Active Research Protocols
here were 105 research studies in progress at last update on November 30, 2006, headed by 66 Principal Investigators from 31 divisions at Cincinnati Children's Hospital Medical Center and the University of Cincinnati. Click on the division name below to view short descriptions of the studies in that area.
Adolescent Medicine | Allergy & Immunology | Cardiology | Preventive Cardiology | Center for Epidemiology & Biostatistics | Center for Health Related Program- UC | Clinical Pharmacology- UC | College of Environmental Health- UC | Digestive Diseases- UC Internal Medicine | Endocrinology | Endocrinology- UC Internal Medicine | Experimental Hematology | Gastroenterology, Hepatology and Nutrition | General Clinical Research Center | General & Community Pediatrics | Hematology Research | Hematology/Oncology | Human Genetics | Mass Spectrometry Laboratory | Nephrology | Neurodiagnostic | Neurology | Nutritional Sciences- UC | Psychiatry- UC | Psychology | Pulmonary Biology | Pulmonary Medicine | Rehabilitation | Rheumatology | Surgery | Translational Research
Adolescent Medicine
Frank Biro, MD frank.biro@cchmc.org
Protocol #:658 Puberty and Cancer Initiation: Environment, Diet and Obesity
This is a study funded by the National Cancer Institute and the National Institute of Environmental Health Services to the University of Cincinnati and Cincinnati Children's Hospital, to look at environmental factors associated with pubertal development and a possible future correlation to breast cancer. It is a longitudinal study examining the impact of diet, physical activity, psychosocial factors, environmental exposures, and genetic factors on the timing of pubertal maturation in a group of 6 and 7 year old girls. Participants are seen every 6 months at their schools or at the GCRC.
Lorah D Dorn, PhD lorah.dorn@cchmc.org
Protocol #:609 Developmental Psychobiology of Premature Adrenarche
The purpose of this study is to examine physiological and psychological characteristics of children with premature adrenarche (PA) and the development of emotional and behavior problems and cognitive differences in this disorder. PA occurs earlier than age 8 in girls and age 9.5 in boys and is manifested by the increase in adrenal androgens and the appearance of sexual hair, body odor and acne. Our preliminary research suggests that there is an increased incidence of emotional and behavioral problems and cognitive differences in PA, compared with ""on time"" children (Dom, Hitt, & Rotenstein, 1999). Because PA is more common in girls than boys, by a 10-1 ratio (Reiter & Kulin, 1972), this study will examine PA in girls only. In a sample of girls ages 6 through 8 , one group with PA and a matched comparison group of on-time girls (Tanner I breast and pubic hair), the aims of the study are as follows: (1) To compare child hormone milieu (gonadal and adrenal hormones, cortisol reactivity), genetic variation associated with hyperandrogenism [mutation of CYP21 or glucocorticoid receptor (GCR)], adjustment (anxiety, depression, and externalizing behavior problems), and cognitive differences (standardized neuropsychological tests) in PA and on-time girls. (2) To examine the mediated moderation of PA by individual genetic variation (mutation of CYP21 or GCR) on child adjustment (anxiety, depression, and externalizing behavior problems) and cognitive function (standardized neuropsychological tests) through child hormone milieu (gonadal and adrenal hormones, cortisol reactivity).
Protocol #:617 Smoking and Metabolic Complications in Adolescent Girls
Adolescence is a time of vulnerability for youth where depression rates increase, particularly in girls, and smoking behaviors are also initiated. Increased morbidity and mortality in women who are smokers has been highlighted by recent statistics showing that women now have an increased rate of smoking over the last several decades. Morbidity and mortality is usually defined by cardiovascular and respiratory disorders. Less attention has been paid to the effect of smoking on aspects of health such as the relationship between smoking and depression and anxiety, and in turn, their combined effects on reproductive and bone health. No studies have examined such issues in puberty. The aims of this study are to examine: (1) baseline relationships between puberty, smoking status, depression anxiety, reproductive and bone health, (2) causal direction between smoking status and depression and anxiety across 3 years, (3) characteristics of individual differences in developmental trajectories of: (a) reproductive and (b) bone health (accrual of bone mineral content; BMC) across a 3 year period, (4) the systematic effects of timing of puberty, smoking status and depression and anxiety on individual differences in developmental trajectories of reproductive and bone health (accrual of BMC) across a 3 year period, (5) the relationship of individual differences in developmental trajectories of adolescent reproductive health with individual differences in developmental trajectories of bone health across a 3 year period, and (6) whether baseline levels of smoking status, depression, and pubertal timing predict the simultaneous developmental trajectories of reproductive and bone health. The study will include 252 girls, ages 11-17 years enrolled in a cross-sequential design for three annual visits. Measures include smoking status, depression and anxiety, pubertal timing, gonadal and adrenal hormones, menstrual cycle information, and accrual of BMC. Examining the combined impact of smoking, depression and anxiety, on timing of puberty has import for future intervention and prevention strategies. Any negative influence during this critical period, such as smoking or depression, may have significant long-term consequences for bone (i.e. increased risk of osteoporotic fracture) or reproductive health (i.e. menstrual irregularity & endocrine disruption, infertility, dysmenorrhea).
Return to top Allergy & Immunology
Marc E. Rothenberg, MD, PhD marc.rothenberg@cchmc.org
Protocol #:575 Effect of Intravenous Anti-IL5 (Mepolizumab) SB240563 on the Outcome and Management of Hypereosinophilic Syndromes
The purpose of the study is to assess the safety of anti IL-5 in 18-24 patients with hypereosinophilia (HES) and determine what effect (good or bad) the study medication has on the management of hypereosinophilic syndromes (high number of a particular kind of white blood cell in the blood or in the tissues).\~ 4 groups of 6 individuals will receive Anti IL-5. Groups A and B are safety groups, receiving anti IL-5 with out changes to their current HES medications during infusions. Group C will receive the drug while their current HES medication ( prednisone, etc) would be reduced up to 25% by end of the study. Group D will follow do the same with up to 50% reduction in Current HES medication. Primary outcome measures for this study are safety in this population and reduction of peripheral blood eosinophil levels and/ or tissue eosinophil level.
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Cardiology
Stephen R Daniels, MD, PhD
Protocol #:542 Epidemiology of Body Mass Index Rebound
The purpose of this study is to precisely determine the age of children at Body Mass Index (BMI) rebound and evaluate potential correlates of the timing of BMI rebound in a cohort of children beginning at age 3 years. Better understanding of the epidemiology of BMI rebound could lead to improved identification of children at high risk of future obesity prior to excess weight gain. Elucidation of the determinants of the timing of BMI rebound could lead to the development of strategies to prevent the development of obesity. A major objective is to evaluate the relationship of changes in BMI with changes in body composition using dual energy x-ray absorptiometry (DXA). We will examine the association of the timing of BMI rebound and the percent body fat at the time of BMI rebound with gender, ethnic group, and socioeconomic status. We will evaluate the potential determinants of the timing of BMI rebound including diet, physical activity, and parental body mass index. We will examine the relationship of the timing of BMI rebound to percent body fat, distribution of body fat, blood pressure, plasma lipid and lipoprotein concentrations, fasting insulin, glucose and leptin levels and left ventricular mass at age 7 years.
Protocol #:561 Genetic Epidemiology of Energy Metabolism in Black African-American Girls
The purpose of this research study is to better understand how genes may influence resting energy expenditure in 12 - 16 year old African American girls which may contribute to the development of obesity during adolescence. There are two parts to the study. Initially, we will buccal screen 1000 girls for genotyping. Those that are a match the specific genes we are interested in, will be asked to come for an overnight visit at Cincinnati Children's Hospital Medical Center's General Clinical Research Center. At the overnight visit, the subject will have measurements of body composition such as height, weight and skinfolds. The subject will also have a DXA scan, blood draw, and a Resting Energy test.
Catherine Dent, MD catherine.dent@cchmc.org
Protocol #:678 Trial of Right Ventricle Vs. Modified Blalock-Taussig Shunt in Infants with Single Ventricle Defect Undergoing Staged Reconstruction
Hypoplastic left heart syndrome (HLHS) and related single right ventricle (RV) anomalies are the highest-risk congenital cardiovascular malformations (CCVM). Surgical palliation for these patients consists of the Norwood procedure during the newborn period, a stage II procedure at 4-6 months and the modified Fontan procedure at approximately 18 to 36 months. The Norwood procedure remains one of the highest risk procedures in congenital heart surgery. Recently, improved outcomes have been reported in a few small, non-randomized studies of a novel approach to the Norwood procedure, which uses a right ventricle to pulmonary artery (RV-to-PA) shunt to provide pulmonary blood flow rather than the standard modified Blalock-Taussig shunt (MBTS). The Pediatric Heart Network's proposed multi-institutional, randomized clinical trial will evaluate early and intermediate-term outcomes for patients undergoing a Norwood procedure with either the RV-to-PA shunt or MBTS. Infants with a diagnosis of single, morphologic right ventricle anomaly will be eligible for inclusion in this study. Participants will be randomly assigned to receive either a MBTS or RV-to-PA shunt, with randomization stratified by aortic atresia (presence or absence) and obstructed pulmonary venous return (presence or absence). Dynamic allocation will be used to ensure treatment arms are balanced across surgeons. Data will be collected at discharge from the Norwood procedure, prior to the stage II procedure (at approximately 6 months of age), and then again at 12 and 14 months post-randomization. The primary aim of the study will be to compare the effect of the MBTS to that of the RV-to-PA shunt on the rate of death or cardiac transplantation 12 months after randomization. Secondary aims include post-operative morbidity following the Norwood and stage II palliation procedures, RV function and pulmonary artery growth at the time of the stage II palliation, and neurodevelopmental outcome at 14 months. The incidence of adverse events will also be compared between the treatment groups. The total sample size target of 466 participants will be recruited over 26 months.
Thomas Kimball, MD thomas.kimball@cchmc.org Protocol #:553 Visceral Adiposity and CVD Risk in Women
Obesity has been well established as a risk factor for type II diabetes mellitus and cardiovascular disease. Concern about obesity has increased as the prevalence and severity of this problem in the United States has increased and the age at onset has decreased. However, the impact of obesity measured by body mass index appears to differ by race. For each unit increase in body mass index, blacks have less of an increase in blood pressure and triglycerides and less of a decrease in HDL cholesterol compared to whites. The explanation for this phenomenon remains unclear. We propose to evaluate the concept that these racial differences in the relationship of adiposity to cardiovascular risk are related to differences in the distribution of fat. We will do this through a cohort study of young adult black and white women who have been followed previously as part of the NHLBI Growth and Health Study. In this study, total body fat will be determined by dual energy x-ray absorptiometry (DEXA), and intra-abdominal (or visceral) fat will be measured by magnetic resonance imaging (MRI). We will also utilize information on pubertal maturation and diet collected on this cohort in childhood and adolescence to evaluate potential.
Protocol #:660 Cardiovascular Disease in Adolescents with Type 2 Diabetes
The prevalence of type 2 diabetes mellitus has increased dramatically in adolescents. This appears to be a direct result of the increase in prevalence and severity of obesity in the pediatric population. In adults with type 2 diabetes, the risk for cardiovascular disease is quite high. It is not known if adolescents with type 2 diabetes have an equivalent high level of risk of CVD. If they do then it would be expected that they would develop clinical CVD in their late 20's or 30's. This would have important clinical implications and would suggest the need for very aggressive management of CVD risk factors and diabetes. This study is a cross-sectional evaluation of cardiac and vascular structure and function in a population of 300 adolescents with type 2 diabetes compared to an obese control group of 300 and a normal weight control group of 300 who have been matched by age, sex and race. Assessment of CVD development will be accomplished using novel non invasive imaging methods including echocardiographic measurement of cardiac structure and function, ultrasound evaluation of carotid intimal-medial thickness, central aortic pressure and augmentation index will be accomplished using the SphygomoCor Pulse Wave Analysis System and evaluation of endothelial function by brachial artery reactivity. The results of this study will fill an important gap in knowledge, will serve as the baseline for future longitudinal studies and may provide the basis for clinical strategies to prevent the development of CVD in young patients with type 2 diabetes.
