• News in Brief

    Study Digs Into the X’s and Y’s of Human Reproduction


    Satoshi Namekawa, PhD, is using a $1.4 million grant to better understand the roots of male infertility, germ cell tumors and other rare conditions related to the basic functions of our chromosomes.

    Namekawa, in the Division of Reproductive Sciences, will explore the connections between DNA damage response pathways and meiotic sex chromosome inactivation (MSCI) – a fundamental process of human reproduction. The research is funded by the National Institute of General Medicine Sciences (NIGMS).

    “Our study focuses on germ cell development,” Namekawa says. “Germ cells maintain and transmit genetic information to our offspring. So it is very important to understand how these cells develop and the underlying mechanisms needed to maintain them.”

    Understanding Male Fertility

    Much of Namekawa’s work zeros in on the male side of the equation, specifically the processes involved in producing properly functioning sperm cells.

    During reproduction, sperm cells carry either a single X or Y chromosome. Fertilization occurs when that chromosome pairs up with the X chromosome carried within the female egg. However, the precursor cells that produce sperm carry an XY pair of chromosomes. During production, the MSCI process “splits” the X’s from the Y’s to produce single-chromosome sperm cells.

    As this occurs, a DNA damage response mechanism watches over the process. It kicks in to prevent the production of sperm with defective genetic information.

    Namekawa is using mouse models to analyze the molecular basis of these functions. This work may help explain the causes of male infertility and could suggest possibilities for male birth control.

    Defects in this process may also be involved in other conditions.

    Disruptions in germ cell development can lead to birth defects and germ cell tumors, Namekawa says. Germ cell tumors include testicular cancer, some cases of ovarian cancer, as well as yolk sac tumors that occur in young children.

    Pinpointing how the chromosome-silencing process works also may shed light upon Klinefelter’s syndrome (males with an extra X chromosome) or Turner syndrome (females with a missing X chromosome).

    Clues to How We Evolved

    The new five-year grant will fund Namekawa’s continued work. Some key findings that led up to this award were published May 1, 2011, in the journal Genes & Development.

    While Namekawa hopes this study leads to future medical applications, he also seeks to contribute to the deeper understanding of human evolution. This work could help illuminate how and why reproduction systems vary so widely among mammals and between mammals and other creatures.

    New Director Looks to Build Strength in Research

    Teri McCambridge, MD, was a competitive gymnast until a knee injury in her senior year of high school put an end to that career.

    Fortunately, she had a backup interest in medicine. And her experience with multiple surgeries and rehab sessions to repair her knee convinced her to focus on sports medicine.

    McCambridge has now joined Cincinnati Children’s as director of the Division of Sports Medicine. After 11 years in private practice in pediatric sports medicine with a part-time clinical appointment at the Johns Hopkins Hospital in Baltimore, the idea of moving into a full-time academic career was appealing.

    “Cincinnati Children’s gives me the opportunity to lead a division with a strong history of research in injury prevention. I can bring my clinical skills to the program while strengthening my research skills and building our research program in sports medicine.”

    Although a career as a gymnast was not in the cards, McCambridge continued as a coach and judge of the sport throughout her medical school years at Johns Hopkins School of Medicine.

    Now, an area of research interest is in strength training to help young gymnasts prevent injuries.

    “One of the common injuries to gymnasts is spondylolysis, a stress fracture of the spine,” McCambridge says. “I want to look at, if we put kids on core strength training before they get injured, when they are younger, can we prevent injuries down the road.”

    McCambridge believes that early strength training is key to preventing injuries in most young athletes. She credits the Sports Medicine team for the work they have already done in preventing athletic injuries, especially in preventing ACL injuries in girls, but wants to take it further.

    “In general, there’s not a lot of sport-specific injury prevention out there,” she says. “That’s an area we’d like to target.”

    Asthma Project Uses Data to Help With Treatment

    The national guidelines of best practices for treating and controlling asthma in children span some 300 pages.

    They offer such an array of medication choices and treatment options that few, if any, pediatricians can keep all that information in their heads.

    As a result, many children with asthma do not receive care that lines up with the guidelines. A project developed at Cincinnati Children’s seeks to change that.

    A team of software developers under the guidance of Carolyn Kercsmar, MD, director of the Asthma Center at Cincinnati Children’s, worked for five years to create the Asthma TreatSmart decision support tool for pediatricians.

    “It distills a highly complex set of treatment guidelines into a quick, real-time reference,” Kercsmar says.

