Grant Accelerates Research

March Of Dimes Grant Amps Up Statewide Research on Prematurity

Too many babies in this country are born before their time. Too many die before their first birthday. In a country that prides itself on ex­ceptional healthcare and the world’s finest hospitals, our rates of prematurity and infant mortality remain a quiet but persistent fail­ure. The problems caused by preterm birth are so devastating to child health that March of Dimes has identified prematurity as its “new polio campaign.” Determined to find solutions, the organiza­tion has pledged $10 million over five years to fund the Prematurity Research Center Ohio Collaborative. The project brings together Ohio’s health research powerhouses – the University of Cincinnati College of Medicine/Cincinnati Children’s Hospital Medical Center; Ohio State University Wexner Medical Center/Nationwide Children’s Hospital; and Case Western Reserve University/University Hospitals MacDonald Women’s Hospital/Rainbow Babies & Children’s Hospi­tal/MetroHealth System.

A Transformative Research Approach

All three institutions already have strong research and clinical pro­grams aimed at reducing prematurity, says Louis Muglia, MD, PhD, Director of the Center for Prevention of Preterm Birth at Cincinnati Children’s, and they have shared information informally. But the Col­laborative will forge a truly innovative type of cooperation.

“Traditionally, investigators have applied research approaches that involve a single discipline at a time, with little crosstalk, and even competition, between investigators,” Muglia says. “The Collaborative will develop an integrated, transdisciplinary research team that tran­scends those usual boundaries.”

Muglia, who will serve as coordinating principal investigator of the Collaborative, adds that this arrangement will allow each institu­tion to pursue its research strengths while minimizing overlap. Find­ings will be shared in a structured manner, and “each institution will contribute valuable population data from our respective regions.”

The Collaborative plans to tackle prematurity on a number of fronts, from the evolution of human pregnancy to genetic variants in prematurity and the role of progesterone signaling in maintaining pregnancy.

The Prematurity Research Center Ohio Collaborative will bring together research institutions in Cleveland, Columbus, and Cincinnati. Ohio’s rate of preterm births remains stubbornly high, at around 15 percent.
Source: National Center for Health Statistics, March of Dimes. .

Extensive Resource Commitment

Beyond contributing talent and time, several participating institutions also have pledged significant funding to further the aims of the Col­laborative.

Cincinnati Children’s will invest $10 million over five years: $5 million for projects and recruitment and a $5 million endowment to ensure sustainability of the effort. The University of Cincinnati’s UC Health has committed $1.25 million. Ohio State and Nationwide will provide 10 years of in-kind research support worth approximately $20 million. Similarly, Case Western University Hospitals and Metro­Health are supporting research programs and faculty effort to partner in this endeavor.

Merck Grant Fuels Fragile X Research

Craig Erickson, MD.A $1 million grant from the John Merck Fund will expand translational research at Cincinnati Chil­dren’s to improve outcomes for children born with Fragile X Syndrome (FXS).

The syndrome is a genetic condition that causes intellectual disability, behavioral and learn­ing challenges and some physical characteristics. Though FXS occurs in both genders, males are more frequently affected than females, and gener­ally with greater severity.

Craig Erickson, MD, Division of Child and Adolescent Psychiatry, plans to use the funds to launch a clinical trial to evaluate acamprosate – a drug currently used to treat alcohol dependence – as a potential treatment for youth with FXS.

In previous, early-stage studies at Indiana University, Erickson reported that acamprosate’s effects on brain chemistry may help improve com­munication and social behavior skills for people with FXS. If the new trial proves successful, the drug also could be evaluated for use in other forms of developmental disability.

The grant is one of three recently announced by the John Merck Fund’s new Developmental Disabilities Translational Research Program, es­tablished in 2011. The three recent grant awards were selected from more than 100 proposals.

