP is a novel independent marker of mortality in HIV-infected women both when HAART was first introduced and currently. As NT-proBNP is often associated with both pulmonary hypertension and left ventricular dysfunction, these findings suggest that these conditions may contribute significantly to adverse outcomes in this population, requiring further definition of causes and treatments of elevated NT-proBNP in HIV-infected women.”

Additional authors on the study were Yingze Zhang, PhD, Kidane Ghebrehawariat, Jong Jeong, PhD, Lorrie Lucht, Quanwei Yang, Yanxia Chu, Mark Gladwin, MD, Alison Morris, MD, all of the University of Pittsburgh; Jason Lazar, MD, of SUNY Downstate Medical Center in Brooklyn, NY; and David B. Hanna, PhD, of Albert Einstein College of Medicine in Bronx, NY.

To view the full abstract, please visit PubMed.gov.

X-linked Gene Mutations Cause Some Cases of Male Infertility, Pitt Study Says

PITTSBURGH, May 13, 2015 – Some cases of male infertility are due to mutations in the maternal X chromosome that prevent development of viable sperm, according to a study led by researchers at the University of Pittsburgh School of Medicine and the Magee-Womens Research Institute (MWRI). The study was published online today in the New England Journal of Medicine.

Nearly half of cases of male infertility not due to a physical obstruction are estimated to have genetic roots, and about 20 percent of infertile men have azoospermia, meaning they don’t make sperm, explained co-principal investigator Alexander Yatsenko, M.D., Ph.D., assistant professor of obstetrics, gynecology and reproductive medicine, Pitt School of Medicine, and an MWRI investigator. He noted the only causes for infertility that have been identified are defects of sex chromosomes, such as the deletions of the Y (male) chromosome or duplication of the entire X (female) chromosome in Klinefelter syndrome.

“Eight times out of 10, conventional genetic testing doesn’t reveal a chromosomal problem, so the cause is considered idiopathic or unknown,” Dr. Yatsenko said. “This study is among the first to describe specific gene mutations on the X chromosome that contribute to azoospermia and male infertility.”

First, the research team scanned the genomes of 15 men with azoospermia and found a deletion in part of the DNA coding of the testis-expressed gene 11 (TEX11) on the X-chromosome, which men inherit from their mothers. The alteration caused meiotic arrest, meaning the precursor cells could not properly undergo meiosis, the cell division process that produces daughter cells with half the parental chromosomes for reproduction.

Then, they found similar TEX11 gene mutations and meiotic arrest in two out of 49 men diagnosed with idiopathic azoospermia from the Center for Fertility and Reproductive Endocrinology at Magee-Womens Hospital of UPMC, and the Institute of Human Genetics of the Polish Academy of Sciences in Poznan, Poland. Also, TEX11 gene errors were found in five out of 240 infertile men from the Center of Reproductive Medicine and Andrology in Münster, Germany.

Dr. Yatsenko noted that it might be possible for an older father, whose precursor sperm cells have a greater likelihood of acquiring a mutation, to pass along the genetic error to his daughter, which could make it impossible for her son to make viable sperm. Also, men without seminal sperm who undergo a procedure to have a few rare, viable sperm extracted from the testes to attempt conception with in vitro fertilization could unknowingly pass a TEX11 gene mutation to a daughter, making her a carrier.

“This research suggests screening for TEX11 gene mutations might be useful in cases of otherwise unexplained azoospermia,” Dr. Yatsenko said. “It might be possible to one day correct these problems with gene therapy and other interventions. More work must be done to identify other genetic causes of male infertility.”

The team included co-senior author Frank Tüttelmann, M.D., and others from of the University of Münster, Germany; the University of Pittsburgh; and the Polish Academy of Sciences.

The project was funded by grant HD058073 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the Pennsylvania Department of Health; MWRI; the University of Pittsburgh; the Polish National Science Centre; and the German Research Foundation.