    The tool was introduced in summer 2011 to three practices in Greater Cincinnati, with plans to roll it out to 35 more by March 2013. These 38 groups serve nearly 13,000 children with asthma.

    This initiative is supported, in part, through the Beacon grant, a regional effort to improve outcomes through innovations in health information technology sponsored by the Department of Health and Human Services.

    The tool helps a physician assess the severity of a child’s asthma, what level of control has been achieved, and recommends ways to adjust treatment.

    “This tool is a way to document, ‘Are your patients doing as well as you think?’” Kercsmar says.

    Making Emergency Care Safer for Kids

    Cincinnati Children’s cares for 125,000 children in our emergency departments every year. That’s nearly 350 kids a day; 15 every hour.

    A place where every second counts might seem an unlikely laboratory for in-depth research. But doctors there would disagree.

    Cincinnati Children’s was just awarded a five-year, $2.7 million grant to oversee emergency care research as part of the national 18-hospital Pediatric Emergency Care Applied Research Network (PECARN).

    Richard Ruddy, MD, director of the Division of Emergency Medicine, is the grant’s principal investigator. Funded by the Health Resources and Services Administration, the grant will cover infrastructure costs supporting a range of emergency care studies at Milwaukee Children’s, St. Louis Children’s Hospital and here.

    Current or planned research by the 18 PECARN network hospitals totals more than $52 million and serves some 1.2 million acutely ill and injured children. PECARN began in 2001 as the first federally funded network designed to apply rigorous research to pediatric emergency care.

    “All of the studies are related to children treated in the emergency room or in pre-hospital settings,” Ruddy says. “They range from best practices for transporting children to hospitals, to looking at all aspects of care in the emergency department. Sometimes they’re observational studies; sometimes they’re clinical trials – testing drugs or therapies.”

    There are 10 studies currently underway among PECARN members, and results of past studies have been widely published. Studies in the pipeline will help reduce the use of CT scans for mild head injury based on a previous decision rule developed by PECARN. Another will study preventing cerebral edema in children with diabetic ketoacidosis during ED and early inpatient management.

    Ruddy says the work of PECARN is essential to ensuring top-notch emergency care and collaboration with medical and surgical specialties to answer important clinical and health services questions.

    Another advantage is the collaboration that results.

    “We interact with 30 to 40 investigators nationwide. We collaborate with other specialties within the hospital,” Ruddy says. “How do we better understand the genomic or proteomic aspects of our patients – what makes them more susceptible to illness or injury? How do we work with families to ensure that they get the best treatment? Partnering with other specialties is really important.”

    Preventing Childhood Obesity Starts at Home, Early

    A lifetime of obesity-related health problems can start as soon as preschool for some children – but initial research indicates that intense, early intervention can make a difference.

    Researchers at Cincinnati Children’s developed a six-month program aimed at 2-to-5- year-olds that includes a mix of office-based parent counseling and home visits. The goal is to teach parents healthier living methods, from how to introduce healthy foods to fussy eaters to encouraging physical activity even when kids are stuck inside.

    The researchers published results of their pilot study online April 15, 2010, in the journal Obesity.

    Initial findings from the Learning About Activity and Understanding Nutrition for Child Health (LAUNCH) program were based on 18 families. The results from this small group were encouraging enough for the NIH to award $3.25 million to expand the project to 168 more families.

    Recruitment began in February 2012. Participating children, ages 2-5 with a body-mass index (BMI) at or above the 95th percentile, will be randomly assigned to treatment or control groups and then tracked for two years.

    Parents Struggle to Set Limits

    The number of obese children age 2 to 5 in the U.S. has grown from 5 percent in the 1970s to 13.9 percent in 2004.

    “There is no single reason for the increase in obesity in this age group,” says Lori Stark, PhD, principal investigator for the LAUNCH project and director, Division of Behavioral Medicine and Clinical Psychology. “We initially thought treating obesity might be easier in this population because parents have more control over the child’s food and activity. But, among other things, we were surprised at how hard it was for parents to set limits on the types and amount of food preschool age children eat.”

    Other reported challenges include perceived lack of time for meal making, difficulty encouraging physical activity, the parents’ own obesity level and the inherent unwillingness of many young children to try new foods.

    Changing Behavior Takes Time

    The pilot study found that achieving measurable changes in behavior in this high-risk group involves intense effort.