“What’s especially exciting about this pro­gram,” says Marsha Mailick, PhD, Chair of the Fund’s Scientific Advisory Board, “is that it sup­ports research with potential game-changing im­pact that is within the realm of probability – not just possibility – and could be achieved within 10 years.”

More Manageable Weight Loss Program Proves Just as Effective

Rohit Kohli, MBBS, MS.

Obesity management programs need not be in­tense to improve outcomes for children with non-alcoholic fatty liver disease (NAFLD), according to a recent study led by our researchers.

Published online March 19 in the Journal of Pediatric Gastroenterology & Nutrition, the study tracked children who completed one year in a “clinically feasible” weight loss program that in­volved 30-minute patient visits every three months to set and monitor nutrition and exercise goals.

The study was led by Rohit Kohli, MBBS, MS, a member of Cincinnati Children’s Steato­hepatitis Center, and Stephanie DeVore, a Clinical Research Coordinator at the Center. Stavra Xan­thakos, MD, MS, Co-Director of the Center, was senior author.

The researchers found that children who stayed with a weight loss program experienced statistically significant improvements in body mass index (BMI), total cholesterol levels and two key NAFLD biomarkers: alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Fatty liver disease affects 10 percent of US children. Its more severe form – non-alcoholic ste­atohepatitis (NASH) – occurs in about two per­cent of US children. Experts know that weight loss helps manage the disease, but have struggled to develop diet and exercise programs that work for patients and in a busy clinic setting.

Patients in the study met with a gastroen­terologist and dietician every three months for 30 minutes to set goals and monitor progress. Doc­tors recommended exercise and set dietary goals focused on reducing sugar and saturated fat.

Kohli and DeVore noted that the children’s improvement was “comparable to that seen in more intensive pediatric weight management pro­grams.”

Alternative to Bariatric Surgery?

In related work, Kohli and colleagues at the Univer­sity of Cincinnati College of Medicine successfully tested a procedure in obese laboratory rats that could lead to less invasive alternatives to bariatric weight-loss surgery.

As reported online in Endocrinology, scien­tists used a catheter to redirect bile from the bile duct into the small intestine, resulting in the same metabolic and weight-loss benefits as bariatric surgery.

“This may help us identify novel ways to treat obesity-related conditions,” says Kohli, who was lead investigator on the study. “Our results provide compelling evidence that manipulation of bile acids is sufficient to recreate the key effects of bariatric procedures, including gastric bypass, and may be especially beneficial to people with obesity-related liver dysfunction.”

Emphasizing that extensive additional research is still required, Kohli adds that even­tually, researchers hope to develop therapeutic agents that can produce the same benefits as bariatric surgery without the surgical procedures that alter intestinal anatomy.

Funding for the study came from the National Institute of Diabetes and Digestive and Kidney Diseases and Ethicon Endo-Surgery.

International Partnerships Expand

Dr. Tingyu Li, President of Chongqing Children's Hospital, and Dr. Arnold Strauss, Director of the Cincinnati Children's Research Foundation.Cincinnati Children’s has established a formal collaboration with the Children’s Hospital of Chongqing Medical University, one of the largest pediatric hospitals and research centers in China.

The three-year agreement, which will focus on cancer and blood diseases, came about as a result of multiple visits between Cincinnati Chil­dren’s and Chongqing Children’s faculty and lead­ership over the years.

Chongqing Children’s faculty will make extended visits here to gain clinical experience in hematology/oncology. Chongqing will host several of our faculty each year for education and to consult on complex cases.

The hospitals also will hold virtual case confer­ences addressing complex patient scenarios several times a month and will consult on research program development and research protocol design.

“We are fortunate to have the opportunity to work with such a strong institution to advance our research programs,” says Tingyu Li, MD, Presi­dent of Chongqing Children’s. “Our hope is that through our patients we can make our contribu­tion to translational research at Cincinnati Children’s.”

Anesthesia Toxic to Adult Brains, Too

Pediatric specialists are well aware of potential harmful effects of anesthesia on children’s devel­oping brains. But new research suggests adults may also be at risk.

