News in Brief

National Registry to Track Eosinophilic Disorders

A $1.6 million federal stimulus grant has enabled Cincinnati Children’s to launch the Registry for Eosinophilic Gastrointestinal Disorders (REGID), an information resource that will serve as a valuable research tool for scientists nationwide, and ultimately, around the globe. The registry is the first of its kind for eosinophilic disorders.

It will allow participating centers to build a database of research-accessible clinical information for thousands of patients with eosinophilic disorders, including identifying patients for clinical trials, comparing treatment outcomes, and expanding knowledge about the conditions. “This registry provides the infrastructure for understanding and treating eosinophilic disorders at a national level, and ultimately, at the international level,” says Marc Rothenberg, MD, PhD, Director of the Division of Allergy and Immunology and the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s. James Franciosi, MD, MS, MSCE, a gastroenterologist and co-developer of the registry, says the data obtained from it will expand learning about the disease.

“Eosinophilic disorders are often classified as other conditions, such as refractory gastroesophageal reflux disease,” Franciosi says.“ As larger multi-center studies are conducted through the registry, we will gain more information about symptoms, quality of life and the effectiveness of treatments. We also will be better able to conduct long-term follow-up.” Cincinnati Children’s is a world-renowned center for research and treatment of eosinophilic disorders. Specialists here see as many as 50 cases a week, including patients from around the world.

Eosinophilic disorders occur when the body’s immune system treats food as a dangerous foreign invader. As a result, the body produces an excess of eosinophils, a type of white blood cell that can cause chronic inflammation and tissue damage. The resulting diseases are diagnosed according to where high levels of eosinophils are found, including the esophagus, stomach, small intestine or large intestine. The extent of harm can vary. In the most extreme cases, patients must be managed with carefully controlled liquid diets. The new registry will help accelerate research into better treatments, Rothenberg says. One of the first uses of the registry will be to compare outcomes between those receiving standard care and patients receiving fluticasone, an experimental medication to block inflammatory mediator production. A 24-week clinical trial involving up to 40 patients is under way. Cincinnati Children’s also has launched the first human clinical trial of a medication that blocks interleukin-13 – a cytokine that mediates allergic inflammation – as a potential treatment for Eosinophilic Esophagitis. The ability to conduct even larger-scale clinical trials will be one of the most important features of the new registry.

“At a minimum, we need a few hundred patients to conduct a large clinical trial. But eosinophilic disorders are relatively uncommon, so it is hard for a single institution to recruit enough participants from its own patient base,” says J. Pablo Abonia, MD, an assistant professor in the Division of Allergy and Immunology, who is participating in the design and creation of the registry.

The registry will involve extracting research data from clinical information stored in electronic medical records. The framework for extracting the data is being orchestrated by Keith Marsolo, PhD, director of software development and the data warehouse for the Division of Bioinformatics at Cincinnati Children’s. While the stimulus funds offer an important jump start for these investigations, those funds will be exhausted within two years, Rothenberg says. Continued research is made possible through the generous support of charities such as CURED (Campaign Urging Research for Eosinophilic Disease) and Food Allergy Project Inc., a charitable arm of the Food Allergy Initiative, a coalition of concerned parents, researchers, educators and experts.

Head Cases: Mild Bumps Might be Worse than Thought

When a child is rushed to the hospital because of a head injury, doctors such as Lynn Babcock, MD, MPH, can immediately tell which cases are severe. It is the mild bumps on the head that keep Babcock up at night. She’d like to be able to pinpoint – during the span of an emergency visit – which kids will have lasting symptoms.

Nationally, more than 650,000 children visit emergency rooms each year to be checked out for traumatic brain injuries (TBI). Most kids are sent home after their injuries are deemed “mild.” But there is growing evidence that up to 50 percent of them will have lasting symptoms, such as headaches, amnesia, fear of loud sounds, dizziness or irritability that can last weeks, months or even years. Even experts cannot see the damage on X-rays or CT scans.

