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Pitt Team Identifies Genes that Play Critical Role in the Development of Congenital Heart Disease

PITTSBURGH, March 25, 2015 – Fetal ultrasound exams on more than 87,000 mice that were exposed to chemicals that can induce random gene mutations enabled developmental biologists at the University of Pittsburgh School of Medicine to identify mutations associated with congenital heart disease in 61 genes, many not previously known to cause the disease. The study, published online today in Nature, indicates that the antenna-like cellular structures called cilia play a critical role in the development of these heart defects.

The findings are the culmination of an effort to find the genetic determinants of structural heart disease in the “Bench to Bassinet” program, launched six years ago by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, led at Pitt by principal investigator Cecilia Lo, Ph.D., professor and chair of the Department of Developmental Biology, Pitt School of Medicine.

“This project has given us new insights into the biological pathways involved in development of the heart,” Dr. Lo said. “The genes and pathways identified in our study will have clinical importance for interrogating the genetic causes of congenital heart disease in patients.”

For the study, Dr. Lo’s team mated mice exposed to chemicals that could create random genetic mutations, resulting in 87,355 pregnancies. They scanned each fetus using noninvasive ultrasound and recovered over 3,000 independent cases of congenital heart defects, all incompatible with life. They sequenced the genes of mutant animals and compared them to those of unaffected offspring to identify 91 recessive mutations in 61 genes.

“We were surprised to learn many of these genes were related to the cilia, or cilia-transduced cell signaling,” Dr. Lo said. “These findings suggest cilia play a central role in the regulation of heart development, including patterning left-right asymmetry in the cardiovascular system critical for efficient oxygenation of blood.”

She added that pathways recovered in the mouse study show overlap with those associated with de novo, or spontaneous, mutations identified in congenital heart disease patients. Co-investigators of the project include other researchers from the University of Pittsburgh; the University of Massachusetts Medical School; the Jackson Laboratory; and Children’s National Medical Center.

The project was funded NHLBI grants HL098180 and HL098188; National Institute of Mental Health grant MH094564; National Human Genome Research Institute grant HG000330; and the University of Pittsburgh School of Medicine.

Rebooting Cell Programming Can Reverse Liver Failure, Says Children’s Hospital/Pitt Study

PITTSBURGH, March 16, 2015 – It might be possible to heal cirrhotic liver disease by rebooting the genes that control liver cell function, according to researchers at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. If validated in human studies, the game-changing strategy, described today in the online version of the Journal of Clinical Investigation, could potentially treat patients who are too sick for liver transplantation and, in the future, reduce the need for transplants.

The project grew out of the observation that not everyone who develops cirrhosis, or scarring of the liver, progresses to liver failure and its life threatening complications, explained Ira Fox, M.D., professor of surgery, Pitt School of Medicine, and director of the Center for Innovative Regenerative Therapies at Children’s Hospital and the McGowan Institute for Regenerative Medicine.

“Even with the large amount of scar tissue that comes with cirrhosis, there should be enough cells left to carry out the normal functions of the liver,” Dr. Fox said. “So when the liver fails, it is the liver cells themselves that aren’t working properly. In this study, we demonstrate what has caused the problem, and more importantly, a way to repair it.”

His team developed a rat model of liver disease that mimics the form of human cirrhosis that progresses to organ failure. In previous work, they found that liver cells taken from animals with cirrhosis, but no liver failure, immediately functioned properly when transplanted into another animal. But cells transplanted from animals with both cirrhosis and liver failure did not function normally at first, indicating that both the liver cells and the liver tissue environment were damaged.

The researchers then compared the genes in the liver cells of the two groups of cirrhotic rats and found unusually low activity levels of the genes that control proteins which play a central role in liver cell function, the most important being a factor called HNF4.

In the new paper, they showed that restoring production of HNF4 by gene therapy reboots the liver cells to normal function. The team first showed this in lab tests and then in rats with liver failure.

“We were pleased to see that the animals got better almost immediately. Remarkably, our tests indicated that it wasn’t stem cells, regeneration or growth of new liver cells that caused improvement. Instead, the diseased cells had healed,” Dr. Fox said. “It seems that in at least some forms of cirrhosis, chronic injury reprograms the liver cells to shut down HNF4 production, a dysfunction that eventually causes liver failure.”

HNF4 gene therapy provided unique insight into the cause of liver failure and has significant potential for human therapy, but the investigators are now looking for other gene targets to develop simpler therapies, such as drugs that block the pathways that mediate failure. The team also is confirming their results with human liver cells.

Co-investigators include Alejandro Soto-Gutierrez, M.D., Ph.D., Joseph Locker, M.D., Ph.D., and other researchers from Children’s Hospital, Pitt School of Medicine and the McGowan Institute; Kyoto Prefectural University of Medicine, Japan; and the University of Pennsylvania.