Computer Simulation Accurately Replicated Real-Life Trauma Outcomes, Says Pitt Team

PITTSBURGH, May 11, 2015 – A computer simulation, or “in silico” model, of the body’s inflammatory response to traumatic injury accurately replicated known individual outcomes and predicted population results counter to expectations, according to a study recently published in Science Translational Medicine by a University of Pittsburgh research team.

Traumatic injury is a major health care problem worldwide. Trauma induces acute inflammation in the body with the recruitment of many kinds of cells and molecular factors that are crucial for tissue survival, explained senior investigator Yoram Vodovotz, Ph.D., professor of surgery and director of the Center for Inflammation and Regenerative Modeling at the University of Pittsburgh School of Medicine. But if inappropriately sustained, the inflammatory response can compromise healthy tissues and organs.

“Thanks to life-saving surgery and extensive supportive care, most patients who require trauma care are now highly likely to survive,” Dr. Vodovotz said. “But along the way, they may experience a variety of complications, such as multiple organ failure, that are difficult to predict in initial assessment. Our current challenge is to identify which patients are vulnerable to certain problems so that we can better implement surveillance and prevention strategies and use resources more effectively.”

Building from a model developed for swine, the research team examined blood samples from 33 survivors of car or motorcycle accidents or falls for multiple markers of inflammation, including interleukin-6 (IL-6), and segregated the patients into one of three (low to high) categories of trauma severity. They were able to validate model predictions regarding hospital length of stay in a separate group of nearly 150 trauma patients. They then generated a set of 10,000 “virtual patients” with similar injuries and found the model could replicate outcomes in individuals, such as length of stay and degree of multi-organ dysfunction. Intriguingly, the in silico model also predicted a 3.5 percent death rate, comparable to published values and to the Pitt group’s own observations, even though the model did not include patients who didn’t survive their injuries.

The in silico model predicted that, on an individual basis, virtual patients who made more IL-6 in response to trauma were less likely to survive. But, as the model predicted, that was not true at the population level: Among nearly 100 real patients whose genetic predisposition to make more or less amounts of IL-6 had been determined, there was little difference in survival between high- and low-IL-6 producers.

“These findings demonstrate the limitations of extrapolating from single mechanisms to outcomes in individuals and populations, which is the typical paradigm used to identify potential treatments,” Dr. Vodovotz said. “Instead, dynamic computational models like ours that simulate multiple factors that interact with each other in complex diseases could be a more efficient and accurate way of predicting outcomes for both individuals and populations. Then we can pursue those avenues that have the greatest likelihood of success in clinical trials.”

“The potential impact of this work is high because clinical trials are difficult and expensive to carry out, and usually can test only a single dose of a drug,” noted co-investigator Timothy Billiar, M.D., George Vance Foster Professor and chair, Pitt Department of Surgery. “Determining the best dose, timing and biomarkers that would characterize patients likely to respond well to therapy is a major thrust of the pharmaceutical and biotechnology companies. This approach could help tailor treatments.”

The project was carried out by the Trauma Research Center, which is headed by Dr. Billiar, and included other researchers from the University of Pittsburgh, the McGowan Institute for Regenerative Medicine, Upstate Medical University in Syracuse, N.Y., and Immunetrics, Inc. It was funded by National Institutes of Health grants GM-53789 and HL-089082.

Children’s Pulmonologist Honored By Association of American Physicians and American Thoracic Society

PrintPITTSBURGH, May 6, 2015 – Juan Celedón, MD, DrPH, Chief of Service in the Division of Pediatric Pulmonology, Allergy, and Immunology at Children’s Hospital of Pittsburgh of UPMC recently was elected to the Association of American Physicians. Dr. Celedón also was chosen for the Innovations in Health Equality — Lifetime Achievement Award from the American Thoracic Society’s Clinicians Advisory Committee and its Health Equality Subcommittee.

Dr. Celedón’s research is focused on the genetics and epidemiology of asthma in Puerto Rican and black children. He also is leading a study of chronic obstructive pulmonary disease (COPD) genetics in Costa Rica.

For more information on Dr. Celedón’s work, please visit the Division of Pulmonary, Allergy, and Critical Care Medicine page.