Steven M. Schwartz, MD steven.schwartz@cchmc.org
Protocol #:672 Trial of ACE Inhibition in Infants with Single Ventricle
This study is being performed by the Pediatric Heart Network and is sponsored by the National Heart, Lung and Blood Institute of the National Institutes of Health. Approximately 14 patients will take part in this study per year at Cincinnati Children's Hospital Medical Center and it is planned that a total of 230 patients will be enrolled from all of the hospitals. Enalapril (Vasotec\'ae) belongs to a class of medications known as angiotensin converting enzyme (ACE) inhibitors. It is used to treat high blood pressure and congestive heart failure in adults and children. ACE inhibitors dilate the vessels that take blood from the heart to the body making it easier for blood to flow through these vessels. This vasodilation reduces the work of the heart in many patients by decreasing how hard it has to squeeze to eject blood. Although enalapril is well tolerated in children, there is only limited data demonstrating the effectiveness of enalapril in children with heart problems, especially in infants with single ventricle hearts. The purpose of this research study is to find out whether enalapril improves heart function and growth in infants with single ventricle hearts during the first year of life.
Elaine Urbina, MD elaine.urbina@cchmc.org
Protocol #:680 Intra-Cranial Carotid Calcification, Calcification, CV Risk Factors and Vascular Function in Children and Adolescents
Calcifications of the intra-cranial carotid arteries (ICA) are frequently found in adults on routine head CT scans. They correlate strongly with CV risk factors & are associated with angiographic vessel stenosis supporting the idea that vascular calcifications are a marker for generalized atherosclerosis. Even simple dental X-rays may identify calcifications which relate to abnormal carotid ultrasound & predict subsequent vascular events. The significance of ICA calcifications in children is not known eve though radiologist frequently recognize them on head CT scans and one small pediatric autopsy study found a high prevalence of such lesions. These data led us to hypothesize that ICA calcifications in children represent early atherosclerotic change. We will test this theory by performing a case-control study selecting subjects from an existing database of children who underwent a temporal bone CT scan. These scans collected over 2 years, were evaluated by Pediatric Radiologist for presence of ICA calcification. Of 408 children, 27% had calcification although only 1 had a medial condition that might explain the findings (diabetes and dyslipidemia). Fifty cases & fifty controls will be studies with 1/2 of the subject younger (6 to < 12 years) and 1/2 older (12 to 19 years) for a total of 100. Demographics, medical and family history, anthropometrics & blood pressure data will be collected. Laboratory analyses will include calcium, phosphorus, glucose & insulin levels, fasting lipid panel, high sensitivity CRP, homocysteine & fibrinogen. Central & peripheral vascular sites tested will include carotid intimate-media thickness & compliance, aortic augmentations index, brachial artery distensibility & pulse wave velocity to the arm, trunk & leg. Analyses will be performed to determine if children with ICA calcification 1) demonstrate other abnormalities in vascular function; 2) have abnormal levels of CV risk factors; and 3) whether vascular abnormalities correlate with levels of CV risk factors. Potential mechanisms underlying early vascular calcifications and dysfunction will also be explored by comparing calcium-phosphate product, levels of systemic inflammation, fibrinogen and homocysteine between cases & controls. The proposed research will allow us to determine the importance of vascular calcification as a marker for early atherosclerotic disease in children allowing earlier intervention in high risk individuals to prevent future adverse cardiac and stroke-related outcomes.
Protocol #: 692 Mechanisms of Vascular Dysfunction in Obesity and the Metabolic Syndrome
Childhood obesity has increased dramatically in the U.S. in the last decade. Unfortunately, these overweight children are at risk for target organ damage, adult diabetes, heart disease and stroke. One of the pathways by which obesity may induce target organ damage involves adiponectin (APN) an adipose-tissue derived cytokine. APN has direct vascular protective effects. However, it is found in reduced levels in obesity, obesity related inflammation and in coronary artery disease. Low levels are associated with insulin resistance and the dyslipidemia found as part of the metabolic syndrome. Therefore, we propose a cross-sectional study of school aged adolescents to study relationships between obesity and vascular function. Analyses will be performed to determine if the mechanisms underlying arterial dysfunction may relate to abnormal levels of CV risk factors, inflammation and APN. Brachial Artery Distensibility, BMI, BP, lipids, high sensitivity CRP, and APN will be measured in the ongoing 'Landmarks in the Progression to Type 2 Diabetes' study currently being conducted in the Princeton School District (N=2000). A sample of this cohort (n=450) will also undergo brachial flow mediated dilatation, measurement of augmentation index & pulse wave velocity. Contrasts in laboratory and vascular measures will be made among normals, obese subjects with normal insulin levels and obese adolescents with hyperinsulinemia. Showing that metabolic abnormalities related to overweight lead to blood vessel dysfunction in children will help doctors identify high risk children for early treatment to prevent future heart attack and stroke.
Return to top Preventive Cardiology
Shelley Kirk, PhD, RD shelley.kirk@cchmc.org
Protocol #:657 Role of Carbohydrate Modfiication in Weight Management Among Obese Children
The treatment of pediatric obesity supported by the medical community is a moderate restriction in calories by modifying intake of fat and simple sugars, along with an increase in energy expenditure through more physical activity. However, this approach is associated with only limited success. As a result, overweight children and adolescents are seeking alternative approaches to weight management, such as diets that modify the type and amount of carbohydrates. However, at this time there is limited data on the safety and efficacy of these diets, particularly with younger children. This study is a controlled clinical trial that compares the safety and efficacy of a low carbohydrate and low glycemic load diets to a more standard dietary intervention for the management of pediatric obesity (i.e. portion-controlled, moderate fat, high carbohydrate diet). This study will involve 150 overweight children (ages 7 to 12) who will be randomly assigned to one of the three diet groups for 12 months. The effects of each diet will be determined by measuring changes in anthropometric measures (body weight, height, body mass index, waist circumference, body composition), other cardiovascular risk factors (blood pressure, fasting lipid profile, fasting glucose and insulin, and inflammatory markers of cardiovascular disease), and measures of psychological well-being and mental status. The results of this study will provide needed information to the public in their quest for safe, effective, and health-promoting weight management strategies for obese children. Such information is vital if we are to address the obesity epidemic in the United States.
Return to top Center for Epidemiology & Biostatistics
Cynthia Molloy, MD cynthia.molloy@cchmc.org
Protocol #: 681 Blood Expression Profiles in Children with Down Syndrome with and without Autism
Autism, a severe neurodevelopmental disorder, occurs at a rate of approximately 1 in 200 children in the general population. Among children with Down syndrome, the rate is about 7%, a greater than 10 fold increase in risk. While the etiology of autism is unknown, there are clearly genetic contributions, and the increased risk in children with Down syndrome (Trisomy 21) may be related to having extra genes on the additional copy of chromosome 21. Among children with Down syndrome who have autism, 50% have a history of regression. This is the loss of established communication skills that occurs in a subset of 20 to 30% of all children with autism. In a study of families with two or more children with autism and regression (without Down syndrome) we observed significant evidence that chromosome 21 is linked to autism with regression. The objective of this study is to examine gene expression patterns in children with Down syndrome with and without autism. This uniquely informative cohort of children all overexpress genes on chromosome 21. The patterns of genes that are expressed differently in the children with and without autism will identify candidate genes for susceptibility to autism with regression. These patterns are expected to identify candidate genes on chromosome 21 and candidate genes on other chromosomes that interact with genes on chromosome 21. These candidates can then be examined for contribution to autism with regression in children with autism who do not have Down syndrome.
Ardythe Morrow, PhD ardythe.morrow@cchmc.org
Protocol #: 662 The Role of Infant Feeding in Childhood Allergy
The Role of Infant Feeding in Childhood Allergy is a prospective observational study of asthmatic and non-asthmatic mothers and their infants enrolled within 2 weeks of birth and followed through 9-12 months postpartum. The aims of the study are to 1) compare the peripheral cytokine phenotypes of breastfed and non-breastfed infants between 9-12 months of age, accounting for maternal history of asthma, 2) compare the cytokine phenotypes of the milk of asthmatic and non-asthmatic mothers, and 3) examine the relationship between cytokine concentrations in maternal milk and the infants' peripheral cytokine phenotypes, accounting for maternal history of asthma and maternal and infant cytokine genotypes. Eligible mothers who consent to participate complete a baseline questionnaire at 2-3 weeks postpartum. Data related to maternal health history, birth history, infant feeding, maternal diet, and demographic characteristics is collected. A sample of human milk is collected at home from all breastfeeding mothers approximately 4-weeks postpartum. Monthly questionnaires are then completed for all subjects to collect data on infant and maternal illness, asthma severity symptoms, and infant feeding. All questionnaires are completed by telephone interview. At 9-12 months postpartum, a blood sample is collected for all mothers and infants during the one outpatient study visit. Allergy skin testing for the mother and her infant is also completed at this visit. Subjects are referred for follow-up with their physician or an allergist for any positive skin test results.
Return to top Center for Health Related Programs- UC
Bonnie J Brehm, PhD bonnie.brehm@uc.edu
Protocol #: 629 Comparison of High Monounsaturated Fat and High Carbohydrate Diets on Glycemic Control and Cardiovascular Risk Factors in Type 2 Diabetes
Diet is an important component of the treatment plan for diabetes. Patients with diabetes are currently advised to consume 60-70% of their daily calories as carbohydrate and monounsaturated fat. This recommendation makes no distinction between high carbohydrate and high monounsaturated fat diets. Studies performed in carefully controlled settings have shown some potential advantages of high monounsaturated fat diets, such as improvement of lipid levels in the blood and, in some cases, lower blood glucose levels. It is unknown whether the improvements shown in these small, short-term studies could be maintained over longer periods in free-living subjects. The purpose of this study is to determine whether high monounsaturated fat diets or high carbohydrate diets are more beneficial to persons with type 2 diabetes. We will study a group of 120 type 2 diabetic subjects randomly assigned to a high monounsaturated fat or high carbohydrate diet for one year. We will determine the effects of diet on 1) body weight, 2) body composition, 3) blood glucose control, and 4) cardiovascular risk factors, such as blood pressure and plasma lipids. The results of this study will provide critical information about diabetic diet recommendations for optimal health.
Return to top Clinical Pharmacology
Alexander Vinks, PhmD, PhD sander.vinks@cchmc.org
Protocol #:679 Development of Population PK-PD Models of Mycophenolic Acid for Bayesian Dose Individualization in Pediatric Kidney Transplant Patients
The purpose of this study is to determine how fast children (age 2-17 years), who have had a recent kidney transplant, absorb, breakdown and eliminate mycophenolic acid (CellCept) following their prescribed dose and how this influences their level of immunosuppression. Subjects will have been receiving CellCept as part of their clinical standard of care. It is anticipated that the clinical portion of the study for each patient will be approximately six months post kidney transplant with four study days: a screening visit pre-transplant, two 10-hour inpatient days at 2-3 and 6-9 days post-transplant, and one (up to 10 hour) outpatient visit at 3-6 months post-transplant. Whole blood samples for drug and effect measurements will be collected at various time points (up to 9 hours post dose) on study days 2, 3, and 4. Safety data to be collected will include physical examinations, measurement of vital signs, and laboratory assessments, as well as data on adverse events and clinical outcomes. The results of this study will lead to better dosing based on individual needs.
Return to top College of Environmental Health- UC
Erin N. Haynes, DrPH, MS erin.haynes@uc.edu
Protocol #:676 Neurobehavioral Effects of Low-Level Manganese Exposure
Manganese (Mn) is an essential element, but it is neurotoxic in excess. The lowest level of Mn associated with adverse effects and the ideal biomarker for measuring low-level Mn exposure is poorly defined. Moreover, there is some evidence that Mn and lead (Pb) are biologically synergistic in their toxicity. A noninvasive method of detecting Mn exposure in the brain, its target organ of toxicity, would be invaluable for the study of Mn neurotoxicity. Mn readily crosses the blood-brain-barrier, selectively accumulating in the caudate and the globus pallidus. Magnetic resonance imaging (MRI) can reflect Mn deposition in the brain. Given the increased use of Mn in gasoline and the emerging data on adverse health effects of low-level Pb exposure, it is critical to conduct studies to identifying a suitable biomarker of Mn exposure and to identify the health effects of low-level Mn exposure. We seek to explore the following specific aims: Specific Aim 1: Validate a noninvasive biomarker of chronic, low-level Mn exposure. Specific Aim 2: Characterize the neurobehavioral effects of chronic, low-level Mn exposure using currently accepted biomarkers of exposure and a MRI biomarker. Specific Aim 3: Characterize the neurobehavioral effects of combined exposure to Pb and Mn using currently accepted biomarkers of exposure and a MRI biomarker. The Cincinnati Lead Study cohort, the longest running cohort study of Pb exposed children, provides a unique opportunity to examine Mn deposition in the brain of young adults with low-level Mn exposure and extensive measures of lifetime Pb exposure and neurological development. If we demonstrate that MRI is a valid measure of low-level Mn exposure and Mn exposure predicts impaired neurobehavioral functions, then this study will substantially advance environmental health research and have broad implications for policy to control environmental exposure to Mn.