Researchers from Cincinnati Children’s report in the June 5 Annals of Neurology that testing in laboratory mice shows anesthesia’s neurotoxic effects depend on the age of brain neurons, not the age of the animal, as once thought.

“Anesthesia-induced cell death in neurons is not limited to the immature brain,” says Andreas Loepke, MD, PhD, a clinician and researcher in the Department of Anesthesiology. “Vulnerability seems to be dependent on the age of the neuron and targets brain cells of a specific age and matu­rational stage.”

The younger the neuron, the more suscep­tible it seems.

New neurons are generated abundantly in most regions of a very young brain, explaining why research had focused on that developmental stage. In a mature brain, neuron formation slows considerably except in the dentate gyrus, which controls learning and memory and keeps forming new neurons late into life. Researchers focused on this area in their study.

They exposed newborn, juvenile and young adult mice to the widely used anesthetic isoflurane in doses approximating those used in surgery.

Newborn mice had widespread neuronal loss in forebrain structures, confirming previous research, with no significant impact on the dentate gyrus. However, in juvenile and young adult mice, the results were reversed. The team discovered that age and maturational stage of the neurons were the defining characteristics for vulnerability to anesthesia-induced neuronal cell death.

More research is needed to confirm the study’s relevance to humans. But Loepke says the goal is to learn enough about anesthesia’s impact on brain chemistry to develop new protec­tive strategies during surgery. He is collaborating with researchers from the Pediatric Neuroimaging Research Consortium at Cincinnati Children’s to examine anesthesia’s impact on children’s brains using non-invasive magnetic resonance imaging technology.

A Boost For Conventional Leukemia Treatment

H. Leighton Grimes, PhD.

Acute lymphoid leukemia (ALL) cells become much more vulnerable to conventional chemo and radiation therapies by inhibiting expression of the Gfi1 protein, according to early-stage studies using humanized mouse models.

A research team led by Cincinnati Children’s and the Institut de Recherche Clinique de Montreal (ICRM) reported the findings February 11 in the journal Cancer Cell.

“Chemo and radiation therapies are very non-specific and can be toxic to patients. Our findings suggest that combining the inhibition of Gfi1 with these treatments may allow the use of lower cyto­toxic doses to directly benefit patients,” says H. Leighton Grimes, PhD, co-senior investigator and researcher in the Divisions of Cellular and Molecular Immunology and Experimental Hematology at Cincinnati Children’s.

ALL is the most common type of leukemia affecting children. Improved treatments are needed because many patients relapse after achieving remission from initial treatment.

Researchers found that the protein Gfi1 is overexpressed in leukemic cells, which helps the cells escape destruction by p53, a well-known tumor-suppressing protein. Inhibiting Gfi1 allowed the tumor suppressor function to return to normal and did not cause harmful side effects in mice.

Research continues to determine if the approach used in the mouse models can be applied to human patients.

Collaborators in the study included co-senior investigator, Tarik Möröy, PhD, President and Scientific Drector of the ICRM; and James Phelan, PhD, and Cyrus Khandanpour, MD.

New Genes Linked to Juvenile Arthritis

Researchers at Cincinnati Children’s have identi­fied 14 more genes linked to juvenile idiopathic arthritis (JIA), the most common rheumatic disease of childhood.

The discovery, reported in the April 21 Nature Genetics, increased the number of genes with a recognized link to JIA from 3 to 17. The anal­ysis re-confirmed JIA’s connection to the original three genes, identified a link to 14 new genes and suggested that at least another 11 genetic regions may be implicated.

“These findings will help us understand how long-suspected genetic contributions to JIA are driving the disease process, with the ultimate goal being earlier and improved diagnosis and treat­ment,” says Susan Thompson, PhD, Division of Rheumatology, who led the study.