Babcock, who has a biochemistry background, is researching the pathology of mild TBI. Her research team is using more sophisticated Diffusion Tensor Imaging, a type of MRI, to study changes in the brain. They are looking for a serum marker protein thought to be secreted after injury that could lead to a blood test to predict lasting problems. “I’m trying to figure out: Are there better tests? Which kids do we need to worry about?” Babcock says. “Brain injuries are the number one cause of disability in children. We’re interested in advancing our diagnostic approaches for these children.”

Scientists Identify Enzyme Critical to Healthy Heart Function

A study led by Cincinnati Children’s researchers has provided the first-ever data to show that the enzyme calcineurin is critical in controlling normal development and function of heart cells and that loss of the protein leads to heart problems and death in genetically modified mice. Published February 26 in the Journal of Biological Chemistry and posted online February 19, the research was led by Jeffery Molkentin, PhD, of the Division of Molecular Cardiovascular Biology, and Marjorie Maillet, PhD.

The study linked calcineurin to proper cardiac muscle contraction and rhythm in mice. The near total absence of calcineurin led to heart arrhythmia,
failure and death, according to the research team. Scientists knew that calcineurin was important to heart function, but the extent of its role had not been defined. The study offered insights that could lead to new approaches in diagnosis and treatment for heart patients. “When we eliminated calcineurin, the genes that regulate calcium in the heart went awry. This led to defects in the growth and proliferation of heart cells, heart disease, arrhythmia, loss of contractility and heart failure and disease,” Maillet says.

The scientists also identified a “feed-forward” mechanism, in which the activation of calcineurin by calcium augments the expression of genes that
regulate calcium-handling proteins in the heart. Maillet works in the laboratory of the study’s senior investigator Molkentin, who is also a Howard Hughes Medical Institute investigator. Also collaborating on the study were researchers from the University Paris-Sud, Châtenay-Malabry, France and the Department of Molecular and Cellular Physiology at the University of Cincinnati College of Medicine. Study funding came from the National Institutes of Health, the Howard Hughes Medical Institute, the Ohio Valley Affiliate of the American Heart Association and a collaborative research grant in cardiovascular disease from the
Fondation Leducq.

Expansion of Headache Center will Increase Treatment, Research

What’s going on in a teenager’s head? Quite possibly, a migraine headache. Researchers have found 28 percent of teen girls suffer from debilitating headaches, compared with 13 percent of the adult population. Headache experts at Cincinnati Children’s say that if they can catch severe childhood headaches early enough, they can treat and possibly reverse the progression of migraines.

Doctors here, who can detect migraines in children as young as 3, are expanding the Headache Center at Cincinnati Children’s, which already is the largest pediatric headache center in the world. The Headache Center currently diagnoses, treats and manages 500 new patients a year and provides more than 1,500 follow-up visits. Doctors expect to see 200 more patients a year beginning in July, when the center begins seeing patients up to age 25, says Andrew Hershey, MD, PhD, FAHS, the center’s director. Continuing to see patients as they turn into young adults will expand the research that pinpoints what triggers teen headaches and teach teens to manage the problem, says Scott Powers, PhD, ABPP, FAHS, the center’s co-director.

“Our goal is to treat children and adolescents so well that they don’t become the adults who have to go get specialty care,” Powers says. “They may still have migraines, but they will have it under control and managed well, effectively coping with their illness.” The Headache Center was the first in the country to establish a pediatric fellowship in Headache Medicine. The expanded center will continue to emphasize training and research.

Social Studies: How does a Child’s Brain Process Emotions After an Injury?