Pitt Team Follows the Zinc to Uncover Brain Pathway that Fine-Tunes Neural Signaling

PITTSBURGH, May 4, 2015 – A study team led by researchers at the University of Pittsburgh School of Medicine who used specially developed technologies to “follow the zinc” have uncovered a previously unknown pathway the brain uses to fine-tune neural signaling—and that may play a role in Alzheimer’s and other diseases. Their findings appear online this week in the Proceedings of the National Academy of Sciences.Zinc signals in the brain

Scientists have long observed the presence of bubble-like vesicles that contain the neurotransmitter glutamate and zinc at the synapses, specialized contacts among neurons where neurotransmitters are released to propagate electrical signals through the brain. Glutamate is the major excitatory neurotransmitter in the brain, but the need for synaptic zinc, an essential element that acts as a co-factor for many enzyme and regulatory proteins, has not been understood, said Thanos Tzounopoulos, Ph.D., associate professor in the Auditory Research Group, Department of Otolaryngology, Pitt School of Medicine.

“Until now, we haven’t had the ability to quantify or follow zinc when it is released into the synaptic cleft,” he said. “In this study, we employed new tools to do that and found a pathway that could be important for conditions such as Huntington’s disease and Alzheimer’s.”

Co-investigator Stephen Lippard, Ph.D., and his team at the Massachusetts Institute of Technology (MIT) developed an agent that fluoresces when it binds zinc, making it possible for the first time to measure zinc levels accurately and track the element’s movements. They also created an agent that blocks zinc activity, thus allowing them to disrupt the metal’s actions to determine its function.

The researchers learned that, indeed, zinc was released from vesicles and diffused from the release site. Surprisingly, it could bind to so-called extrasynaptic glutamate NMDA-type receptors, just like the neurotransmitter glutamate. Whereas glutamate activates these receptors, zinc inhibits them.

“Glutamate acts like an accelerator of neuronal activity, while zinc behaves like a brake that fine tunes that signal,” Dr. Tzounopoulos said. “The receptors that zinc influences are thought to play a role in neurodegenerative diseases, so these findings could open new research avenues in the field.”

The team included Charles T. Anderson, Ph.D., of the University of Pittsburgh; as well as Robert J. Radford, Ph.D., Melissa L. Zastrow, Ph.D., Daniel Y. Zhang and Ulf-Peter Apfel, Ph.D., of MIT. The project was funded by National Institutes of Health grants DC011499, DC013734-01A, GM065519 and DC007905.

National Thyroid Cancer Experts Meet at UPMC to Advance Patient Care

PITTSBURGH, April 30, 2015 – Nearly 200 physicians and researchers from across the country will gather in the Herberman Conference Center at UPMC Shadyside Saturday to discuss adapting the new American Thyroid Association (ATA) guidelines into clinical practice and to find new ways of working together to improve patient care.

The Seventh Annual Multidisciplinary Thyroid Cancer Symposium, which is sponsored by UPMC, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter and the University of Pittsburgh School of Medicine, will bring together leading experts in the field to cover a wide variety of topics, including best practices in managing patients with advanced thyroid cancer, the value in predictive molecular testing,  and the latest surgical approaches in the field.

“Our understanding of thyroid cancer has advanced significantly in recent years, and new treatment guidelines were necessary to incorporate the latest research,” said Robert Ferris, M.D., Ph.D., chief of the Division of Head and Neck Surgery at Pitt and one of the conferences co-chairs. “The predictive molecular testing, which was researched and developed at UPMC, will be part of the recommendations for evaluation of a thyroid nodule and will arise in a new consensus statement recently developed by the ATA.  We are looking forward to the discussion this meeting will generate.”

Approximately 63,000 cases of thyroid cancer will be diagnosed in 2015. Thyroid cancer commonly is diagnosed at a younger age than most other adult cancers, and the chance of being diagnosed has risen in recent years as a result of the increased use of thyroid ultrasound.

The event includes a continuing medical education credit component for physicians.