An international research team analyzed nearly 3,000 patients recruited from more than 40 pediatric rheumatology clinics across the US, Germany and the United Kingdom. It was the largest population of patients with JIA ever studied.

The cause of JIA remains unknown. It can be treated with medications and physical therapy, but for many patients persists into adulthood.

The scientists stressed that they will continue their work to identify additional genetic links and to begin conducting functional studies to pinpoint disease processes.

Researchers from Wake Forest School of Medicine, the University of Manchester in the United Kingdom, and Emory University School of Medicine collaborated on the study. Funding came, in part, from the National Institutes of Health.

Nursing Expands Research

Rita Pickler, PhD, RN.

More nurse-scientists will soon be joining our ranks as part of a new initiative to expand research by nurses at Cincinnati Children’s.

Rita Pickler, PhD, RN, has taken on the new role of Scientific Director of Nursing Research. She will lead efforts to increase the number of nurse-scientists on staff as well as the number of projects they oversee.

“Nationwide, the numbers of PhD-level nurses who are focused on children’s health are relatively limited,” Pickler says. “But with Cincin­nati Children’s so well established in pediatric research, we have great potential to develop a large, patient-oriented research program in nursing.”

In addition to leading her own NIH-funded research, Pickler will work to enhance nursing research collaborations between Cincinnati Children’s, the University of Cincinnati, and other academic institutions. She also will serve as a mentor for junior research faculty, says Scott Holland, PhD, Director of Research in Patient Services at Cincinnati Children’s.

Pickler joined Cincinnati Children’s in May 2011 following a 21-year career at Virginia Commonwealth University, where she held an endowed professorship and was acting Associ­ate Dean for Research. Her research has focused on preterm infant care and feeding, maternal well-being and pregnancy outcomes, and the impact of transitions between intensive care and home.

She received her bachelor’s and master’s degrees in nursing from the University of North Carolina at Greensboro and her PhD from the University of Virginia. She is a Fellow in the American Academy of Nursing and Co-Chair of the Child, Adolescent, and Family Expert Panel. Pickler also belongs to the National Association of Neonatal Nurses; the Association of Women’s Health, Obstetric, and Neonatal Nursing; the Midwest Nursing Research Society; the Council for the Advancement of Nursing Science; and the National Association of Pediatric Nurse Practitioners.

Sickle Cell a Focus for New Hematology Director

Russell Ware, MD, PhD.

The Division of Hematology will have a new Director beginning July 1. Russell Ware, MD, PhD, will assume the post, as well as that of Executive Co-Director of the Cancer and Blood Diseases Institute. He will also serve as Associate Director of the Center for Child Global Health.

Ware’s research interests focus on sickle cell disease, especially the use of hydroxyurea to ameliorate symptoms, including preventing stroke and managing iron overload, while improving quality of life. His efforts extend to treating sickle cell disease in Africa, leading to his focus in global child health. He is well funded by the NIH and several foundations for this work.

Ware received his medical degree from Duke University and completed his pediatric residency at Baylor College of Medicine and Texas Children’s Hospital. He completed a fellowship in pediatric hematology and oncology and a PhD in Immunology at Duke University. Ware began his academic career at Duke before moving to St. Jude Children’s Hospital, then Baylor, where he served as Chief of Hematology.

Developmental Biology Director Named

Raphael Kopan, PhD.Raphael Kopan, PhD, will join Cincinnati Children’s as Director of the Division of Developmental Biology this fall.

Kopan’s primary research interest is the Notch1 protein, instrumental in guiding the devel­opment of embryonic cells into a variety of cell types, organs and tissues.

Studying the effects of Notch1 disruption has proved challenging because of the protein’s essential role in embryonic development. Kopan’s team solved the problem by engineering a mouse in which the Notch1 gene remains present throughout embryogenesis but becomes condi­tionally knocked out in adults.

One of their recent findings, reported in the The Journal of Clinical Investigation, suggests that inactivating Notch1 in mice may cause abnor­mal proliferation of endothelial tissue, leading to vascular tumors, particularly in the liver.