The project was funded by National Institutes of Health grants DK48794, DK099320 and DK099257, as well as grants from the U.S. Department of Defense.

Pediatric Rehabilitation Chief Asked to Participate in CDC, AAP Activities

PITTSBURGH, March 5, 2015 – Amy Houtrow, MD, PhD, MPH, chief, Division of Pediatric Rehabilitation Medicine and a member of the Brain Care Institute at Children’s Hospital of Pittsburgh of UPMC, recently was invited by the Centers for Disease Control and Prevention (CDC) to participate in its National Center on Birth Defects and Developmental Disabilities (NCBDDD) and the Division of Human Development and Disability. Selected for her expertise in the area of disability and health, Dr. Houtrow also serves as associate professor and vice chair in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh. The group’s goal is to develop concrete recommendations to inform a current and innovative Disability and Health Branch roadmap over the next decade.

Dr. Houtrow also has been asked to serve on the American Academy of Pediatrics (AAP) National Conference & Exhibition Planning Group, a cross-section of more than two dozen practicing pediatricians, medical, and surgical pediatric subspecialists. The group reviews and accepts approximately 350 sessions — out of more than 500 proposals — that comprise the conference program.

Pitt Study Finds Popular YouTube Videos Drown Viewers with Positive Portrayals of Drunkenness

PITTSBURGH, Feb. 20, 2015 – The 70 most popular videos depicting drunkenness on YouTube account for more than 330 million views, with little portrayal of the negative outcomes of excessive alcohol consumption, according to an analysis led by the University of Pittsburgh Center for Research on Media, Technology, and Health (CRMTH).

The popularity of such videos on YouTube could be an opportunity for public health interventions aimed at educating teenagers and young adults of the negative consequences of intoxication, the researchers suggest in an article published in today’s issue of the journal Alcoholism: Clinical and Experimental Research.

“There has been little research examining Internet-based, alcohol-related messaging,” said lead author Brian A. Primack, M.D., Ph.D., director of CRMTH and assistant vice chancellor for health and society in Pitt’s Schools of the Health Sciences. “While we know that some viewers may be savvy enough to skeptically view music videos or advertisements portraying intoxication as fun, those same viewers may be less cynical when viewing user-generated YouTube videos portraying humorous and socially rewarding escapades of a group of intoxicated peers.”

Dr. Primack’s team mined YouTube for five terms synonymous with alcohol intoxication – drunk, buzzed, hammered, tipsy and trashed – winnowing their findings down to the most relevant.

There were a total of 333,246,875 views for all 70 videos combined.

  • Humor was juxtaposed with alcohol use in 79 percent of the videos.
  • Motor vehicle use was present in 24 percent.
  • Although 86 percent of the videos showed active intoxication, only 7 percent contained references to alcohol dependence.
  • An average of 23.2 “likes” were registered for every “dislike.”
  • While 89 percent of the videos involved males, only 49 percent involved females.
  • A specific brand of alcohol was referenced in 44 percent of the videos.

“This is the first comprehensive attempt to analyze YouTube data on intoxication, and these statistics should be valuable in guiding interventions,” said Dr. Primack, also a practicing physician. “For example, we know that men tend to report more frequent binge drinking than women and that alcohol use is perceived as more socially acceptable for men. Because they are portrayed more frequently in YouTube videos, it may be useful to target men with future interventions debunking alcohol-related myths propagated on social media.”

Dr. Primack found it concerning that nearly half the videos contained specific brand references. While this could indicate industry influence, the researchers did not note any clear indication of intentional advertising. Past research has linked exposure to brand references in popular media to encouraging alcohol consumption.

Additional authors on this research are Jason B. Colditz, M.Ed., and Kevin C. Pang, both of Pitt; and Kristina M. Jackson, Ph.D., of Brown University.

This research was funded by ABMRF/The Foundation for Alcohol Research.

Pitt Expert Talks Teenage Brain Development at American Association for the Advancement of Science Annual Meeting

PITTSBURGH, Feb. 14, 2015 – Teenage exploration and risk taking could be explained by dramatic changes in the brain that allow elaborate planning and are driven by the need for immediate reward, according to a University of Pittsburgh neuroscientist who will be talking about her research in a panel discussion and press briefing at the American Association for the Advancement of Science annual meeting, Feb. 13 to 16, in San Jose, Calif.

Using an elegant model in which eye movements, or saccades, reveal insight into executive brain function, Beatriz Luna, Ph.D., Staunton Professor of Psychiatry and Pediatrics, Pitt School of Medicine, has studied hundreds of young volunteers to examine brain development during the transition between childhood and adulthood.

