News in Brief
Gene Vital to Early Heart, Skull Formation Found
Researchers at Cincinnati Children’s have found the gene that could be responsible for congenital heart and other defects.
In a study led by Jeffrey Robbins, PhD, scientists reported that too little of the enzyme SHP2 interferes with development of neural crest cells. These cells are supposed to differentiate during early embryonic development and give rise to certain nerve tissues, craniofacial bones or smooth muscle tissue of the heart. Without SHP2, this doesn’t happen.
The study was published online in June by the Proceedings of the National Academy of Sciences.
“Our findings show that a deficiency of SHP2 in neural crest cells results in a failure of cell differentiation in the developing embryo,” says Robbins, co-director of the Heart Institute at Cincinnati Children’s and senior investigator of the study. “This leads to anatomical and functional deficits so severe that it precludes viability of the developing fetus.”
SHP2 is a tyrosine phosphatase – an enzyme that helps trigger a cascade of biochemical reactions in cells as they specify to form certain tissues.
The study was conducted using mouse embryos, but the findings are significant in understanding congenital malformations of the heart and craniofacial region in humans. Researchers believe the insights gained into early molecular events during embryonic development might help explain such birth defects.
According to Robbins, the study’s findings can be used to develop drugs that would target the affected pathway, leading to treatment of heart and craniofacial malformations.
In addition to these findings, researchers want to explore the alterations in neural crest cell migration, expansion and differentiation that contribute to birth defects of other organ systems.
Doing Research? Just Ask the Concierge
Young researchers with ideas that could lead to innovative discoveries may have an easier time getting their projects off the ground, thanks to a $23 million Clinical and Translational Science Award (CTSA) from the National Institutes of Health.
The five-year grant, awarded this year to the Center for Clinical and Translational Science and Training (CCTST), is for a joint effort between Cincinnati Children’s and the University of Cincinnati research community to essentially provide a concierge service for people who want to do research.
“We’re trying to create a portal where somebody could come and get help to create and develop a research program,” says a main force behind the project, James E. Heubi, MD, co-director of the Center for Clinical and Translational Science and Training at Cincinnati Children’s.
The idea is to pair people with novel ideas with teams to help them advance their research, says Heubi, who’s also associate dean for clinical and translational research at UC’s College of Medicine.
Cincinnati Children’s and its research partners will use the grant to connect junior researchers with experienced ones, such as statisticians and subject experts who can give feedback and encouragement based on their field of expertise.
“Until we think more broadly and look at a problem from different perspectives, we’re not going to get big advances,” Heubi says. “And that’s what this whole program is about.”
The most successful people in medicine now, in terms of research, he says, are groups of investigators with a variety of backgrounds who bring their separate expertise to bear on a single problem. That’s what this project aims to do.
“Most investigators work within a relatively narrow group of people,” he says. “And the trend of the future in research, clearly, is interdisciplinary.”
Natural Killer Cells Could Be Cause of Infant Liver Disease
One of the immune system’s key weapons against infection – natural killer, or NK, cells – could actually contribute to biliary atresia, one of the most common causes of liver disease in children.
Researchers here have linked the overactive response of NK cells to the onset of biliary atresia in infants, a problem in which blocked bile ducts cause severe liver damage and can lead to death.
Blocking the gene that helps the NK cells attack bile duct tissues lessens the damage, according to a study published in the August 3 Journal of Clinical Investigation.
“Our findings underscore the developing immune system’s role in causing injury to bile ducts soon after birth,” says Jorge A. Bezerra, MD, senior investigator of the NIH-funded study. Bezerra is research director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s.
“The next steps for translating these findings into clinical application would include pre-clinical trials of biologics to halt disease progression by blocking the Nkg2d receptor and depleting NK cells at the time biliary atresia is diagnosed.”
Little is known about the cause of biliary atresia, which affects about one in every 15,000 babies.
The current frontline treatment is surgery to remove and replace obstructed bile ducts with sections of the child’s intestine. The surgery is successful 65 to 85 percent of the time and is not considered a cure, although it can allow babies to have several years of fairly good health. In more severe cases, children may require a liver transplant.