Return to top Digestive Diseases- UC Internal Medicine
Kenneth E Sherman, MD, PhD kenneth.sherman@uc.edu
Protocol #:578 Response of Hepatitis C Virus to Pegylated Interferon Alpha-2A and Ribavirin in Hemophilic Patients with and without Coinfection with the Human Immunodeficiency Virus
Patients with Hemophilia and Hepatitis C (with and without HIV co-infection) are being treated with latest generation of Pegylated Interferon plus Ribavirin for 48 weeks. The viral response is being measured at multiple time points during the first 2 weeks of treatment so that we can understand factors associated with early response. In addition, we are studying how the body's immune system contributes to viral clearance. We believe that viral mutations play a key role in treatment outcome and are using sophisticated methods to study the selection of mutants over time.
Return to top Endocrinology
Phillippe Backeljauw, MD philippe.backeljauw@cchmc.org
Protocol #: 602 Glucocorticoid Effects on Growth and Bone Mineral Accretion in Infants with Hemangioma
This study will evaluate linear growth and bone accretion via DXA scanning in infants started on steroids prior to 1 year of age exposed to prolonged high dose oral steroids. Infants seen through the Hemangioma clinic are often treated with oral steroids without understanding the potential impact on growth and bone maturation. This study is attempting to objectively analyze these criteria to provide better knowledge to future physicians when considering long-term steroid therapy as well as provide better knowledge of potential sequelae. Study to enroll subjects and controls from January 2004 through December 2005 for data collection and analysis.
Protocol #: 606 Adrenal Suppression Following Glucocorticoid Treatment in Infants with Hemangioma
This study will evaluate healthy infants with hemangiomas requiring treatment with prolonged oral steroid to assess the potential risk for subsequent adrenal insufficiency following steroid withdrawal. Anticipated goals of the study are to establish a gradual weaning protocol for infants exposed to prolonged high-dose steroids to minimize risk for subsequent adrenal insufficiency and morbidity. Thus far, using a fairly standard weaning regimen, none of the infants have had adrenal insufficiency based on followup adrenal stimulation testing. Continuing to collect data from study patients and controls for further analysis from January 2004 through December 2005.
Steven D Chernausek, MD
Protocol #:405 Long-Term rhIGF -1 in Children with Short Stature due to Growth Hormone Insensitivity Syndrome (GHIS)
Growth hormone insensitivity syndrome occurs when the actions of pituitary growth hormone (GH) are chronically attenuated. Isolated GH insensitivity most commonly results from either loss of function mutations in the GH receptor or from high levels of circulating antibodies that neutralize GH. In the complete form of the syndrome, patients manifest extreme growth failure, decreased lean body mass, and metabolic abnormalities such as hypoglycemia. The disorder is very rare, and there is no commercial agent available that will effectively treat the condition.
Lawrence M Dolan, MD larry.dolan@cchmc.org
Protocol #:544 Landmarks in the Progression to Type 2 Diabetes
"Landmarks in the Progression to type 2 diabetes" is a five year, population-based, prospective, longitudinal study of students in grades five through twelve in a large, urban-suburban, Non-Hispanic white / African-American school district. The purposes of the study are 1) to determine the frequency of insulin resistance (decreased insulin action), carbohydrate intolerance (early signs of abnormal sugar metabolism), and diagnosed and undiagnosed diabetes and risk factors associated with type 2 diabetes in the study population and 2) to determine each year the progression to insulin resistance, carbohydrate intolerance and diabetes in a cohort of adolescents over the 5 years of the study. Two thousand five hundred and four students entered the study in the fall of 2001. In the course of the first three years of the study we maintained a high retention rate: Year 1-Year 2, 88%; Year 2 to Year 3, 92%; Year 4 data collection is ongoing. "Landmarks" is designed to identify factors that will predict the development of obesity, insulin resistance, abnormal carbohydrate metabolism, and diabetes. In conjunction with Dr Elizabeth Goodman (Understanding Social Status' Impact on Adolescent Health, R01-HD41527) the study has been expanded to examine the frequency and characteristics of metabolic syndrome in the study cohort and the effect of social status on adolescent health. In addition, a collaboration has been established with Dr. Lisa Martin, Jessica Woo, and Nancy Crimmins (American Diabetes Association grant: "The metabolic syndrome: the role of plasma adiponectin and common genetic polymorphisms in adolescents") to focus on the potential role of adiponectin (a protein produced in fat cells) and the adiponectin gene and the adiponetin gene receptor in this process. Finally, in conjunction with Dr Elaine Urbina, the "Landmarks" study is utilizing non-invasive techniques to define the frequency of sub-clinical cardiovascular disease (CVD) in the study population and the relationship between sub-clinical CVD and obesity, insulin resistance, carbohydrate intolerance, diabetes, and the metabolic syndrome.
Protocol #:577 SEARCH for Diabetes in Youth
SEARCH is a national, multi-center, population-based study examining the burden of diabetes in individuals less than 20 year of age and the changes in the frequency and characteristics of the various types of diabetes over time. The study is also developing efficient and practical approaches to identifying the various types of diabetes. The study began with a definition of the major types of diabetes based on the cause of each type of diabetes. SEARCH is in the process of testing and refining these definitions. In the next year SEARCH will develop practical algorithms to identify types of diabetes that can be used by clinicians, public health workers, and researchers. SEARCH is also examining trends over time in the delivery of health care and the complications of diabetes. This year SEARCH initiated a protocol to examine the frequency of sub-clinical cardiovascular disease in the study population.
Protocol #: 639 Type 1 Diabetes Genetics Consortium
The Type 1 Diabetes Genetics Consortium (T1DGC) is a collaborative effort looking to undertake molecular genetic studies to identify individual genes that determine an individual's risk of or protection from type 1diabetes. The study's objectives are: -to obtain, study, and establish a renewable source of DNA on 3,000 families worldwide with at least 2 siblings with type 1 diabetes, their parents, and up to 2 siblings without diabetes for studies to identify genes that affect the risk for type 1 diabetes; -to create a database for the scientific community with clinical, genetic and medical history information that will facilitate the search for genes that make one susceptible to type 1 diabetes; -to provide a central DNA repository to allow targeted studies of genetic structure and function for type 1 diabetes; and -to evaluate opportunities to extend the results of research to develop methods of risk prediction, prevention, and therapy in the area of type 1 diabetes.
Deborah A Elder, MD deborah.elder@cchmc.org
Protocol #:661 Beta-Cell Function in Adolescents with Type 2 Diabetes
Type 2 diabetes (T2DM) is emerging as an important problem in American adolescents. In adults T2DM requires the presence of insulin resistance but does not develop until \'e2-cell failure is present. It has been commonly assumed that a similar process occurs in adolescents, but no study has characterized \'e2- cell dysfunction in this population. Whether T2DM in adolescents represents a distinct form of diabetes or is simply an early presentation of type 2 diabetes in adults is unknown. To begin to characterize the metabolic phenotype of T2DM in adolescents, we measured b-cell function and insulin sensitivity in 16 adolescents with T2DM who had been diagnosed for at least one year and 26 age-weight matched and lean non-diabetic, healthy, controls. The diabetic subjects had severe hyperglycemia, > 15 mM at presentation, but were under excellent glycemic control at the time of study. All were obese and had acanthosis nigricans. Similar to adult T2DM, the adolescents had insulin resistance that was significantly greater than age, and weight-matched non-diabetic controls. In contrast to what is seen in adults with T2DM, islet dysfunction in the adolescents was different. Specifically, the adolescents had (1) an intact first phase of insulin release but of a magnitude that was inappropriately low for the degree of insulin resistance, (2) normal plasma glucagon concentrations, and (3) a normal proinsulin/insulin ratio. From this study it is not clear whether the islet dysfunction in the adolescents is simply an early stage of the insulin secretory abnormalities found in adults or evidence for a distinct process of b-cell dysfunction in adolescents. We hypothesize that b-cell dysfunction in diabetic adolescents represents an early phase of the insulin secretory abnormalities found in adults with T2DM. We will test this hypothesis by accomplishing the following specific aim. To establish whether adolescents with T2DM share the defects in insulin secretion that typify adult diabetic patients. Classic abnormalities in b-cell function of adults with T2DM include decreased b-cell sensitivity to glucose, a decrease in functional b-cell mass, and an impaired incretin effect. These parameters will be assessed cross-sectionally in adolescents with T2DM of greater than 12 months duration and in age, race, gender, weight-matched adolescent control subjects. We anticipate that compared to controls adolescents with T2DM will have: defects in \'e2-cell sensitivity to glucose as tested by dose-response relationship to graded glucose infusion; decreased \'e2-cell mass as tested by maximal glucose potentiation of the insulin response to arginine; and impaired incretin effect as assessed by oral glucose tolerance test and isoglycemic intravenous glucose infusion. These studies will establish whether the defects in insulin secretion that occur in young people with T2DM differ from those characteristic of adult diabetes. This is a critical first step in understanding the pathophysiology of this condition and will define specific parameters of b-cell dysfunction. It is anticipated that the new information generated by this study will lead to the development of specific interventions to prevent, limit or treat diabetic youth, as well as providing insights into b-cell dysfunction in T2DM.
Protocol #:673 Longitudinal Assessment of Beta-Cell Function in Adolescents with Diabetes
The goal of this study is to define the natural history of b-cell function in adolescents with T2DM. The first phase insulin response to intravenous glucose and the insulin response to intravenous arginine will be performed at diagnosis, 6 months and annually for 4 years in adolescents with T2DM, race and gender-matched adults with T2DM and age, race, gender and weight-matched adolescent controls. We predict that first phase insulin release in adolescents with T2DM will be severely compromised at diagnosis, undergo a phase of recovery with the institution of treatment, and then progress to a state of greater -cell failure despite anti-diabetic therapies.
David J Klein, MD david.klein@cchmc.org
Protocol #:601 Safety and Efficacy of Metformin and Diet in Managing Weight Gain After Initiation of Olanzapine Therapy
This is a research study to determine the safety and effectiveness of Metformin to reduce gained weight after taking Zyprexa, Risperdal, or Seroquel. The study subjects are children between the age of 10 and 17 who have gained more than 10% of their body weight or are overweight and stable on Zyprexa, Risperdal or Seroquel. Volunteers will be accepted until 40 participants qualify. This is a 16 week study with 6 scheduled visits per child. Subjects will have 3 REE's, 5 blood draws for safety and study test, 3 food recalls and 2 dietary consults. This is a double \endash blind study with half the volunteers receiving Metformin and half receiving a placebo. Upon completion of the study, participants receive notification of weather they have been on active drug Metformin or a placebo.
Susan R Rose, MD susan.rose@cchmc.org
Protocol #:595 Endocrinopathies After Head Injury
Children with endocrinopathies resulting from head injury may not present with symptoms for several years after the injury. No prospective trial has been reported assessing the frequency of endocrinopathy after head injury in children.We hypothesize that systematic endocrine evaluation six months after the injury will identify those children at risk for developing later endocrinopathy. Specifically, we hypothesize that an abnormal pattern of thyrotropin (TSH) or growth hormone (GH) secretion, or an elevated serum prolactin concentration, will predict development of other hypothalamic-pituitary dysfunctions.In the current study, 40 children who have survived significant head injury will have baseline thyroid, cortisol, growth hormone screen, and prolactin measurement at the time of injury and 2 to 3 months later. They will then undergo study of their pattern of overnight TSH and GH secretion at 6 months after injury. Subsequently, their growth rate and endocrine screening tests will be evaluated at one year after injury. Inclusion Criteria: Head injury Glasgow Coma Scale 12 or less Age 18 months to 18 years Informed Consent Exclusion Criteria : Medically unable to tolerate testing protocol at 6 months after injury Unable to travel for 6 months or one year follow up Pregnancy in the subject
Protocol #:633 Thyroid Hormone in Children with Fanconi Anemia
The purpose of this research study is to find out whether children with Fanconi anemia will grow taller when treated with thyroid medicine. Children with Fanconi anemia are often shorter than other children their age and do not grow to normal height. This may be due low levels of thyroid hormone in the body. This medicine raises thyroid hormone levels in the body. Thyroid is a normally occurring chemical messenger in the body that is needed to grow taller. The second purpose of this study is to find out what effect (good or bad) thyroid hormone has on blood counts. Each child will be randomized to receive either treatment or placebo first for a total of 7 months in each treatment period. Each child will be in the study for a total of 14 months.