Doctors used to rely on a battery of intelligence tests to predict which kids would do well in school after a traumatic brain injury. But an emerging field of developmental social neuroscience is beginning to rethink how kids function  socially and emotionally after a brain injury. Shari Wade, PhD, and Nicolay Chertkoff Walz, PhD, psychologists at Cincinnati Children’s, are working on multiple federally funded studies to better understand how kids with brain injuries handle mental stresses, such as reading facial expressions and making friends. The research goal is to come up with better interventions to help children and families cope after an injury. “We are finding some differences in how children with brain injury process emotion,” Wade says. For example, they found preschoolers with brain injuries had more difficulty than their peers distinguishing emotions such as fear and sadness. “Historically, the research has been all about testing for IQ, memory and planning,” Wade says. “But those measures don’t accurately reflect how these kids function in the real world.” This area of research is novel in the sense that the way the brain processes
social and emotional skills is understudied, Walz says.

“Clinically, patients and their parents tell us social outcomes impact their quality of life the most,” Walz says. “Kids might have a lot of basic cognitive recovery, but they might not have friends, or they’re socially isolated, or they have outbursts. We’re exploring theories about which skills lay the groundwork for social success that might be disrupted by brain injury.”

New Center for Communication Sciences Research

Our ability to communicate through spoken language requires the proper function of a wide range of capabilities – hearing, speech and the brain’s capability to convert sounds into words with meaning. Likewise, understanding what happens when language and communication skills do not develop properly requires a broad spectrum of expertise. The newly formed Communication Sciences Research Center at Cincinnati Children’s was founded to bring together exactly that kind of expertise.

“In the past eight years, we have developed a significant body of knowledge about language development,” says Scott Holland, PhD, scientific director for the new center. “This new collaboration represents a $5 million investment on the part of this institution to assemble a team to build upon that knowledge.” More than 20 researchers affiliated with the center will focus on translating basic research into more effective treatments for hearing loss, apraxia, dyslexia and other language processing disorders.

The center’s steering committee includes Holland, who also directs the Pediatric Neuroimaging Research Consortium at Cincinnati Children’s; Ellis Arjmand, MD, PhD, Director of the Ear and Hearing Center; Lisa Hunter, PhD, Senior Clinical Director of the Audiology Division; and Ann Kummer, PhD, Senior Director of Speech Pathology. Kummer credits Robin Cotton, MD, director of Otolaryngology/Head and Neck Surgery at Cincinnati Children’s, for his vision and support in developing the center. “Many years ago, he recognized that there was tremendous untapped potential for a strong, integrated clinical research center for pediatric communication disorders,” Kummer says. The newly endowed “Cotton Chair for Otolaryngology” will help support faculty recruitment.

‘Never give up’ Coma Survivor Helping Researchers and Families

Devin Carr (at left) is one of those miracle stories that leaves people inspired every time he talks about it. Just weeks after doctors discussed the possibility of donating his organs because they did not expect him to live, Devin, then 12, woke from a coma and learned to walk and talk again. Once a victim of severe head trauma, Devin has returned to Cincinnati Children’s to help brain-injury experts figure out how to help families cope after accidents like his.

In 1998, a speeding pickup truck struck Devin as he waited for his school bus in a suburb just north of Cincinnati. His injuries were so severe that he spent five
weeks lying in a coma. Just as everyone expected him to die, his coma lifted. Not only did he relearn how to walk and talk, Devin, now 23, caught up with his peers to graduate from Miami University. He hopes to build a career in encouraging patients’ families. From a research standpoint, he wants to help pediatric rehabilitation psychologists such as Shari Wade, PhD, find out how to better access patients’ ability to recover. Devin will never be the same as he was before his accident. His sports dreams have largely been sidelined. The left side of his body remains weaker, and his damaged vocal cords make him sound like he always has a cold. But his optimistic nature makes him think he is a stronger person than he might have otherwise been.

“I never saw that I was done recovering, so I just kept pushing forward,” he says. “I like being here. Children’s is like another home for me. I like to think what I’m doing here is like coming full circle. Maybe what I can share with people is just to never to give up.”