    The Cincinnati Children’s program includes repeated meetings with experts in child psychology and nutrition. Participants receive a half-dozen home visits, including staffers who show up with big red boxes to assist in removing unhealthy foods.

    “We spend a lot of time with these families,” Stark says. “We work to take the stress out of making healthy food so that busy parents aren’t as tempted to just buy fast food.”

    Facts About Childhood Obesity

    • Nearly 14 percent of children ages 2 to 5 are obese, up from 5 percent in the 1970s.
    • An obese preschooler at age 5 years is 48 times more likely than a nonobese child to be overweight at age 12. Obese and overweight teens are much more likely to remain obese as adults.
    • Childhood obesity can lead to type 2 diabetes, a leading cause of disability and death.
    • Some obese children also build plaque in their blood vessels, increasing the odds of a heart attack or stroke later in life.

    When Kids with Sickle Cell Grow Up

    Many of the worst complications of sickle cell disease – organ and bone damage, neurocognitive deficits, pulmonary problems and more – tend to strike during young adulthood.

    “This is a time of life when young adults are going through college, getting that first job, getting started with life. To think about changing doctors is often too much,” says Lori Crosby, PsyD, a clinician and researcher in the Division of Behavioral Medicine and Clinical Psychology at Cincinnati Children’s.

    It’s also a time when ignoring their illness can have dire consequences. Deaths and complications from sickle cell disease have long been known to rise as patients move through their 20s.

    Crosby is using a four-year, $1.7 million grant from the National Heart, Lung and Blood Institute (NHLBI) to try to change this. She believes some of these negative outcomes can be avoided through better communication with patients and more effective transitions between pediatric and adult care providers.

    “This is also a time when young people may not be employed, or may be working without health benefits. Yet because of their age they can no longer receive treatment here, where they’ve been followed for their entire lives,” she says.

    For patients nearing adulthood, the program involves self-management classes and training on how to talk to doctors (a task often handled by parents). The project also will create a patients-only “portal” to access information through MyChart, a feature built into Cincinnati Children’s electronic patient records system.

    For providers, the project helps doctors not affiliated with Cincinnati Children’s tap into the vast amount of expertise and data the medical center has regarding sickle cell patients.

    “Here, we have a team of specialists who work with hundreds of sickle cell patients. In the adult world, a hematologist might have two or three sickle cell patients in their entire practice,” Crosby says. “We want to remove the barriers that may prevent those physicians from coordinating care with us.”

    Grant Could Yield Missing Piece for Neurofibromatosis

    With the help of a five-year, $1.7 million renewal of a study in its 22nd year, Nancy Ratner, PhD, believes this phase of the work could identify potential treatments.

    Ratner studies neurofibromatosis type 1(NF1), the more common of the disease’s two types. NF1 affects one in 3,000 children. Its symptoms range from mild skin discolorations and bumps (cutaneous neurofibromas) to severe growths (plexiform neurofibromas) that can cause deformity and can lead to cancer. Children with NF1 also often have developmental and learning disabilities.

    Understanding of the disease has progressed remarkably over the last two decades, Ratner says. “When this grant was first funded, we didn’t even know what the NF1 gene was.” Now, researchers here and elsewhere have cloned the gene, created animal and cell culture models to analyze its expression, and are looking at molecular pathways that provide avenues for treatment.

    Finding successful treatments remains the missing piece.

    “We have about 1,000 patients in the neurofibromatosis clinic registry here, and there are clinicians clamoring at our doors to test treatments based on our laboratory findings,” Ratner says.

    With this renewal from the National Institute for Neurological Disorders and Stroke, she hopes to move closer to that goal.

    “We will use mouse models and cell culture systems with large-scale knockdown of the genes whose expression is high,” Ratner says. “We’re coupling bioinformatics with animal models and in vitro studies to find the major drivers of tumor formation.”

    Children with neurofibromatosis type 1 lack the NF1 gene. This gene acts as a crucial “off signal” for ras proteins. In the absence of NF1, there is too much ras pathway signaling, causing cells to divide and change their properties. The result is that neurofibromas (tumors) form within nerves throughout the body.

    About half the cases of NF1 are inherited; the rest result from spontaneous genetic mutations.

    NF1 typically can be identified in children by 2 to 3 years of age based on hyperpigmented “café au lait” spots on the skin. Some children with NF1 develop plexiform neurofibromas, which Ratner describes as “sometimes exceedingly large and very disfiguring tumors that can cause a great deal of morbidity.” Plexiform neurofibromas often form in early childhood; they can be visible or internal.