Kopan has been the Wolff Distinguished Professor of Molecular Biology and of Medicine at Washington University School of Medicine in St. Louis, where he has worked since 1994. He earned a bachelor’s degree in biology in 1981 and a master’s degree in zoology in 1984, both from Tel Aviv University. Following a stint in the Israeli Defense Force, Kopan received his doctorate in molecular genetics and cell biology at the Univer­sity of Chicago and completed post-doctoral training at the Fred Hutchinson Cancer Research Center in Seattle.

Fetal Therapy Study Aims to Cure Disease Before Birth

Aimen Shaaban, MD.Prenatal stem cell transplant is emerging as an al­ternative to bone marrow transplant for hereditary conditions such as sickle cell disease and thalas­semia. But first, experts must find a way to beat a developing infant’s natural killer (NK) cells.

That’s the mission for Aimen Shaaban, MD, a fetal surgeon who joined Cincinnati Children’s last year to become Director of the Center for Fetal Cellular and Molecular Therapy. He is using a five-year, $1.9 million grant from the National Heart, Lung & Blood Institute to learn more about when NK cells become active during fetal development.

The potential advantage of fetal stem cell therapy comes from providing treatment before the immune system develops.

“We have the technology to detect specific genetic diseases as early as six or seven weeks’ gestation, which gives us an opportunity to pro­vide therapy while the fetus still has no immune system. This could cure certain diseases before symptoms ever begin,” Shaaban says.

While some successes in human fetal ther­apy have been reported, clinicians also have re­ported unexpected, repeated failures. Shaaban and colleagues may have found a way to improve the odds.

Preliminary studies in mice reveal that knock­ing down the function of NK cells – an early-developing part of the immune system – gives transplanted stem cells the time they need to es­tablish themselves. After a few weeks, when NK-suppressing drugs are stopped, the transplanted cells continue to function as intended.

Shaaban’s team is expanding on these find­ings by determining more precisely how and when NK cells become active during fetal development. Their findings could help set new protocols for fetal therapy ranging from the timing and volume of donor cell doses to determining the need for booster transplants.

Prior to joining Cincinnati Children’s, Shaaban directed fetal cellular therapy laboratories at the University of Iowa and the University of Wisconsin

Improving Outcomes for Kids on Dialysis

Mark Mitsnefes, MD, MS.Children with end stage kidney disease (ESKD) face enormous health hurdles, and a significantly shorter life expectancy. But a recent report shows that the outcome of dialysis treatment they require is improving.

In a study published in the May 8 issue of the Journal of the American Medical Association, Mark Mitsnefes, MD, MS, of the Division of Nephrology at Cincinnati Children’s, and co-investigators from McGill University and Children’s Hospital of Phil­adelphia found that death rates among children and adolescents undergoing dialysis for ESKD in the United States have declined significantly over the past two decades.

For children whose kidney disease has progressed to end stage, kidney transplant remains the treatment of choice. But while they await transplant, dialysis is a life-saving therapy.

The researchers conducted a study to deter­mine if all-cause, cardiovascular and infection-related death rates changed between 1990 and 2010 among patients younger than 21 with ESKD initially treated with dialysis.

They identified a total of 23,401 children and adolescents in the United States who began ESKD treatment with dialysis during those two decades, and noted a significant decrease in mortality rates among the patients over that time period.

Children under age 5 who started dialysis in 1990-1994 had a mortality rate of 112.2 per 1,000 person-years. For those who began dialysis in 2005-2010, the rate fell to 83.4 per 1,000 person-years. Among those 5 and older, the mortality rates declined from 44.6 per 1,000 person-years to 25.9 over the same time period. Significant decline occurred in both cardiovascular and infec­tion-related mortality.

Although further research is needed to deter­mine the factors responsible for the decrease, the investigators reported that “improved pre-dialysis care, advances in dialysis technology and greater experience of clinicians may have played a role.”