Ear Probe Offers new way to Measure Hearing Loss

Every year, thousands of new parents receive unwelcome news from routine newborn screening tests – results indicating that their children are not hearing as well as they should. However, upon more thorough testing, about 90 percent of these unnerving initial results turn out to be “false positives” that may unnecessarily alarm families and drive up health costs. Lisa Hunter, PhD, director of the Audiology Division at Cincinnati Children’s, says there may be a better way.

“If we can find out which babies have a middle ear problem versus a permanent hearing loss, we can reduce the number of infants receiving unnecessary diagnostic testing,” Hunter says. “We also think we will be able to give pediatricians more accurate information about why babies don’t pass the initial screening test. We hope this study will improve the referral process after newborn screening.”

Cincinnati Children’s and Good Samaritan Hospital, which operates the area’s largest maternity unit, have begun enrolling up to 1,800 newborns in a five-year study to assess an ear probe that can double-check initial test results without putting so many babies through more expensive, full-scale diagnostic tests.
The study will use a $1.37 million grant from the National Institutes of Health to assess a technology called wideband reflectance. Participants will receive follow-up hearing tests through age one year to compare against results at birth to find out which babies have normal hearing, or have continued fluid in the ear, versus permanent hearing loss. “What this tool measures is how much sound is able to get through the baby’s ear,” Hunter says. “When babies are born, they still have some amniotic fluid in the ears. This fluid can interfere with newborn hearing screening, which is usually done in the first day or two after birth.”

The probe used in wideband reflectance testing can be connected to a desktop or laptop computer. The tool has shown promise in a preliminary study of 250 infants that Hunter conducted at the University of Utah. Hunter joined Cincinnati Children’s two years ago, where she is continuing her research.
For more information about the study, contact Edie Eads, research coordinator at Cincinnati Children’s (513-636-2216) or Candi Dixon at Good Samaritan (513-862-4070).

The wideband reflectance study is administered through Cincinnati Children’s new Communication Sciences Research Center. Co-investigators include: David Brown, PhD, director of research, Division of Audiology; Jareen Meinzen-Derr, PhD, a quantitative epidemiologist with the Division of Pediatric Otolaryngology; Daniel Choo, MD, director of Otology/Neurotology; and Sally Schott, MD, pediatric otolaryngologist.

Landmark Epilepsy Study to Continue

Cincinnati Children’s has been awarded $11.7 million from the National Institute for Neurologic Disorders and Stroke (NINDS) to continue leading a nationwide study comparing the effectiveness of the three most common medications for childhood absence epilepsy. The new, 4-year study led by Tracy Glauser, MD,
will compare the long-term effects of ethosuximide (Zarontin) to valproic acid (Depakote) and lamotrigine (Lamictal).

On March 4, 2010, the key findings from the first phase of the study were published in the New England Journal of Medicine. The study concluded that ethosuximide – the oldest and least expensive of the three medications – also provided the best short term results for controlling absence seizures with the least negative effects on attention. Absence epilepsy is the most common form of childhood epilepsy. Affected children can suffer dozens, even hundreds of quick seizures a day; often called “petit mal” seizures.

The new study will follow 446 patients who participated in the first study. It involves 31 medical centers throughout the U.S. and is slated to begin in July, 2010.
“The first study showed that newer isn’t necessarily better,” says Glauser, director of the Comprehensive Epilepsy Center at Cincinnati Children’s. “Now, we’re asking whether ethosuximide remains the best drug for long-term therapy.”

Some children who begin with “petit mal” seizures gradually have more intense, but less frequent tonic clonic seizures, also called “grand mal” seizures.
The new study will explore which of the three medications does the best job of preventing this progression and which has the least impact on quality of life and cognitive function, Glauser says. Meanwhile, work related to the first trial continues, including genetic analyses to determine why most children fared better on ethosuximide while others fared better on the other medications. A survey also is planned to measure the first study’s impact on prescribing patterns.