Two-Week International Diet Swap Shows Potential Effects of Diet on Colon Cancer Risk

PITTSBURGH, April 28, 2015 – African-Americans and Africans who swapped their typical diets for just two weeks similarly exchanged their respective risks of colon cancer as reflected by alterations of their gut bacteria, according to an international study led by researchers at the University of Pittsburgh School of Medicine published online today in Nature Communications.

Principal investigator Stephen O’Keefe, M.D., professor of medicine, Division of Gastroenterology, Hepatology and Nutrition, Pitt School of Medicine, observed while practicing in South Africa that his rural patients rarely had colon cancer or intestinal polyps, which can be a cancer precursor. In the Western world, colon cancer is the second-leading cause of cancer death and African-Americans carry the greatest disease burden in the United States.

“The African-American diet, which contains more animal protein and fat, and less soluble fiber than the African diet, is thought to increase colon cancer risk,” Dr. O’Keefe explained. “Other studies with Japanese migrants to Hawaii have shown that it takes only one generation of Westernization to change their low incidence of colon cancer to the high rates observed in native Hawaiians. In this project, we examined the impact of a brief diet change on the colon in a controlled setting where we didn’t have to worry about the influence of smoking and other environmental factors on cancer risk.”

After assessment of their in-home diets, 20 African-American and 20 rural South African volunteers ages 50 to 65 were housed at a University of Pittsburgh site and at an African lodging facility respectively. There they ate meals prepared by the researchers using ingredients and cooking techniques typical of the other group. The team examined fecal and colon content samples, obtained during colonoscopy, of each volunteer at baseline and after the two-week study period.

Although the diet change was brief, each group took on the other’s rates of turnover of cells of the intestinal lining, levels of fiber fermentation, and markers of bacterial metabolic activity and inflammation associated with cancer risk. In particular, African-Americans experienced an increase in butyrate production, which is thought to play a key role in anti-cancer pathways. The researchers also noted they removed intestinal polyps from nine of the African-American volunteers, but none were present in the Africans.

“We can’t definitively tell from these measurements that the change in their diet would have led to more cancer in the African group or less in the American group, but there is good evidence from other studies that the changes we observed are signs of cancer risk,” said co-author Jeremy Nicholson, Ph.D., of Imperial College London.

According to Dr. O’Keefe, increasing the amount of fiber in the diet – from approximately 10 grams to more than 50 for African-Americans in the diet swap – likely led to biomarker changes reflecting reduced cancer risk, but eating less animal fat and proteins also could be helpful.

“These findings are really very good news,” he said. “In just two weeks, a change in diet from a Westernized composition to a traditional African high-fiber, low-fat diet reduced these biomarkers of cancer risk, indicating that it is likely never too late to modify the risk of colon cancer.”

The team included other researchers from the University of Pittsburgh and Imperial College London, as well as Wageningen University in the Netherlands; University of Helsinki, Finland; University of Illinois; and the University of KwaZulu-Natal in South Africa.

Funding for the study was provided National Institutes of Health grants CA135379, RR024153 and TR000005; the National Institute for Health Research Imperial Biomedical Research Centre, UK; the Academy of Medical Sciences; the Spinoza Award of the Netherlands Organization for Scientific Research, the European Research Council and the Academy of Finland.

Geriatric Incontinence Expert to Present at AUA 2015

PITTSBURGH, April 27, 2015 – Neil Resnick, MD, Thomas Detre Professor and Chief of the Division of Geriatric Medicine, is schedule to present on brain activity in overactive bladder at the upcoming American Urological Association (AUA) Annual Meeting.

Dr. Resnick’s research has helped to pioneer the field of geriatric voiding dysfunction and incontinence, improving the understanding of these conditions and leading to the development of novel diagnosis and treatment strategies. His work has been recognized nationally by the National Institutes of Health (NIH), the International Continence Society, the Society for General Internal Medicine, and the AUA.

Dr. Resnick’s presentation, entitled “Aging and Urologic Manifestations: Brain Activity in Overactive Bladder,” is scheduled to be presented during a basic science symposium on Friday, May 15.

For more information about the AUA Annual Meeting, please visit the conference page.

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