“Our studies are beginning to challenge the traditional concept that the teenage brain can’t plan because of an immature prefrontal cortex,” Dr. Luna said. “Our findings indicate that the teen prefrontal cortex is not much different than in the adult, but it can be easily overruled by heightened motivation centers in the brain. You have this mixture of newly gained executive control plus extra reward that is pulling the teenager toward immediate gratification.”

In the experiments, volunteers are instructed to immediately look away from a small light that randomly appears on a screen in front of them. This “anti-saccade” test shows if the brain is able to engage the planning centers of the prefrontal cortex to overcome the impulse to look toward the light rather than away from it. Dr. Luna’s team has found in previous studies that children succeed in about half their tries, teens in about 70 percent of tries and adults in about 90 percent of tries. People with mental illnesses typically struggle with the task.

The study team had volunteers do the same tasks while scanning their brains with functional MRI. They found that much of the architecture of mature brain is in place by adolescence, but the ability of the networks to talk to one another and integrate information is still a work in progress.

“Further enhancement of this network integration is likely why adults can switch and very quickly adapt their behavior to changing circumstances, which is more difficult for adolescents,” Dr. Luna explained.

She added that while parents and teachers sometimes find bewildering the choices teens might make, their brains are perfectly adapted to explore and take some chances as they become independent adults.

“Across societies and species, we know that adolescence is a period of increased sensation seeking that can lead to risk taking, which increases mortality rate,” Dr. Luna said. “Also, we often see during this period the first signs of mental illnesses such as schizophrenia, depression and eating disorders. All of these have a neurobiological basis, so if we know how the brain is changing, we might be able to figure out a way to intervene earlier in life.”

Dr. Luna and researchers from the Children’s National Medical Center, Washington, D.C.; Columbia University Medical Center; and University of California, Berkeley, will present their work from 1:30 to 4:30 p.m., Saturday, Feb. 14, during a AAAS session called “From Womb to Tomb.”

They also will participate in a news briefing that day which will be webcast at 10 a.m. PT, 1 p.m. ET, at http://www.eurekalert.org/aaasnewsroom/2015/.

Watch a video of Dr. Luna describing her work.

Pediatric Rehabilitation Chief to Serve on IOM Committee

PITTSBURGH, Feb. 9, 2015 – Amy Houtrow, MD, PhD, MPH, chief, Division of Pediatric Rehabilitation Medicine and a member of the Brain Care Institute, recently was asked to serve on the Institute of Medicine’s (IOM) Standing Committee of Medical Experts to Assist Social Security on Disability Issues. Dr. Houtrow was chosen for the committee because of her work on the IOM’s Consensus Committee on Social Security for Children with Mental Health Disabilities.

Dr. Houtrow is board certified in physical medicine and rehabilitation and pediatrics. Her clinical focus is on children with disabling conditions and improving their function and quality of life. Dr. Houtrow is the youngest member of the committee and the only representative from the field of pediatric rehabilitation.

The IOM committee will assist the Social Security Administration in improving its criteria for determining disability in adults and children. It will survey literature, clinical practices, and published studies related to disability, and collect and analyze relevant data and information. It also will organize and lead outreach conferences with members of the public to provide a neutral ground for the debate and analysis of emerging disability issues. The work of the committee has the potential to impact the lives of millions of children and adults with disabilities.

For more information on the Standing Committee of Medical Experts to Assist Social Security on Disability Issues, please read the full activity description on the IOM website.

Pediatric Neurology Researcher Receives NIH Grant

PITTSBURGH, Feb. 3, 2015 – Sharyl L. Fyffe-Maricich, PhD, assistant professor of pediatrics at the University of Pittsburgh School of Medicine, has been awarded an NIH Research Project Grant (R01) for her submission, “The Role of ERK1/2 MAP Kinase Signaling in CNS Myelination.” The grant was awarded on Dr. Fyffe-Maricich’s first submission, which is a high honor. Her immediate goal is to improve therapy for multiple sclerosis (MS) and other demyelinating diseases.

A member of the Society for Neuroscience, Dr. Fyffe-Maricich joined the Division of Child Neurology at Children’s Hospital of Pittsburgh of UPMC in 2013 and quickly established a highly productive lab. She was the focus of a recent documentary produced by the National Multiple Sclerosis Society about her research.

To see Dr. Fyffe-Maricich in the documentary, please visit the National Multiple Sclerosis Society’s YouTube page.

New Center at Children’s Hospital of Pittsburgh of UPMC Offers Hope to Kids From Around the World With Rare Diseases

PITTSBURGH, Feb. 2, 2015Children’s Hospital of Pittsburgh of UPMC has established a Center for Rare Disease Therapy, focused on providing new, sometimes breakthrough treatments for infants, children, adolescents and young adults from around the world who have been diagnosed with rare diseases and disorders. The center brings together experts from across the hospital and health system to tackle complex problems.