Return to top Endocrinology- UC Internal Medicine
David A D'Alessio, MD david.d'alessio@uc.edu
Protocol #:565 Pancreatic Islet Cell Function and Glucose Tolerance in Humans Following Islet Cell Transplantation
This study is designed to measure the insulin secretion in patients who have had an islet transplant. The pancreatic islets are the cells that make insulin and damage to these cells results in diabetes. Islet transplantation is a procedure that has been developed to give islets from organ donors to diabetic patients to cure diabetes (allotransplantation), or to return the islets from persons having their pancreas removed (autotransplantation). Six patients have had islet allotransplantations, and 45 islet autotransplantations at the University of Cincinnati over the last 4 years. Many of these patients have been enrolled in this study which measures their insulin secretion before and after transplantation. The overall goal is to determine the amount of insulin secretion that can be returned with islet transplantation and the stability of function over time.
Protocol #: 613 Regulation of Nutrient Stimulated Insulin Secretion by Glucagon-Like Peptide (GLP-1)
This study is designed to test the effect of the intestinal hormone GLP-1 to control insulin secretion in healthy persons and those with diabetes. To do this research volunteers will have insulin levels measured after meals on two occasions. The effect of GLP-1 will be determined by giving a blocker of GLP-,1 called exendin-(9-39, in one of the studies. By comparing insulin secretion with and without GLP-1 blockade, the effect of GLP-1 can be estimated from the difference in the two studies.
Return to top Experimental Hematology
Punam Malik, MD punam.malik@cchmc.org Protocol #:570 Donation of Peripheral Blood Stem Cells for Use in Experiments Involving In Vitro Expansion and Gene Transfer
The purpose of the study is to provide researchers with a source of normal donor blood products for use in experiments focusing on inherited diseases. Normal healthy donors between the ages of 18 and 40 who meet eligibility criteria are enrolled in the study. Donors complete a medical history questionnaire, which is reviewed by a physician to verify eligibility. Donors undergo a physical exam and blood tests. A stem cell mobilizing agent, granulocyte colony stimulating factor (G-CSF), is given for 4 days prior to the collection of white blood cells. White blood cells are collected through the use of a specialized machine (leukapheresis), which removes the white blood cells from the blood. Once the collection is completed, a complete blood count is drawn to ensure blood counts are within normal range. Donors are compensated for their participation in the study. The product is stored in an IRB approved tissue repository. Cincinnati Children's Hospital Medical Center Investigators that have an IRB approved protocol may request cells from the repository.
Return to top Gastroenterology, Hepatology and Nutrition
William F Balistreri, MD william.balistreri@cchmc.org
Protocol #: 637 Pegylated Interferon +/- Ribavirin for Children with HCV
The goals of this study include: I. To assess the safety and efficacy of peginterferon alfa-2a (PEG-2a) in combination with ribavirin (RV) and PEG-2a alone for the treatment of chronic hepatitis C virus (CHC) infection in children. II. To determine whether PEG-2a in combination with RV or PEG-2a alone will result in a higher sustained virologic response rate in children with CHC. III. To examine the effects of PEG-2a (with or without concomitant RV) treatment on body mass index, body composition, and linear growth in children infected with hepatitis C. IV. To characterize short- and long-term outcomes, including health-related Quality of Life (QOL), cognitive and developmental and psychological functioning, and behavior in children treated with PEG-2a (with or without concomitant RV). This 5 year study will enroll 112 children between the ages of 5-18 who are infected with hepatitis C. The children will be enrolled from 11 participating centers across the United States. Children will be randomized into groups that receive PEG 2a alone or a combination of PEG 2a and ribavirin. Treatment duration can range from 48 weeks up to 100 weeks depending on how the child responds to treatment. Children who do not respond to PEG 2a alone will be switched to the combination therapy group at week 24. Following completion of the treatment phase, there is a 20 week untreated follow-up period as well as annual visits for the next 2 years thereafter.
Michael D. Bates, MD michael.bates@cchmc.org
Protocol #:689 Defects of Digestive System Structure/Function: Molecular Genetic Studies
The purpose of this study is to identify the genetic causes of defects of digestive system structure and motor function, with a primary focus on anorectal malformations. Such defects are relatively rare (1 in 2,000-5,000 live births), but the national and international reputation of the surgeons of the Colorectal Center of Cincinnati Children's Hospital Medical Center results in a large base of potential subjects. Affected individuals and family members who are seen as outpatients and inpatients at Cincinnati Children's are asked to participate. As part of the research procedures, families agree to answer questions related to the proband's family history, medical and surgical history as well as environmental questions. Blood samples are obtained from the subject, his/her biological parents and, in cases with a positive family history, other affected family members. Blood samples are aliquoted for storage as whole blood or buffy coats. DNA extracted from blood samples will be used for candidate gene and association studies to determine the genetic basis of anorectal malformations.
John C Bucuvalas, MD john.bucuvalas@cchmc.org
Protocol #:636 A Prospective Database of Infants with Cholestasis
Infants, less that age 6 months, who present with neonatal cholestasis (high levels to bilirubin in the blood) to any of the centers participating in the Biliary Atresia Research Consortium will be contacted to take part in this study. Enrolled infants will be followed prospectively for a period up to 10 years. Information about the infants will be obtained using standardized forms. These data will be entered into a central database and will be used to characterize the natural history of the child's disease and to identify risk factors related to the onset, outcome and success of treatments for the different cholestatic diseases, with a special emphasis on biliary atresia. Blood, urine, bile and tissue samples will be obtained from enrolled infants and placed in a national repository for research purposes. Blood samples will be obtained when the infant is having blood tested as part of standard medical care. Bile and tissue samples will be collected from unused portions of samples collected as part of diagnostic or treatment procedures. Parents will be given the option to provide samples of their blood to the national repository for research purposes.
Protocol #:697 Biliary Atresia Study in Infants, Children and Adults (BASIC): A Protocol of the Biliary Atresia Research Consortium (BARC)
Biliary atresia (BA) is a progressive inflammatory process involving the biliary tree. As the disease progresses, there is loss of patency of the lumen and obstruction to bile flow. BA occurs in one in 8-15,000 live births resulting in 250-400 new cases per year in the US. Untreated, the disease leads to complete biliary obstruction with cirrhosis, and is uniformly fatal. After a hepatoportoenterostomy (Kasai procedure), children have a variable disease progression with less than 20% surviving beyond the teen years without liver transplantation. Little is known about the factors that cause biliary atresia nor the factors that influence disease progression. A variety of genetic, autoimmune and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics, as well as, natural history. The purpose of this study is to collect the pertinent clinical information, genetic material and body fluid samples obtained from older infants, children and adults with biliary atresia.
Lee A Denson, MD lee.denson@cchmc.org
Protocol #:628 Mechanisms of growth hormone resistance in colitis
Growth failure and poor tissue healing are significant complications for many children with chronic inflammatory diseases including Inflammatory Bowel Disease (IBD). The primary focus of Dr. Denson's research project is to determine the mechanisms by which chronic inflammation inhibits normal childhood growth and tissue healing. These studies involve children with a type of IBD called Crohn's disease. We are specifically examining the manner in which chronic inflammation blocks beneficial actions of growth hormone, leading to poor growth and tissue healing. Conversely, we are also examining new anti-inflammatory effects of growth hormone itself. This work has recently led to the identification of specific inflammatory proteins which may serve as targets for new therapies, as well as the potential for using growth hormone together with standard therapy. Ongoing studies in children with Crohn's disease will now determine the effectiveness of blocking these inflammatory proteins. This work should lead to improved therapeutic approaches for childhood IBD which will optimize both growth and intestinal healing.
Protocol #:655 Phase II Randomized Trial of Growth Hormone Therapy in Pediatric Crohn's Disease
The optimal treatment goals in childhood CD include: 1) clinical remission in conjunction with mucosal healing and 2) restoration of normal growth and development. Current therapy in most cases includes induction of remission with corticosteroids followed by maintenance of remission with 6-mercaptopurine (6-MP) or mesalamine. With this approach, the goals of achieving mucosal healing with normalization of growth are not achieved in a significant number of children. GH therapy is now used in several chronic childhood diseases which are complicated by growth failure despite adequate GH secretion. These include chronic renal failure (CRF), juvenile rheumatoid arthritis (JRA), and Turner's syndrome. However, despite a comparable frequency and magnitude of permanent growth failure, the efficacy of GH therapy in this respect has not yet been determined in a controlled trial for CD. Moreover, whether GH therapy may also directly reduce disease activity and promote intestinal healing is not known. This represents a significant clinically unmet need in this patient population. Therefore, new therapeutic approaches are needed to both improve final adult height and enhance intestinal mucosal healing in children with CD. The primary objective of this study is to determine the effect of growth hormone (GH) therapy upon colon mucosal healing in a 12 week randomized trial in children with Crohn's Disease (CD). Children with active CD will be randomized to GH + prednisone (GP) or prednisone alone (P) for a 12 week period.
James E. Heubi, MD james.heubi@cchmc.org
Protocol #:400a Pathogenesis of Liver Disease with Inborn Errors of Bile Acid Metabolism
Infants with inborn errors of bile acid metabolism represent a relatively heterogeneous group of patients with a variety of clinical manifestations. They can range from neonatal cholestasis and severe liver injury in the neonate to fat-soluble vitamin deficiency and its manifestations in the older child or even end-stage cirrhosis in later childhood. In addition, defects of peroxisomal metabolism of bile acids may be manifest in peroxisomal disorders such as Zellweger syndrome or infantile adrenoleukodystrophy. Using techniques of mass spectrometry including fast atom bombardment on urine samples, electron microscopy and MRI-spectroscopy, we have evaluated a growing group of infants and children with these disorders.
Protocol #:400b Investigations in the Potential Benefit of Bile Acid Therapy for Patients with Peroxisomal Disorders Affecting Bile Acid Metabolism
See description for project 400a.
Protocol #: 505 Regulation of Plasma Cholesterol Levels by Cholesterol Absorption, Synthesis and LDL-Receptors in Humans: Effects of Intraluminal Bile Acids and Dietary Fatty Acids
The role of variations in cholesterol absorption on plasma lipids, cholesterol synthesis and the development of atherosclerosis is poorly studied in humans. Although there is known to be tremendous variation in cholesterol absorption amongst certain populations, little study has been undertaken to understand the underlying mechanisms of these variations. The purpose of this study is to assess the effects of differing biliary bile acid composition, differing dietary fatty acid composition and differences in plasma cholesterol concentration on cholesterol absorption, cholesterol synthesis and factors responsible for cholesterol metabolism in adults and a group of children and adults with inborn errors of bile acid metabolism. This outpatient study involves feeding subjects a standardized meal for 20 days with collection of blood samples to assess plasma lipids and factors that might influence cholesterol metabolism, a collection of bile after a meal stimulus to study events within the intestine involved with cholesterol absorption, a measurement of cholesterol synthesis using a stable isotope technique and finally the measurement of cholesterol synthesis using a novel technique that measures stable isotope incorporation into red blood cells.
Protocol #: 562 Antiresorptive Therapy for Osteopenia Associated with Chronically Immobilized Children and Adults with Neuromuscular Disease
Bone disease and fractures are a significant problem for children and adults with neuromuscular diseases such as cerebral palsy. Studies from a number of centers have suggested that there is an increased risk of fracture among adults and children spastic quadriplegia with frequencies as high as 1-10%/year. Additional studies from a number of centers have suggested that bone density is reduced in this population. Based upon a cross sectional study at our institution, we have initiated a single center clinical trial to assess the efficacy and safety of a bisphosphonate, risedronate, on bone mass accretion in adults and children with neuromuscular disease that precludes ambulation. This double blind placebo controlled trial is designed to enroll 20 subjects in each arm with the treated group receiving 5 mg/day of risedronate if weighing greater than 30 kg or 5 mg every other day if weighing 15-30 kg. Both groups receive supplemental vitamin D and calcium and have DEXA scans of the lumbar spine and serum bone markers performed every 6 months for 2 years.