Managing the Business of Clinical Operations
Jana Bazzoli, MBA, MSA, CMPE, recently joined the Cincinnati Children’s Research Foundation and the Department of Pediatrics as vice president of Clinical Affairs. Bazzoli has nearly 20 years’ experience in hospital administration, having earned her MBA at Augusta State University in Georgia and her MSA at Central Michigan University. Her most recent position was associate administrator of outpatient operations at Nemours/Alfred I. DuPont Hospital for Children in Wilmington, Delaware.
At Cincinnati Children’s, Bazzoli will work closely with departmental business directors and division directors to improve clinical care and systems. One of her first responsibilities will be to develop a program to transition children who “outgrow” our pediatric care to an adult setting that matches Cincinnati Children’s quality of care.
“I’m excited to have the opportunity to work at a nationally recognized children’s hospital and to support its continued growth and success,” Bazzoli says.
Testing for Healthier Pregnancies
Jill S. Huppert, MD, MPH, is in the business of fertility preservation.
She wants teen girls she sees at Cincinnati Children’s to have healthy pregnancies when they are adults. That often means treating their sexually transmitted diseases now.
“Women with STDs are at higher risk for perinatal complications like miscarriage or preterm labor,” Huppert says. “If we could find and eradicate STDs before the girls got pregnant, we’d have better pregnancy outcomes.”
Huppert, an obstetrician and gynecologist who does research in adolescent medicine, helped change hospital practice in that direction. Two years ago, she encouraged clinicians to use tests to tell within 10 minutes whether a patient had the common trichomonas infection, which until then had been an underdiagnosed but easily treatable STD. Now the rapid test is used routinely.
Her research involves making the same advances happen for chlamydia tests. Although chlamydia is the most frequently reported STD in the US and can damage a woman’s reproductive organs, there’s no reliable rapid test for it approved by the Food and Drug Administration.
Huppert aims to change that. She has been testing rapid chlamydia tests and finding out whether teenage girls would be comfortable doing the tests themselves, like a home pregnancy test.
Having rapid STD tests available in drugstores is still at least a few years away. But Huppert would love to get more women talking about preserving their sexual health as easily as they set up appointments for pap smears and mammograms.
Learning Right From Left
What causes the body to stray from its expected developmental blueprint?
Stephanie Ware, MD, PhD, of the Division of Molecular Cardiovascular Biology, will explore the question and what it means for the heart with the help of a 5-year, $750,000 Clinical Scientist Award from the Burroughs Wellcome Fund.
Ware will focus on the genetic causes of heterotaxy – the body’s failure to establish a proper right and left side - and how they relate to congenital heart defects.
“As the heart forms, it follows a blueprint and needs to know its left from its right side to develop properly,” Ware says. “The anatomy in heterotaxy is some of the most complicated seen by cardiologists. A child’s overall prognosis is determined by the severity of the heart defect; often they do not do very well.”
Heterotaxy is present in about 3 percent of children with congenital heart defects, but it likely causes other heart defects as well. Ware says physicians can identify the precise genetic cause in fewer than 10 percent of children with heterotaxy.
The grant will allow Ware to perform genetic analysis on 1,500 DNA samples from patients with heterotaxy and their parents collected in collaboration with Baylor College of Medicine.
“We’re looking for very small chromosome abnormalities - loss or gain of one or more genes,” she says. “We want to find genes that have never before been known to affect heart development and prove it. Then, we’ll have a novel cause of heterotaxy in patients that we can screen for.”
Treatment Could Halt Brain Injury in Newborns
The enzyme known to dissolve blood clots in adult stroke victims could have detrimental effects on newborn brains, researchers here report. Tissue plasminogen activator, or tPA, appears to cause the brain injury in newborns suffering from restricted oxygen and blood flow.
Their report in the July Journal of Neuroscience showed that blocking the brain enzyme activator tPA prevents the hypoxic-ischemic brain damage, which is a leading cause of cerebral palsy, mental retardation and even death.