    This new grant is one of five Ratner has that are focused on NF research and keep her staff of 15 researchers busy. Some of her other studies are looking at early treatment trials in animal models.

    “With this grant, I hope to identify new targets for preclinical therapeutics,” she says.

    Center to Step Up Battle Against Preterm Birth

    Medical science has achieved tremendous advances in helping infants as tiny as 1 pound survive premature birth.

    Much less progress has been made in preventing such early births from occurring in the first place.

    Louis Muglia, MD, PhD, is on a mission to change that. In January, Muglia came to Cincinnati Children’s to serve as co-director of our Perinatal Institute and to direct our new Center for Prevention of Preterm Birth. The Center will identify and address causes of preterm birth, from the molecular pathways that affect the timing of birth to the epidemiologic trends influencing pregnancy.

    The challenge is clear. Premature birth ranks as the second-leading cause of infant mortality in the United States, behind congenital malformations. Preterm birth rates in America exceed most other developed nations. And for nearly half of all preterm births, the cause is unknown.

    Researchers, policymakers and physicians have a great deal of work to do to reduce America’s current preterm birth rate – 12.2 percent – to 7.8 percent by 2020. That’s the target set by Healthy People 2020.

    A first initiative for the Center for Prevention of Preterm Birth will be to develop innovative interactions across disciplines. At least 30 scientists will be involved, Muglia says.

    “Prematurity is the single most important problem right now in maternal and child health,” Muglia says. “The bottom line is we still don’t know what the key signals are for the normal timing of birth in humans and we don’t know what the most common causes of preterm birth are in humans.”

    The Center will pursue five research areas: the genetics of unique human populations; the evolutionary biology of the child birth process; the molecular and developmental biology of pregnancy; host-microbe interactions and adverse pregnancy outcomes; and perinatal epidemiology and nutrition.

    With the combined talents of Cincinnati Children’s, the University of Cincinnati College of Medicine and other research institutions around the country, Muglia believes we can take understanding and preventing prematurity to the next level.

    Degen Named AAAS Fellow

    Sandra Degen, PhD, has been named a Fellow of the American Association for the Advancement of Science (AAAS).

    Degen is associate chair for academic affairs at Cincinnati Children’s and interim chair of Molecular Genetics, Biochemistry and Microbiology in the UC College of Medicine.

    The award recognizes Degen’s research in blood proteins and coagulation, her service in research administration and her mentoring of students interested in science careers.

    Her lab’s work in blood coagulation and cancer research has earned three patents. Degen has served as principal investigator on many National Institutes of Health (NIH) grants.

    Equally important to Degen is her mentorship of faculty and undergraduate students who pursue research careers. She was instrumental in helping create the Schmidlapp scholarship program for young women scientists. A number of Schmidlapp scholars are now among Cincinnati Children’s top researchers.

    Degen’s office conducts an annual science career day that draws more than 1,200 undergraduate students to apply for 100 spots in the medical center’s summer research programs.

    “I love that our institution realizes that programs for students are the pipeline for new researchers,” Degen says. “We are part of a major research-comprehensive university and all it has to offer. It’s a strength we are proud of."

  • Awards & Appointments

    D. Woodrow Benson, MD, PhD, Division of Cardiology, received a five-year, $2.3 million grant from the National Heart ,Lung and Blood Institute to participate in the Pediatric Heart Network Prairieland Consortium.

    Lori Crosby, PsyD, Division of Behavioral Medicine and Clinical Psychology, received a four-year, $1.7 million grant from the National Heart, Lung and Blood Institute for “Patient- Provider Interventions to Improve Transition to Adult Care in Sickle Cell Disease (SCD).”

    Sudhansu K. Dey, PhD, Division of Reproductive Sciences, received a five-year, $1.9 million grant from the National Institute of Child Health and Human Development to study “Molecular Signaling in Uterine Receptivity for Implantation.”

    David Glass, MD, Division of Rheumatology, received a five-year, $6.9 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to study “Gene Expression in Pediatric Arthritis.”

    Alexei Grom, MD, Division of Rheumatology, received a five-year, $1.7 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to study “MUNC13-4 Gene Polymorphisms in Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.”

    Gurjit Khurana Hershey, MD, Division of Asthma Research, received a five-year, $7.3 million grant from the National Institute of Allergy and Infectious Diseases to study “Epithelial Genes in Allergic Inflammation.”