Protocol #: 648 Fecal Behenic Acid: A New Marker for Fat Malabsorption
Fat malabsorption (steatorrhea) results from impaired digestion or absorption of dietary fats and it can be caused by multiple diseases including cystic fibrosis, chronic pancreatitis, cholestatic liver disease, celiac disease, and inflammatory bowel disease. If untreated, fat malabsorption may result in malnutrition, growth failure, and deficiencies of fat-soluble vitamins A/E/D/K with resultant skin and visual changes, neurologic deficits, osteoporosis/rickets and coagulopathy. Currently the gold standard test to diagnose steatorrhea remains the fat balance study, which is based on the premise that fat intake minus fat output equals fat absorbed. This test is very time consuming as it requires a three to five day stool collection and complete dietary history. These limitations make this test impractical in the clinical setting and stress the need for a facile, accurate test of fat malabsorption. The development of a facile means to quantitative measure fat loss in the stool is urgently needed. Despite previous attempts to develop simpler methods than the 72 hour fecal fat collection method, none have proven to be easier and as reliable as the gold standard. In the current proposal, fat absorption will be measured by assessing stool behenic acid concentration in "spot stool" samples after giving a standardized dose will predictable correlate with fat absorption assessed using the quantitative measure of fat absorption in the gold standard, the 72 hour fecal fat collection in healthy control adults. The ratio of behenic acid in a "spot sample" of stool after ingestion of a known quantity of this fatty acid compared to total fatty acids in stool will be measured and compared to the results of absorption using behenic acid as a marker compared to the "gold standard," the 72 hour fecal fat collection method when subjects are treated with pancreatic enzymes compared to a period when they are receiving no pancreatic enzyme supplements.
Protocol #: 651 Correlation Between Small Intestinal Cholesterol Transporters and Measured Cholesterol Absorption in Humans
Studies undertaken by the investigators in the NIH funded Program Project Grant entitled "Molecular Basis of Cholesterol Absorption" have led to some valuable observations both in humans and animals. This work has included human studies of the effects of bile acids on cholesterol absorption and metabolism. Parallel animal studies have led to some interesting and important observations. These studies have suggested that gastric emptying and intestinal transit may influence cholesterol absorption. These observations have not been evaluated in humans. Work from other laboratories in animal models suggest that the ABC cassette transporter G5G8 and another transporter NPC1-L1 may play important roles in cholesterol export from the enterocyte and cholesterol import into the enterocyte, respectively. If these transporters are integral to the absorption of cholesterol, understanding the relationship between their expression and measured cholesterol absorption in humans would be extremely valuable. This study is designed to test the hypothesis that genetic heterogeneity in intestinal Abc g5/g8, NPCl-L1 and pancreatic triglyceride lipase (PTL) will impact cholesterol absorption and cholesterol fractional synthetic rates. We will measure Abcg5/g8, NCPC1-L1 mRNA and protein in intestinal mucosa from subjects in whom fractional cholesterol absorption and fractional cholesterol synthetic rates have been measured and assess relationships between each.
Protocol #: 669 Intralumenal Effects on Cholesterol Absorption/Synthesis
Cholesterol absorption plays a key role in cholesterol homeostasis and understanding the lumenal events that play key roles in absorption remain poorly understood. The aims of the present study are fourfold: 1) To determine whether previously observed effects on cholesterol absorption during bile acid feeding are related to changes in pool size and intestinal transit or meal stimulated gall bladder emptying or plasma cholecystokinin levels. 2) To determine the effect of dietary sphingomyelin on cholesterol absorption, micellar solubilization and synthesis in normal adults and to assess the effects of intraluminal cholesterol solubilization, absorption and synthesis in adults with heterozygous mdr 3 deficiency (a defect leading to low biliary phospholipid content). 3) To determine the mechanism of action of a non-ionic detergent, Pluronic F-68, by evaluating its effect on cholesterol solubilization and distribution between micelles and vesicles, on cholesterol absorption and synthesis. 4) To evaluate the intraluminal solubilization and distribution within micelles and vesicles of biliary compared to dietary cholesterol in humans and assess the impact of ezetimibe treatment on absorption of endogenous or exogenous cholesterol by assessing absorption of human contents in the biliary diverted, rat lymph fistula model. For each of these aims, subjects will be studied while consuming well-controlled diets as outpatients with a combination of human and animal techniques. Integration of animal/human techniques provide tools to characterize the role of modifications of the intraluminal environment on cholesterol solubilization and human cholesterol absorption and synthesis.
Protocol #: 690 Intralumenal Effects on Cholesterol Absorption/Synthesis
Cholesterol absorption plays a key role in cholesterol homeostasis and understanding the lumenal events that play key roles in absorption remain poorly understood. The aims of the present study are fourfold: 1) To determine whether previously observed effects on cholesterol absorption during bile acid feeding are related to changes in pool size and intestinal transit or meal stimulated gall bladder emptying or plasma cholecystokinin levels. 2) To determine the effect of dietary sphingomyelin on cholesterol absorption, micellar solubilization and synthesis in normal adults and to assess the effects of intraluminal cholesterol solubilization, absorption and synthesis in adults with heterozygous mdr 3 deficiency (a defect leading to low biliary phospholipid content). 3) To determine the mechanism of action of a non-ionic detergent, Pluronic F-68, by evaluating its effect on cholesterol solubilization and distribution between micelles and vesicles, on cholesterol absorption and synthesis. 4) To evaluate the intraluminal solubilization and distribution within micelles and vesicles of biliary compared to dietary cholesterol in humans and assess the impact of ezetimibe treatment on absorption of endogenous or exogenous cholesterol by assessing absorption of human contents in the biliary diverted, rat lymph fistula model. For each of these aims, subjects will be studied while consuming well-controlled diets as outpatients with a combination of human and animal techniques. Integration of animal/human techniques provide tools to characterize the role of modifications of the intraluminal environment on cholesterol solubilization and human cholesterol absorption and synthesis.
Stavra Xanthakos, MD stavra.xanthakos@cchmc.org
Protocol #: 598 Prevalence and Determinants of Non-Alcoholic Fatty Liver Disease in Young Adult Women
Increased body mass index (BMI) and the metabolic syndrome are risk factors for NAFLD in older adults. Childhood and adolescent determinants that predict increased risk of NAFLD in young adulthood have not been well-defined. Specific aims: 1.) To define the prevalence of hepatic steatosis in young adult females and 2.) to determine childhood and adolescent determinants of NAFLD in young adulthood. Central hypothesis: High visceral adiposity, high BMI, insulin resistance, and high dietary intake of saturated fat and carbohydrate in childhood and adolescence will increase the risk of NAFLD in young adulthood. Methods: 300 subjects will be recruited from a cohort of 623 black and white women (age 25-27) followed since the age of 9 -10 years as part of the NHLBI Growth and Health study. Exclusion criteria include weight; 300 pounds (MRI limitation), average alcohol intake; 20 gm/day, hepatotoxic medications, hepatitis B, C or autoimmune hepatitis. Liver function tests will be performed to screen for hepatic injury. Abdominal MRI images will be analyzed to measure degree of hepatic steatosis and visceral adiposity. Statistical analysis: Hepatic fat index will be analyzed both as a categorical and a continuous outcome using univariate and multiple variable regression analysis to evaluate correlations with blood pressure, BMI, total body fat, central adiposity, triglycerides, cholesterol and insulin resistance in childhood, adolescence and young adulthood.
Nada Yazigi, MD nada.yazigi@cchmc.org
Protocol #:536 Multi-Center Group Study of Acute Liver Failure
The objectives of this study include 1) a prospective collection of clinical and epidemiological data concerning acute liver failure and 2) the collection of serum and tissue samples on the same cohort of patients. These data will be used to analyze trends, to develop prognostic information, as well as to provide materials to investigators in this field. The overall aim is to provide a comprehensive approach to the study of acute liver failure and to impact significantly the outcome of patients in the United States with this life-threatening disease. All patients regardless of age, race or gender who present with acute liver failure and meet defined clinical criteria are eligible for enrollment in this Multi-center Acute Liver Failure (ALF) Study. Standardized admission and outcome data collection forms will be completed on all enrolled patients. Serum samples will be collected daily for the first 7 days following enrollment or until transplantation or death, whichever occurs first. Samples of liver tissue will be collected from clinically indicated biopsies, liver explants or autopsies. Serum and tissue will be shipped to the ALF Study Group central storage site in Dallas, TX.
Return to top General Clinical Research Center
Suzanne Summer,RD suzanne.summer@cchmc.org
Protocol #:704 Changes in Lifestyle and Health Status of Students During Medical School
Americans seek advice on health and disease prevention from their physicians, but such advice may be less effective if the doctors themselves do not follow it. Medical school is a time of great stress and challenge for students, and may bring about undesired changes to the lifestyle and health status of future doctors. The purpose of this study is to determine changes in lifestyle and health status of medical students during medical school. The study will be separated into two specific aims, and approximately 377 volunteers will be recruited. In Aim 1 of the study, we will assess changes in lifestyle and health by comparing results of several indicators measured in the first year and again in the fourth year of medical school. Indicators to be measured are: dietary intake, physical activity and fitness, blood pressure, body composition, fasting blood lipids and blood glucose, waist circumference, and body mass index (BMI). Aim 2 is a continuation of an ongoing study in which a subset of these indicators (body composition, blood lipids, and BMI) are already being measured in a group of medical students (n=177). All clinical procedures will take place in the General Clinical Research Center (GCRC) of Cincinnati Children's Hospital Medical Center (CCHMC). Because this is a descriptive study only, there will be no intervention involved and volunteers will not be randomized. The information gained from conducting this research study will help determine possible intervention and education needed to prevent decline of health status during medical school and beyond. Univariate statistics will be generated for each variable, including means, standard deviations, distributions, range, and skewness for each continuous variable. For categorical variables, frequencies will be computed. Paired-t-tests (Aims 1 and 2) and multiple linear regression (Aim 2) will be used to generate analytic statistics.
Return to top General & Community Pediatrics
Heidi J Kalkwarf, PhD heidi.kalkwarf@cchmc.org
Protocol #:584 Bone Mineral Density in Childhood Study (BMDCS)
The BMDCS is a 3-year longitudinal study of bone mass accretion in an ethnically diverse cohort of 1530 healthy children and adolescents between 6 and 16 years of age at enrollment. The goal of the BMDCS is to obtain pediatric standards for bone mineralization by dual energy x-ray absorptiometry (DXA) in relation to age, body size, skeletal development and sexual maturation. Longitudinal measures of bone mineralzation will be obtained so that normal ranges of bone mineral accrual through childhood and adolescence can be established. Subjects will be recruited over a 12-month period at five clinical centers in the U.S.: Columbia University, Children's Hospital of Philadelphia, Cincinnati Children's Hospital, Creighton University, and Children's Hospital, Los Angeles. Children will be enrolled in the study after a detailed screening to ensure that they have normal growth and maturation and are free of factors known to affect bone mineralization. Bone mass and density will be measured by DXA at baseline and then annually for three years. DXA scans will be obtained of the total body, left hip, lumbar spine and non-dominant forearm. A hand \endash wrist x-ray for bone age determination and detailed measurements of growth and pubertal maturation will be obtained in conjunction with the DXA measurements. Information on physical activity, dietary intake and general health also will be obtained at each visit.