Pollution Linked to Hyperactivity

Nicholas Newman, DO, MS.In a study published May 21 in Environmental Health Perspectives, a team led by Nicholas Newman, DO, MS, Director of the Pediatric Envi­ronmental Health and Lead Clinic at Cincinnati Children’s, reported that children exposed to high levels of traffic-related air pollution (TRAP) during their first year of life were more likely to have “at risk” scores for hyperactivity by age 7.

The study followed children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study. They were born in the Cincinnati metro­politan area between 2001 and 2003 and were selected based on family history of allergy and proximity to a major highway or bus route. They were followed from infancy to age 7, at which time parents completed a behavioral question­naire and reported on symptoms including hyper­activity, attention problems, aggression, conduct problems and atypical behavior.

Of 762 children initially enrolled in the study, 576 completed the tasks necessary for inclusion in the final analysis. Results showed that children exposed to the highest amount of TRAP during the first year of life were more likely to have hyper­activity scores in the “at risk” range. “At risk” means that children should be monitored for the development of clinically important symptoms.

Newman says “several biological mecha­nisms” could explain the connection between TRAP and hyperactive behaviors, including direct toxicity to the brain. Investigators at Cincinnati Children’s are currently working to better under­stand these mechanisms.

He notes that studies have shown that approximately 11 percent of the US population lives within 100 meters (328 ft.) of a four-lane highway and that 40 percent of children attend school within 400 meters of a major highway.

“Traffic-related air pollution is one of many factors associated with changes in neurodevelop­ment,” Newman says, “but it is one that is poten­tially preventable.”

New Treatment for Severe Arthritis Gets Thumbs Up

Studies performed by pediatric rheumatologists in the US, Europe and South America have led to US Food and Drug Administration (FDA) approval of canakinumab (Ilaris) to treat active systemic juve­nile idiopathic arthritis (SJIA) in patients aged 2 and older.

Canakinumab, an interleukin-1 beta (IL-1 beta) inhibitor, works by blocking an immune system protein that plays a key role in some inflammatory disorders. The drug is given as a monthly subcutaneous injection.

Approval came as a result of two interna­tional, multicenter phase III trials in children with SJIA between the ages of 2 to 19; the majority of children treated showed significant improve­ment. Hermine Brunner, MD, MSc, and Daniel Lovell, MD, MPH, in the Division of Rheumatology at Cincinnati Children’s, led the studies.

Only one other drug is currently approved to treat SJIA - tocilizumab, an IL-6 inhibitor. Chil­dren with SJIA suffer from a variety of debilitating systemic symptoms and having another treatment option that controls these symptoms is, says Lovell, “a huge breakthrough.”

He adds that having two approved treat­ments also improves the odds of more children living healthier lives with this serious disease.

“We have more options to discuss with fami­lies and a much greater chance of having at least one therapy work. I’m very excited about what the future holds for these kids.”

Logan to Lead Sports Medicine

Kelsey Logan, MD, MPH.Kelsey Logan, MD, MPH, will begin as Director of the Division of Sports Medicine July 1.

Logan’s primary interest is in mild traumatic brain injury. Her publications address evaluat­ing cognitive function after concussions for safe return to sports activities. Most recently, she led the sports concussion program at Ohio State University.

Logan received her medical degree from the University of Alabama and completed a combined medicine and pediatrics residency at the Univer­sity of Mississippi Medical Center. She completed a fellowship in pediatric and adolescent sports medicine at the University of Wisconsin.

She is active in the American Academy of Pediatrics Section on Young Physicians, Council on Sports Medicine and Fitness, and Section on Combined Internal Medicine and Pediatrics. Logan also serves on the Research and Publications committees for the American Medical Society for Sports Medicine and has been appointed to the National Collegiate Athletic Association Commit­tee on Competitive Safeguards and Medical Aspects of Sports.