    Kevin Hommel, PhD, Center for Adherence Promotion and Self Management, received a five-year, $2.8 million grant from the National Institute of Child Health & Human Development to study “Telehealth Enhancement of Adherence to Medication in Pediatric Inflammatory Bowel Disease (IBD).”

    Thomas Inge, MD, PhD, Division of Bariatric Surgery, received a five-year, $5.7 million grant from the National Institute of Diabetes and Digestive and Kidney Disorders to continue the “Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study.”

    Carole Lannon, MD, Anderson Center for Health Systems Excellence, received a five-year, $4.2 million grant from the Agency for Healthcare Research and Quality to support the pediatric “Centers for Education and Research on Therapeutics (CERT).”

    Daniel Lovell, MD, Division of Rheumatology, received a 15-year, $5.5 million grant from Bristol-Myers Squibb to continue the “BMS Services Agreement-Rheumatology.”

    Jeffery Molkentin, PhD, Division of Molecular Cardiovascular Biology, received a five-year, $2.1 million grant from the National Heart, Lung & Blood Institute to study “Ca Signaling Domains Programming Cardiac Hypertrophy.”

    John Pestian, PhD, Division of Biomedical Informatics, received a three-year, $1.1 million grant from the National Library of Medicine to develop a “Multi-Institutional Pediatric Epilepsy Decision Support Tool.”

    Scott Powers, PhD, and Andrew Hershey, MD, PhD, Divisions of Neurology and Behavioral Medicine and Clinical Psychology, received a five-year, $7.6 million grant from the National Institute of Neurological Disorders and Stroke to study “Amitriptyline and Topiramate in the Prevention of Childhood Migraine Headaches.”

    Nancy Ratner, PhD, Division of Experimental Hematology and Cancer Biology, received a five-year, $1.8 million grant from the National Institute of Neurological Disorders and Stroke to study “Mitogenic Activities in Neurofibromatosis.”

    Jeffrey Robbins, PhD, Division of Molecular Cardiovascular Biology, received a five-year, $1.3 million grant from the Fondation Leducq to study “Proteotoxicity: An Unappreciated Mechanism of Heart Disease.”

    Richard Ruddy, MD, Division of Emergency Medicine, received a four-year, $2.7 million grant from the Health Resources and Services Administration for an “Emergency Medical Services for Children (EMSC) Network Development Demonstration Project.”

    Mary Allen Staat, MD, Division of Infectious Diseases, received a five-year, $1.7 million grant from the Centers for Disease Control and Prevention for “Enhanced Surveillance for New Vaccine Preventable Diseases.”

    Daniel Starczynowski, PhD, Division of Experimental Hematology and Cancer Biology, received a $1.9 million grant from the National Heart, Lung & Blood Institute for the “Identification and Characterization of Genes in del(5q).”

    Lori Stark, PhD, Division of Behavioral Medicine and Clinical Psychology, received a five-year, $3.3 million grant from the National Institute of Diabetes and Digestive and Kidney Disorders to study “Clinic and Home Family-Based Behavioral Treatment for Obesity.”

    Arnold Strauss, MD, and Marc Rothenberg, MD, PhD, received a five-year, $2.2 million grant from the National Institute of Child Health & Human Development to support the “Child Health Research Career Development Award (K12).”

    Susan Thompson, PhD, Division of Rheumatology, received a five-year, $3 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to support the “Cincinnati Rheumatic Diseases Core Center.”

    Jennifer Vannest, PhD, Division of Neurology, received a five-year, $2.6 million grant from the National Institute of Neurological Disorders and Stroke for “Imaging the Effect of Centrotemporal Spikes and Seizures.”

    Avani Modi, PhD, received a Schmidlapp Scholar Award from the Fifth Third Bank/ Charlotte R. Schmidlapp Women Scholars Program. Modi is the 18th scholar to receive the $100,000 award, given annually to support career development of female faculty.

    Srikant Iyer, MD, has been selected to the Centers for Medicare and Medicaid Services’ (CMS) Innovation Advisors Program. The initiative, launched in October 2011, helps health professionals deepen skills that will drive improvements to patient care and reduce costs.

    Sandra Degen, PhD, has been named a Fellow of the American Association for the Advancement of Science (AAAS). The honor recognizes her career in research, her service as an administrator and her role as a mentor to students pursuing careers in science.