Protocol #:594 Structural Effects of Renal Osteodystrophy During Growth
Renal osteodystrophy (ROD) is a multifactorial disorder of bone metabolism in individuals with renal insufficiency. As renal failure progresses, ensuing abnormal parathyroid hormone (PTH) secretion and calcium metabolism result in sclerosis of trabecular bone and thinning of cortical bone. During childhood and adolescence, skeletal growth is normally characterized by marked expansion of cortical dimensions and increases in trabecular density. Therefore, the growing skeleton may be particularly vulnerable to the structural effects of renal osteodystrophy. Underlying renal disorders associated with elevated systemic levels of inflammatory cytokines and renal therapies, such as glucocorticoids, also may impair bone accretion. Although the impact of these threats to normal bone development among children with renal failure is not fully known, they plausibly may lead to an irreversible failure to develop normal skeletal architecture and peak bone mass. Structural insufficiency may not regress even in the face of kidney transplantation, which reverses many of the metabolic effects of kidney failure that induce renal osteodystrophy. Unlike traditional densitometric measures of bone mass, peripheral quantitative computed tomography (pQCT) permits the discrete assessment of trabecular and cortical bone density and dimensions, and bone strength can be reliably estimated. Therefore, pQCT is an ideal tool to study the structural implications of renal osteodystrophy during growth. Accurate characterization of the structural bone deficits and the risk factors for impaired skeletal development in children with renal disease has not yet been performed and is the focus of this proposed investigation. The hypotheses are that (a) compared to normal controls, expansion of cortical bone volume is significantly impaired in children and adolescents with renal failure, resulting in substantial reduction of bone strength, (b) among children with renal disease, the magnitude and progression of the bone deficit is associated with poor growth and development, and with variability in the renal diseases (e.g., systemic inflammatory renal diseases) and therapies (e.g., glucocorticoids), and (c) the recovery and reconstitution of bone structure following renal transplantation is modulated by skeletal maturation at the time of transplantation, immunosuppressive therapies, rejection episodes, and allograft renal function. AIMS: 1. To perform a cross-sectional study of bone mass (dimensions, density, and strength) comparing children and adolescents with chronic renal failure to healthy controls and subsequently compare subgroups of children with chronic renal failure to identify predictors of decreased bone mass, such as the underlying renal disease, the severity of renal dysfunction, poor growth status, delayed skeletal bone age, decreased muscle strength, prior immunosuppressive therapies (e.g., glucocorticoids, cyclosporine), calcitriol therapy, and serum PTH levels. 2. To perform a longitudinal study of bone mineral accretion velocity (changes in dimensions, density, and strength) comparing healthy controls to each of three groups with renal disease: children with chronic renal failure, children on dialysis, and children following renal transplantation. 3. To compare dual energy x-ray absorptiometry (DXA) and pQCT in the assessment of skeletal structure and bone mineral accretion during childhood renal disease in order to demonstrate that the distinct effects of renal osteodystrophy on bone size and density are not well-characterized by DXA. 4. To determine if baseline levels of serum PTH and biomarkers of bone turnover can predict the subsequent pattern of growth and bone mineral accretion (changes in dimensions, density, and strength) over the follow-up interval among the chronic renal failure, dialysis, and transplantation subjects.
Protocol #: 694 Reference Values for Bone Mass and Density of Lumbar Spine for Children 6-36 Months of Age
Dual energy x-ray absorptiometry (DXA) is widely used to assess bone mass and density in children with chronic illnesses. Knowledge of the normal distribution of values of bone mineral content (BMC) and bone mineral density (BMD) in healthy children is necessary in order to evaluate bone health in children with chronic disease. The aim of this project is to obtain a set of reference data on BMC and BMD of the lumbar spine from children between the ages of 6 to 36 months. Two hundred infants and children, 6-36 months of age, will be recruited for this cross sectional study. The Hologic QDR 4500 densitometer will be used to obtain measurements of BMC and BMD of the lumbar spine. Body weight and length also will be measured. BMC and BMD reference curves that describe the BMC and BMD at specific percentiles for age will be generated.
Karen Wosje, PhD karen.wosje@cchmc.org
Protocol #: 638 Least significant changes in fat and lean mass by dual energy x-ray absorptiometry in obese children and adolescents.
Methods for determining the composition of weight lost as the result of exercise, nutrition, behavioral, and/or surgical interventions in obese children and adolescents are needed in order to monitor progress and to ensure adequate lean mass preservation. The purpose of this study is to determine the precision (i.e., reproducibility) of whole body fat mass and lean mass measurements in obese children and adolescents using dual energy x-ray absorptiometry (DXA, Hologic QDR 4500). Precision estimates will be used to calculate least significant changes between two measurements on a single subject. Least significant changes, expressed in kilograms or as percentages, can be used by clinicians monitoring weight loss in obese children and adolescents to determine if changes in fat or lean mass are "real" or are within the precision error of the DXA technique. Our first objective is to provide clinicians with a simple reference chart and an explanatory written guideline describing the amounts of fat and lean mass loss or gain that can be considered as real for obese children and adolescents. Our second objective is to test the hypothesis that precision error estimates within individuals increase with increasing abdominal tissue thickness, i.e., there is a positive relationship between precision errors for individual subjects and abdominal tissue thicknesses.
Return to top Hematology Research
Franklin Smith, MD franklin.smith@cchmc.org
Protocol #: 623 Oxandrolone for the Treatment of Bone Marrow Aplasia in Patients with Fanconi anemia (IND # 67,936)
This research study will primarily evaluate the safety of the drug oxandrolone in patients with Fanconi anemia (FA), and secondarily determine if this drug can help in the treatment of bone marrow failure in these patients. It is hoped that oxandrolone will have less side effects than oxymetholone, the androgen used most frequently in the short-term treatment of bone marrow failure in FA patients. Subjects will be enrolled for approximately 18 to 30 months (12 - 24 months of treatment and 6 months additional monitoring). The oxandrolone starting dose is 0.04mg/kg/day. Study monitoring includes weekly complete blood counts, monthly serum chemistry labs, quarterly physical examinations including virilization exams and liver ultrasounds. Semi-annually, hand radiographs are obtained for bone maturation and behavioral assessments are conducted to detect any aggressive behavior or mood changes. If no improvement n the subject's blood counts are noted after 4 months of therapy, the dose will be increased to 0.08mg/kg/day for a period of 4 more months. If no improvement is noted after a total of eight months, oxandrolone will be discontinued. If the blood counts show improvement, then the drug will continue for a minimum of twelve months. Subjects may remain on study and receive a total of 24 months of therapy if they have a response in their blood counts without unacceptable side effects. Post-treatment monitoring includes blood work and ultrasound every three months, and hand radiograph at six months.
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Hematology/Oncology
Karen Kalinyak, MD karen.kalinyak@cchmc.org
Protocol #:445 Dipyridamole/Magnesium to Improve Sickle Cell Hydration
This is a multi-center trial recruiting both adults and pediatrics with sickle cell anemia (SCA). The overall goal of this study is to determine the benefits and risks of treating patients with SCA with oral dipyridamole, oral magnesium or a combination of both drugs. While they operate by blocking different pathways, both dipyridamole and magnesium appear to block or reduce the formation of dense erythrocytes (RBC) that drive the pathophysiology of vaso-occlusion in patients with SCA. Our proposed study will focus on the following aims and hypotheses: assessing effects on red cell hydration, assessing effects on red cell survival, determining side effects and evaluating clinical outcomes such as correlation between red cell hydration effects and the clinical course of the patients. This study consists of two parts: Part I, is a phase II randomized, double blind treatment study which primary endpoint is to measure red cell hydration and Part II is a randomized, clinical trial between group comparisons with the primary endpoint being red cell survival (biotin label technique). The sample size will consist of forty eight patients enrolled in Part I and eighteen patients will be recruited for Part II. The patients in Part II do not have to have participated in Part I.
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Human Genetics
Gregory A Grabowski, MD greg.grabowski@cchmc.org
Protocol #:545 Studies of Gaucher Disease: A Prototype Lipidosis
The overall objective of the proposed research is to elucidate the molecular mechanisms leading to the remarkable phenotypic variability in Gaucher disease, a prototype inborn error of metabolism. Gaucher disease is due to the deficiency of acid-glucosidase, a lysosomal enzyme encoded by the GBA locus. Two hypotheses to be addressed in these investigations include: 1) that polymorphic variations at the GBA locus in conjunction with known disease-related mutations lead to phenotypic variability of GC and to altered expression of mutan enzymes from this locus. 2) The in vivo activity levels of enzymes in inborn errors of metabolism, with GD as a prototype, is a primary determinant of their regional, tissue or cellular pathophysiology.
Nancy Leslie, MD nancy.leslie@cchmc.org
Protocol #: 607a Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Recombinant Human Acid alpha-Glucosidase Treatment in Patients > 6 and < 36 Months Old
The purpose of this study is to learn about the safety and effectiveness of a new drug, called Myozyme, used to treat infantile-onset Pompe disease. In infantile Pompe Disease, too much glycogen builds up and is stored in certain body tissues, especially heart, skeletal muscle, and liver tissues. This prevents the tissues from performing their normal functions. This causes the heart to enlarge (cardiomegaly) and its walls to thicken (hypertrophic cardiomyopathy), which causes less pumping of blood (heart failure). Every 2 weeks, 16 patients worldwide will be given an intravenous infusion (IV) of Myozyme, the enzyme that is missing in the bodies of persons with Pompe disease. The children will be followed closely to see how the disease and the study medicine affects the body, health, and the child's ability to grow and develop motor skills.
Protocol #:621 Iduronate-2-Sulfatase Replacement Therapy in Mucopolysaccharidosis II
This study examines the safety of long-term use of enzyme replacement therapy (replacing the enzyme that, when missing, causes the disease) for MPSII. If proven safe, this drug has the possibility of greatly improving the health and quality of life of all individuals affected with Mucopolysaccharidosis type II (MPS II), a disease for which there is currently no cure. The study design allows patients who successfully completed the phase I/II trial to continue to receive treatment with enzyme replacement therapy, and for patients who had received placebo in the previous trial to cross-over and receive enzyme replacement therapy.
Richard J Wenstrup, MD richard.wenstrup@cchmc.org
Protocol #:591 Trial of Alendronate Disodium in Pediatric Gaucher Disease
The purpose of this study is to determine whether osteopenia and growth retardation observed in most children with Gaucher disease can be corrected by the addition of Fosamax to the existing enzyme replacement therapy. To do so, a double blind, two-arm controlled trial of alendronate will be conducted on children with Gaucher disease who have received at least 18 months of regular enzyme therapy with Cerezyme. This study will be conducted with anl initial three week single blind trial period to evaluate compliance, after which a 1:1 drug:placebo randomization will occur. At the end of the 18 month double blind placebo phase, there will be a 12 month open label extension to evaluate longer-term safety and efficacy. Ninety patients between 6 and 18 years of age who are receiving enzyme therapy will be randomized to receive alendronate or placebo for 18 months. Therapeutic outcome will primarily be monitored by measurement of bone density at the lumbar spine and total body. Changes in weight and height will be assessed with measurements being taken at the time of entry into the study and at 6 month intervals for 18 months and again at 30 months. Skeletal maturation, sexual maturity and responses to a pediatric quality of life questionnaire will also be evaluated. The successful outcome of these studies may lead to new therapeutic regimens for Gaucher disease that control or reverse osteopenia in children, and may lead to more effective preventive interventions for the pediatric and adult Gaucher bone disease.
Protocol #: 620 Intravenous Zoledronic Acid Compared to Intravenous Pamidronate in Children with Severe Osteogenesis Imperfecta
This study compares the safety and effectiveness of two medications in children with severe osteogenesis imperfecta. Children between 1 and 17 years of age who have types III and IV osteogenesis, or who have type I osteogenesis with a history of 3 or more minimal trauma fractures in the past two years or a history of limb deformity requiring surgery are eligible. One of the medications, pamidronate, has already been shown to reduce fractures in osteogenesis imperfecta. Aledronate is a new drug of the same type as pamidronate, but it is more powerful and may be a good alternative if it is effective and safe. This study is the first time zoledronate is being used in children with osteogenesis imperfecta. This study lasts for 13 months and includes 10-15 visits. Children are treated with one of the study drugs at either 2 month or 3 month intervals during that year. Physical exams, blood and urine studies, x-rays and bone density measurements are made throughout the study. In addition to the study medication, children take multivitamins and calcium supplements. This is an international, multi-center study, and 136 children will be treated, study-wide. Half of the children will receive treatment with pamidronate and half will receive treatment with zoledronate. Some children who receive zoledronate will have additional lab work to study the pharmacokinetics (processing by the body) of this drug in children.
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Mass Spectrometry Laboratory
Kenneth Setchell, PhD kenneth.setchell@cchmc.org
Protocol #: 675a The Soy Isoflavone Metabolite Equol: It's Formation and Fate (Aim 1)
Equol is an important metabolite made in the body when soy is eaten. It is made by intestinal bacteria and not found in the urine and blood of infants before 4-months of age. We will determine when equol first appears in early life and whether it is breast feeding, cows milk formula or soy formula, or the composition of the post-weaning diet that predispose to the production of equol. Breast-feeding leads to differences in intestinal bacterial colonization and a lower pH compared with bottle-feeding, and this is expected to facilitate equol formation. In adults we will examine three broad dietary groups- those consuming low, medium and high fiber as determined by a validated diet history questionnaire, to determine the role of adult diet in predisposition to make equol. We will also determine the pharmacokinetics of equol formation, and the long-term stability of equol-production in adults and its response to antibiotic use. For unknown reasons only one-third of adults consuming soy foods make equol. Recent studies of osteoporosis prevention, cardiovascular health, and menopause have shown that beneficial effects from soy foods are significantly greater in people who are 'equol-producers' compared with those unable to make equol. Since there are advantages to being an equol-producer it is important to understand the factors governing equol production. Given the clinical relevance of equol a greater understanding of factors governing its production is essential. This will facilitate future strategies to manipulate equol production and enhance the overall clinical effectiveness of soy foods.