The experimental treatment involved putting a naturally occurring substance called plasminogen activator inhibitor-1 (PAI-1) into the brains of newborn rats, says Chia-Yi “Alex” Kuan, MD, PhD, senior investigator on the study and a researcher in the divisions of Developmental Biology and Neurology at Cincinnati Children’s. Besides demonstrating that the brain’s plasminogen activator system plays a pivotal role in brain injury, Kuan says the study also shows this system may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy (HIE).
In human newborns, hypoxic brain injury usually occurs right before, during or shortly after birth, affecting two to four of every 1,000 births. The causes are mostly unknown, although some studies point to the possibility of problems with the placenta, maternal blood pressure or complications related to the umbilical cord. Close to 20 percent of newborn children with hypoxicischemia die and 25 percent of those who survive suffer from lifelong neurological problems.
“Not only is hypoxic-ischemic encephalopathy an important cause of perinatal mortality and permanent neurological morbidities, but there are no specific medications against HIE in current medical practice,” says Ton J. deGrauw, MD, PhD, director of Neurology at Cincinnati Children’s. “The findings of this study may have important clinical implications because they show that, in a rodent model, inhibiting plasminogen activators in functional areas of the brain is a powerful strategy for brain protection.”
Earlier studies have demonstrated the role of certain brain proteases, or enzymes, in adult brain injury following stroke, but little has been understood about what these enzymes do in neonates, the researchers say. Additional studies are needed to test the effectiveness and safety of PAI-1 therapy in other experimental animal models. The research team also recommends studies to determine whether infants diagnosed with HIE, or at high risk of cerebral palsy, have elevated levels of tPA and plasmin in their brains or cerebrospinal fluid.
Growth Hormone Effective for Children with Crohn's Disease
Growth hormone therapy has proven to be effective in countering the deleterious effects of steroid therapy for children with Crohn’s disease.
Investigators from Cincinnati Childen’s report that children with Crohn’s disease on long-term corticosteroid therapy show improved height and weight with growth hormone therapy.
Twenty children, ages 7 to 18, were randomized by Lee (Ted) Denson, MD, and his team in the Inflammatory Bowel Disease Center. Children in the growth hormone therapy group received 0.075 mg/kg daily in addition to maintenance corticosteroid therapy.
“We had three main endpoints,” says Denson. “The primary endpoint was mucosal inflammation and signs of healing at 12 weeks. We also looked for symptom improvement and an improvement in growth. We did not see significant signs of healing, but there was an improvement in symptoms and there was a catch-up in growth equivalent to where they were before they got sick.”
Researchers also reported that the children receiving the growth hormone experienced no negative side effects and saw a decrease in disease activity.
Denson is encouraged by the findings and plans to develop a multi-center study.
“The therapy may prove to be helpful to improve growth and reduce symptoms in some children with Crohn’s disease,” he says. “The optimal window to give it is early in puberty.”
Obese Children More Prone to Lower Body Injuries
Researchers have added injury to muscles and bones to the list of health problems caused by overweight.
A recent study by Cincinnati Children’s showed that obese children are more vulnerable to injuring the bones and muscles of the lower body.
The study analyzed body weight and injury severity for children who visited the hospital’s emergency department between 2005 and early 2008. More than 23,000 children were admitted for ankle and leg sprains, the most common lower body injuries. About one-sixth of the children were obese.
“Because obese patients have an increased body mass and force, they are more likely to twist or roll on a lower extremity and cause injury than the non-obese children,” says Wendy Pomerantz, MD, emergency medicine physician and lead author of the study. The overweight children also experienced fractures and lacerations.
In addition to the increased susceptibility to injury, obesity is likely to lengthen a child’s recovery time, noted Pomerantz, since the added weight and stress to the body can cause even more damage.
Exercise and diet remain the best ways to combat the growing obesity epidemic, says Pomerantz. “Parents of an obese child who want the child to exercise but who are afraid of the child getting injured should work with a specialist to get a diet and exercise regimen to help them lose weight.”
Pomerantz added that there are many programs across the country like Cincinnati Children’s HealthWorks! that can safely help children reach their weight loss goals.