“Patient families travel from all over the world to Children’s Hospital looking for hope and answers, especially when they can’t find it at their local hospital. We are different in that we have developed expertise in every single aspect of pediatric care,” said David H. Perlmutter, M.D., physician-in-chief and scientific director, Children’s Hospital, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, Pitt School of Medicine. “From the research that is done to develop a specific therapy, to the multidisciplinary team that puts the care program together and helps the family to execute it, our work gives hope for families.”

According to the National Institutes of Health (NIH), a rare or “orphan” disease is one that affects fewer than 200,000 individuals in the United States. Today, there are nearly 7,000 different rare diseases and disorders, with more being discovered every day.

Children’s treats a multitude of rare diseases, including Byler disease, combined immune deficiency syndrome, Hurler syndrome, Krabbe disease, glycogen storage disorders, maple syrup urine disease (MSUD), and many more. Internationally renowned physicians at the hospital who are experts in their fields include:

  • Maria Luisa Escolar, MD, MS, director, Program for the Study of Neurodevelopment in Rare Disorders
  • Ira Fox, MD, director, Center for Innovative Regenerative Therapies
  • Mark Lowe, MD, PhD, chief, Division of Gastroenterology, Hepatology, and Nutrition
  • George V. Mazariegos, MD, FACS, chief, Pediatric Transplantation
  • Michael Moritz, MD, clinical director, Pediatric Nephrology
  • Ken K. Nischal, MD, FRCOphth, chief, Division of Pediatric Ophthalmology, Strabismus, and Adult Motility
  • David H. Perlmutter, MD, physician-in-chief and scientific director, and chair, Pediatrics
  • Robert Squires, MD, Pediatric Hepatology Program
  • Paul Szabolcs, MD, chief, Bone Marrow Transplantation and Cellular Therapies
  • Jerry Vockley, MD, PhD, chief, Medical Genetics

In addition, the center actively collaborates with physicians and institutions engaged in researching and diagnosing rare diseases in children and supporting them and their families. One example is the ongoing collaboration with the Clinic for Special Children in Strasburg, Pa. In collaboration with the clinic, Children’s became the world’s first hospital to establish a liver transplantation protocol for patients with MSUD and now more than 50 children with MSUD have received liver transplants here. By concentrating on specific rare diseases, like MSUD, the new center is able to bring together its experts and form necessary collaborations to focus on the advancement of innovative therapies.

For more information on the Center for Rare Disease Therapy, visit www.chp.edu/rarecare.

Save the Date: ‘Care Across the Continuum’ BCI Conference

PITTSBURGH, Jan. 5, 2015 – The Brain Care Institute (BCI) of Children’s Hospital of Pittsburgh of UPMC will host a one-day conference on Aug. 1, 2015, in the Mary Jo Howard Dively Auditorium at the John G. Rangos Sr. Research Center at Children’s Hospital. Entitled “Care Across the Continuum,” the meeting is designed to provide local pediatricians and pediatric specialists with information regarding the multidisciplinary experts and services available to them via the BCI.

The topics will highlight the advantages of collaboration between the BCI and area pediatricians in the diagnosis and development of treatment plans for patients. The speakers are all BCI experts in their respective fields and include:

Please save the date, and check back soon for more information and registration details.

Pitt Researcher Contributes to Analysis of Inequities in Health Care Needs for Children With Medical Complexity

PITTSBURGH, Jan. 2, 2015 – Amy Houtrow, MD, PhD, MPH, associate professor and vice chair in the Department of Physical Medicine and Rehabilitation for pediatric rehabilitation medicine, was part of a team that analyzed secondary data on children with special health care needs to examine the prevalence, health care service use, and needs of children and youth with special care needs, as reported by their families.

Data from the National Survey of Children with Special Health Care Needs from 2005-06 and 2009-10 was used to examine inequities based on race/ethnicity, primary language in the household, insurance type, and poverty status.

The study, which was published in Health Affairs, found that children with medical complexity were twice as likely as children without medical complexity to have at least one unmet need. Unmet needs were not associated with primary language, income level, or having Medicaid In the children with medical complexity. The authors, led by Dennis Z. Kuo, MD, MHS, associate professor of pediatrics at the University of Arkansas for Medical Sciences, concluded that medical complexity itself can be a primary determinant of unmet needs.

Additional authors on the study were Anthony Goudie, PhD, of the University of Arkansas for Medical Sciences; Eyal Cohen, MD, of the Hospital for Sick Children and University of Toronto; Rishi Agrawal, MD, of Ann and Robert H. Lurie Children’s Hospital and the Northwestern University Feinberg School of Medicine; Adam C. Carle, PhD, of Cincinnati Children’s Hospital Medical Center and the University of Cincinnati; and Nora Wells of Family Voices, Inc.

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

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