Protocol #: 675b The Soy Isoflavone Metabolite Equol: It's Formation and Fate (Aim 2)
Equol, a non-steroidal estrogen of the isoflavone class, is the most important metabolite of ingested soy isoflavones. It is made by intestinal bacteria from the isoflavone daidzein, and not found in the urine and blood of infants before 4-months of age. For unknown reasons daidzein's conversion to equol is variable in adults consuming soy foods and seems diet related. Recent studies of osteoporosis prevention, cardiovascular health, and menopause have shown that beneficial effects from soy foods are significantly greater in people who are 'equol-producers' compared with those unable to make equol, and it is now realized that these two distinct populations need defining in dietary intervention studies. Equol exists in two enantiomeric forms, R-equol and S-equol, and we have shown that S-equol has a high affinity for estrogen receptor ER-beta and shows negligible binding to ER-alpha. R-equol on the other-hand has potent anti-androgen properties, antagonizing the actions of dihydrotestosterone, making it of pharmacological interest. For the first time, the pharmacokinetics of S- and R-equol will be determined. Our aim is to prove that S-equol occurs in human plasma and urine not because of differences in the absorption of the two enantiomers, but due to bacterial enantiomeric-specific formation. Since there are advantages to being an equol-producer it is important to understand the factors governing equol production.
We will determine when equol first appears in early life and whether it is differences in the type of early infant nutrition, or the composition of the post-weaning diet that predispose to the production of equol (Aim 1). Breast-feeding leads to differences in intestinal bacterial colonization and a lower pH compared with bottle-feeding, and this is expected to facilitate equol formation. Preliminary in vitro and human data suggest higher intakes of certain prebiotic macronutrients conducive to colonic fermentation favor equol formation. This will be determined by comparing equol-production in healthy adults relative to their dietary intakes of macronutrients using fiber intake determined from food frequency questionnaire and 3-day diet records to stratify groups (Aim 2). We will determine the long-term stability of equol-production in adults and its response to antibiotic use (Aim 3). Also, we will determine the metabolism and pharmacokinetics of R-equol and S-equol in subjects taking a single oral bolus dose (Aim 4). Given the clinical relevance of equol, a greater understanding of factors governing its production will facilitate future strategies to manipulate equol production and enhance the overall clinical effectiveness of soy foods.
Return to top Nephrology
John J Bissler, MD john.bissler@cchmc.org
Protocol #:614 Rapamycin Therapy of Renal Angiomyolipomas in Patients with Tuberous Sclerosis Complex and Sporadic Lymphangieomyomatosis
Approximately one out of 5,000 individuals has tuberous sclerosis complex (TSC), representing approximately 56,000 patients in the United States and 1 million patients worldwide. This disease process does not cluster in ethnic groups and has no gender predilection. Renal failure has been reported to be the leading cause of death in adult tuberous sclerosis patients, in most cases due to replacement of healthy kidney tissue by fatty tumors called angiomyolipomas. Approximately 40% of female patients with TSC also develop a pulmonary disease called lymphangioleiomyomatosis (LAM). LAM is characterized by smooth muscle cell infiltration in the lungs leading to cystic degeneration of lung tissue, impaired gas exchange, respiratory failure and death. There is recent evidence that LAM may be caused by metastases of angiomyolipoma cells to the lung. Angiomyolipoma cells are uniquely vulnerable to treatments that select for the presence of the correct gene product from the TSC genes. The gene products of TSC1, hamartin, and TSC2, tuberin, are key players in a pathway that regulates cell growth. Rapamycin mimics the function of the tuberin/hamartin complex, which is dysfunctional in TSC. Rapamycin inhibits the growth of tuberin and hamartin deficient cells from humans, rats, mice and flies, and produces tumor regression in rats and mice. Thus, the aim of this study is to determine if the administration of Rapamycin can reduce or eliminate angiomyolipomas in patients with TSC and sporadic LAM as it does in human cell culture and animal models.
Protocol #:665 RAD001 Therapy of Angiomyolipomata in Patients with Tuberous Sclerosis Complex and Sporadic Lymphangioleiomyomatosis
Targeted molecular therapy is the ultimate objective for the management of malignancy, but only a few examples exist, due in large part to the complexity of genetic events that result in unregulated cell growth. Tuberous sclerosis is an inherited cancer syndrome associated with the formation of hamartomas in multiple organs, including angiomyolipomas in the kidney, caused by well-characterized inactivating mutations at genetic loci that encode the interacting proteins, tuberin or hamartin. Recent studies have elucidated the pivotal role of the tuberin/hamartin complex in controlling the Akt signaling pathway that regulates cell growth and division. The objective of this study is to determine if an mTOR inhibitor reduces the volume of angiomyolipomas. This goal will be accomplished by treatment of thirty patients with angiomyolipomas, either in the setting of tuberous sclerosis, or a related disease associated with mutations in tuberous sclerosis genes called sporadic lymphangioleiomyomatosis, with dose-adjusted RAD001 for a period of one year. The size, number, volume and tissue composition of renal angiomyolipomas will be monitored by MRI or CT scans of the kidney, performed prior to treatment, at six months, one and two years. The dose of RAD 001 will be modified to see if there is a threshold does that leads to apoptosis versus a mere cell volume change.
Mark Mitsnefes, MD mark.mitsnefes@cchmc.org
Protocol #:552 Vascular Abnormalities in Children and Adolescents with Chronic Renal Disease
Project 1: Cardiac disease in children with chronic renal failure IK23 HL69296-01A1
Cardiovascular disease (CVD) is the leading cause of death in adult and pediatric patients with end-stage renal disease (ESRD). Cardiovascular changes are frequently present in children with advanced renal failure. Left ventricular hypertrophy (LVH) is already highly prevalent in children at the initiation of chronic dialysis therapy, and remains prevalent during long-term dialysis and after renal transplantation. Exactly when these abnormalities first appear in the course of renal failure is not known. The fact that LVH is already prevalent at the time of entry to chronic dialysis strongly indicates that abnormalities develop during early chronic renal insufficiency (CRI). We also postulate that in addition to LVH, pediatric patients with CRI develop abnormalities of function as well as vascular abnormalities. The hypothesis underlying the proposal is that cardiovascular changes occur in children with relatively mild CRI, and progress as end-stage disease approaches. To test this concept, we will assess cardiac and vascular abnormalities and identify risk factors for these abnormalities in pediatric patients with CRI. Specifically, we will examine: 1. Cardiac structure by evaluation of LV mass, LV geometry; 2. LV systolic and diastolic function using rest and stress echocardiography; 3. Vascular structure by assessment of carotid artery intima-media thickness (IMT); 4. Vascular function by assesment of endothelium-mediated vasodilatation of the brachial artery using high-resolution B-mode ultrasound. In addition, we will determine the role of blood pressure by ambulatory blood pressure monitoring, anemia, etiology and rate of progression of CRI, hyperlipidemia and hyperhomocysteinemia as possible risk factors for cardiac or vascular abnormalities and assess the changes of cardiovascular structure and function by repeating the evaluation 2 years after initial examination. Evaluation of the relationships between LV structure, LV function, carotid IMT and endothelial function will help to gather the important information needed for future mechanistic studies of development of cardiovascular disease in children with CRI. By understanding the risk factors and temporal evolution by which cardiovascular abnormalities develop in these patients, we may then be able to develop and test preventive interventions. It is possible that mild-to-moderate CRI is the optimal time during which identification of modifiable risk factors and early intervention might lead to elective treatment and even to prevention of cardiac disease over the long term. Thus, the long-term goal will be to decrease the incidence and prevalence of cardiovascular disease in young adults who developed chronic renal disease during childhood.
Project 2: Cardiovascular abnormalities in children and adolescents with renal transplantation AHA #0160214B
Our research is aimed at understanding how cardiovascular disease develops and progresses in children and adolescents with renal transplantation. In particular, we are trying to show that even after successful renal transplantation these patients present with abnormalities of heart structure and function as well as abnormalities of large blood vessels. Recently we showed high frequency of left ventricular hypertrophy (increased size of the left pumping chamber of the heart) in children on chronic dialysis and after transplantation. Since some of the risk factors and mechanisms for the development of heart hypertrophy and blood vessels injury are similar, it is likely that vascular damage such as increased thickness and stiffness of the blood vessel wall are present in children after renal transplantation. We will evaluate cardiovascular structure and function by applying non-invasive methodologies such as rest and stress echocardiography (ultrasound of the heart) as well as high resolution B-mode ultrasound of the blood vessels. We will also evaluate blood pressure using ambulatory blood pressure monitoring, anemia, lipid abnormalities and abnormal blood viscosity as possible risk factors for cardiac or vascular abnormalities. It is hoped that the mechanisms by which cardiovascular disease develops in children and adolescents with renal transplantation will be better understood as a result of this proposal.
Protocol #:619 Ambulatory Blood Pressure Monitoring and End Organ Damage in Children and Young Adults with Renal Transplantation
Recent studies showed that nighttime hypertension as determined by ambulatory BP monitoring (ABPM) occurs almost universally in both adults and children after renal transplantation (Tx). We hypothesize that after renal Tx, increased nighttime BP in children who had normal office BP, will be associated with hypertension-related end-organ damage such as increased left ventricular mass (LVM), increased arterial stiffness and decreased kidney function. If nighttime BP is a better predictor of target organ damage than office BP, the use of ABPM would detect patients at risk and provide the rational guideline for therapy. To test this concept, we will assess in children with renal Tx cardiovascular structure and function and allograft function at baseline and after one year. Cardiac structure will be evaluated by measurement of LVM, vascular structure and function by measurement of carotid artery intima-media thickness (IMT) and allograft function by measurement of glomerular filtration rate (GFR). These measurements will be correlated with multiple variables, the most important of which will be daytime and nighttime BP as measured by ABPM. Hypertension is a strong and independent risk factor for poor long-term outcome in adults and children with renal Tx. It is hoped that improved detection of hypertension by 24-hour ABPM, especially nighttime hypertension, will lead to more effective treatment which will prevent or slow the progression of cardiac disease and allograft dysfunction. Thus, the long-term goal will be to decrease the incidence and prevalence of cardiovascular disease and delay graft failure in children and young adults with renal Tx.
C. Frederic Strife, MD frederic.strife@cchmc.org
Protocol #:558 Evaluation of the Impact of Normalization of Hematocrit in Pediatric Patients with Chronic Renal Failure
Anemia is a major complication associated with chronic renal (kidney) failure. Prior studies have shown that anemia in children with chronic renal failure may cause decreased school performance. This anemia can be treated with recombinant human erythropoetin (r-HU EPO). Current standards will allow for the correction of anemia to a goal hematocrit of between 33-36%. Normal hematocrit levels for children range from 40-44%. Our hypothesis is that the normalization of hematocrit, by increasing the r-HU EPO dose described, will improve cognitive functioning. Anemic pediatric patients between the ages of 6-19 years with chronic renal failure will have formal cognitive functioning studies administered. These studies include a Wechsler intelligence score to test intelligence, Digit Span to test memory, and Continuous Performance Test to measure vigilance. These studies will be conducted when the patient has a hematocrit of 30% or less, when the patient's hematocrit has been raised to 33-36% and once again when it has been raised to 40-44%. Each patient will be kept stable at the respective hematocrits for three months in order to establish stabilization of the hematocrit. Hematocrit levels will be monitored on a monthly level as part of routine medical care. Iron levels will also be obtained upon enrollment into the study to eliminate iron deficiency as a contributor to the anemia. In order to eliminate test familiarity as a factor in the results, control patients will be patients with chronic renal failure without anemia, so the patients do not have the need for r-HU EPO therapy.
Protocol #:656 Chronic Kidney Disease in Children
The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung and Blood Institute (NHLBI) funded a cooperative agreement to conduct a prospective epidemiological study of children with chronic kidney disease (CKD). The primary goals of this study are to determine the risk factors for decline in kidney function and to define how a progressive decline in kidney function impacts neurocognitive function and behavior; the risk factors for cardiovascular disease; and growth failure and its associated morbidity. The specific aims are:Identify novel and traditional renal disease risk factors for the progression of CKD (e.g. decline of GFR) in children; Characterize the impact of a decline in kidney function on neurodevelopment, cognitive abilities, and behavior; Identify the prevalence and evolution of traditional and novel cardiovascular disease risk factors in progressive CKD; and Examine the effects of declining GFR on growth and the treatment of growth failure, and to assess the consequences of growth failure on morbidity in children with CKD. Children 1 to 16 years old (before 17 birthday) with mild to moderate CKD will be recruited for this study. About 540 children will be in this study at 57 different sites around the country. About 20 children will be asked to be in this study at Cincinnati Children's Hospital Medical Center.
Protocol #:686 Novel Therapies for Resistant FSGS
Primary focal segmental glomerulosclerosis (FSGS) is a serious renal disease, accounting for nearly 10-15% of all pediatric and adult patients requiring chronic dialysis or transplantation. The etiology of FSGS remains obscure and there is no proven therapy. The current management of primary FSGS is predicated on the assumption that the disease is caused by an immune-mediated disturbance in glomerular barrier function. Therefore, most treatment protocols include immunosuppressive drugs given singly or in combination. However, the efficacy of this type of therapy has been disappointing and the long-term prognosis for renal survival in patients with FSGS resistant to immunosuppressives is poor. An alternative approach targets the fibrosis pathway and may represent a novel approach to the treatment of immunosuppressant-drug resistant FSGS. This proposal will evaluate the safety and efficacy of two novel agents that may have the capacity to reduce renal fibrosis and slow the rate of deterioration of disease in patients with resistant FSGS. This proposal is a phase I study to test the safety, tolerance, and pharmacokinetic profile of a tumor necrosis factor- antagonist and a peroxisome proliferator activator receptor-agonist.
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Neurodiagnostics
Mark Schapiro, MD mark.schapiro@cchmc.org
Protocol #:666 Language Processing Studies with Functional Resonance Imaging in Persons with Down Syndrome
Multiple FMRI paradigms have been developed to study language processing in healthy normal subjects; however few, if any, exist to study language in developmentally delayed populations. Persons with Down syndrome (DS) exhibit disproportionate language deficits relative to their level of cognitive impairment, with syntax comprehension most affected. We report on differences in patterns of language activation for semantic classification and syntactic language tasks in persons with DS compared to healthy controls. METHODS: Eleven healthy persons with trisomy 21 DS (M 6;F 5) and 12 healthy controls matched for sex and age (M 5;F 7) completed FMRI scanning with syntactic and semantic paradigms developed to elicit suitable performance from both developmentally delayed and normal populations. Ages ranged from 12 -23 years. The semantic classification paradigm involved visual presentation of animals; subjects pressed a button if the animal lived on a farm. Control epochs consisted of abstract images; subjects pressed a button upon presentation. The syntax paradigm involved visual presentation of both aspects of a reversible situation. Subjects heard a sentence describing one picture, e.g. "The cat is chasing the dog". For the control epoch, subjects were shown two pictures; the name of one picture was repeated four times e.g. "dog, dog, dog, dog". Subjects pressed a button indicating the picture matching the auditory stimuli. FMRI scans were acquired on a Bruker 3T scanner using a T2* weighted gradient echo EPI sequence (TR = 3000 ms, TE = 38 ms). Composite activation maps based on random effects analysis were created for both groups. RESULTS: Behavioral data demonstrated adequate performance in both persons with DS and healthy controls. Semantic classification: Activation of inferior frontal gyrus (BA 47, 45/44) was bilateral (L>R) in controls, but right-sided in the DS group. Both DS and control subjects showed bilateral activation (L>R) in middle frontal gyrus (BA 46).Syntax: Activation of inferior frontal gyrus (BA 44/45 only) was again bilateral (L>R) in controls, however activation in the DS group was left-sided. Unlike the semantic classification task, no inferior activation representing BA 47 was seen in either group. Both DS and control subjects showed bilateral activation in middle frontal gyrus (BA 46); areas of activation were slightly asymmetrical (anterior-posterior) for both groups.
Return to top Neurology
Tracy Glauser, MD tracy.glauser@cchmc.org
Protocol #:646 Childhood Absence Epilepsy RX, PK, PD Pharmacogenetics
Childhood Absence Epilepsy (CAE), a common pediatric epilepsy syndrome affecting 10-15% of all children with epilepsy, and the basis for the inter-individual variation in response to therapy, has not been defined. Commonly misperceived as a benign epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, and demonstrate long-term psychosocial difficulties. The objectives of this proposal are 1) to identify the anti-epileptic drug (AED) that produces and sustains the highest rate of seizure control coupled with the lowest incidence of treatment limiting toxicity for children with CAE, and 2) to determine the pharmacogenetic and non-heritable factors underlying the inter-individual variation in AED efficacy and toxicity. randomized, double blind comparative trial of ethosuximide (ETX), lamotrigine (LTG) and valproate (VPA) as initial monotherapy will be performed in children with CAE utilizing freedom from failure rate as the primary endpoint. Twenty sites in the U.S. will enroll 473 children, 2- 13 years of age, over a 3-year period. Treatment success will be defined as a composite of seizure control and short and long-term tolerability. Each AED's impact on cognition (especially attention), behavior, and quality of life will be studied. Each patient's epilepsy syndrome will be extensively phenotyped with video EEGs. Individual systemic drug exposures, determined using a population pharmacokinetic (pK) approach, will define the impact of interpatient variability in drug disposition on AED efficacy and toxicity, and will be utilized in pharmacogenetic (pG) correlative studies of select drug metabolizing enzymes. The role of polymorphic variation in the genes coding for the subunits of the T type calcium channels in response to therapy will be investigated. Factors potentially predictive for the most common treatment limitations of each AED will be studied, including the pG, pK and clinical profiles of patients developing LTG associated rash, VPA induced weight gain or evidence of impaired neurocognitive skills (potential limitation of all AEDs). This study will determine the AED that provides for the greatest likelihood of seizure control coupled with the best short and long term tolerability. By comprehensively defining the phenotypic spectrum of absence seizures along with pG and non-heritable factors that underlie interpatient variability in AED response, this proposal will form the foundation of a pharmacologically rational approach to syndrome based AED therapy. Knowledge gained by this study will lead to individualized treatment for children with CAE that can be generalized to other pediatric and adult seizure disorders.
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Nutritional Sciences- UC
Grace A Faciglia, PhD grace.faciglia@uc.edu
Protocol #: 649 Effects of High Protein, Low Carbohydrate Diet on Acid-Base Balance: A Pilot Study to Examine the Potential Differences in Older Compared to Younger Adults
Although it has been established that high-protein diets result in the generation of excess acid load and that the kidney's ability to eliminate that excess acid is reduced as a consequence of aging, the effects of high-protein diets on systemic acid base balance in older populations have not been studied. The purpose of this study is to examine the effects of a high-protein, low-carbohydrate diet on acid-base balance and renal calcium excretion in older (aged 55-70) compared to younger (aged 25-40) adults. A total of 24 healthy subjects (12 older and 12 younger) will participate in this 6-week feeding study. This crossover study design consists of two cycles, both of which are comprised of a 2-week "washout" (usual) diet followed by a 1-week experimental diet, either high or low in protein (2.0 or 0.5 g protein/Kg body weight). During the washout period the subjects will consume and record their self-selected usual diet. During the experimental diet the subjects will consume the metabolic meals provided to them. The fat, calcium, phosphorous, sodium, and potassium content of the diet will remain the same while only protein and carbohydrate content varies. Fasting blood and urine samples and 24-hour urine samples will be collected a total of four times over the course of the study. Differences in acid excretion, serum acidity, and calcium excretion as a function of age and in response to the high-protein, low-protein, and usual diet will be compared and analyzed using an Analysis of Covariance.
Return to top Psychiatry- UC
Erik B Nelson, MD erik.nelson@uc.edu
Protocol #: 580 Hypothalamic-Pituitary-Adrenal Axis Dysregulation and Phenomenology of Major Depression
Studies suggest that hypothalamic-pituitary-adrenal (HPA) axis dysregulation influences the presentation of depression related to specific groups of symptoms. A better understanding of the mechanisms underlying these differences could lead to novel targets for the treatment of depression, and help to explain variability among previous studies that typically included subjects with varying symptoms of depression. This study is designed to assess HPA activity and measures of acute stress responses in healthy volunteers and depressed patients as they relate to specific groups of symptoms. The hypothesis is that elevated HPA axis activity in depression is associated with insomnia, loss of appetite/weight loss, and anxiety, whereas low HPA activity is linked with fatigue, increased appetite/weight gain and lack of energy. Moreover, increased HPA activity, symptoms of insomnia, loss of appetite/weight loss and anxiety are hypothesized to correlate with a greater response to stress, whereas low HPA activity and symptoms of fatigue, increased appetite/weight gain and lack of energy are hypothesized to correlate with a decreased response to stress. These hypotheses will be tested by collection of stress hormones in the blood, urine and saliva during three separate conditions; baseline, following a diagnostic test using two FDA approved medications, and in response to a social stress test.
Return to top Psychology
Robert T Ammerman, PhD robert.ammerman@cchmc.org
Protocol #: 551 Neuropsychological Functioning and Psychosocial Adjustment in Adolescents with Spina Bifida and NLD
Adolescents with spina bifida exhibit a variety of neurocognitive deficits that are thought to impact psychosocial adjustment. It is believed that up to 40% and 50% have neuropsychological impairments indicative of nonverbal learning disability (NLD), which in turn is strongly associated with poor social adjustment and internalizing behavior problems (e.g., depression). In general, adolescents with spina bifida display problems in behavioral, social, and personality adjustment, although there is considerable variability in this population. This study (entitled the Learning and Development Project) is examining the relationship between type and severity of neuropsychological impairment, in particular the NLD profile, and psychosocial functioning in adolescents with spina bifida. Specifically, 160 adolescents with spina bifida between the ages of 10-17 years and their families are being recruited. They are divided equally between those with and without NLD using specific criteria. Adolescents are divided equally between four age groups (10-12, 12-14, 14-16, 16-17 years) and by gender. At baseline, adolescents complete a comprehensive neuropsychological battery, which will be used to create the two groups and more fully elucidate the NLD profile. At this time, parents and adolescents also complete several measures of the child's psychosocial functioning and family adjustment. Eighteen months later, they receive a follow-up assessment measuring behavioral, social, and personality functioning. At both assessment points, the adolescent's teacher completes several measures of psychosocial functioning. A third group of 75 adolescents with NLD, but without spina bifida or hydrocephalus, is also being recruited and administered the same protocol at each time point. Finally, a fourth group of 75 adolescents without NLD or spina bifida or hydrocephalus, is being recruited to serve as controls. Primary goals of the study are to (1) contrast the four groups to identify differential patterns of psychosocial maladjustment at different points in adolescent development, (2) determine the predictive utility of the NLD profile to subsequent psychosocial functioning, and to determine if psychosocial problems increase with age in those with NLD, and (3) test whether family functioning moderates the association between neuropsychological impairment and psychosocial adjustment. Results from this study will elucidate causal relationships between neuropsychological impairment and psychosocial functioning in adolescents with spina bifida, delineate risk factors that will contribute to early identification and the design of more effective interventions, and reveal patterns of psychosocial functioning across age in adolescence.
Dean Beebe, PhD dean.beebe@cchmc.org
Protocol #: 605a The Neurobehavioral Effects of Obstructive Sleep Apnea among Obese Teens and Preteens
Occurring in 1-3% of the general population, Obstructive Sleep Apnea (OSA) has been associated with daytime cognitive and behavioral deficits ("neurobehavioral deficits") in young children and in older adults. Little is known about the effect of OSA in adolescents, who differ from these groups in neurodevelopment, sleep behaviors and social context. Adolescents are also unique from a treatment perspective, because OSA treatment for them typically requires patient adherence, yet they often display poor adherence to medical directives. Within this population, obesity is a major risk factor for OSA. Even so, little is known about the nature or reversibility of the neurobehavioral deficits associated with OSA among obese teens and preteens. This study will test the hypothesis that OSA among obese teens and preteens is associated with neurobehavioral morbidity. This will be accomplished via examination of data from 200 obese participants, each of whom will undergo comprehensive evaluations of sleep and neurobehavioral functioning. A comparison group of 20-25 lean adolescents will also be assessed. The study will further determine the immediate and long-term neurobehavioral effect of a non-surgical airway treatment, continuous positive airway pressure (CPAP), on obese adolescents with OSA. A subgroup of obese adolescents with OSA will be followed as they receive clinical CPAP treatment, then compared to a matched subgroup without OSA who are not receiving an airway treatment. Upon completion, the study will clarify the relationships between sleep and neurobehavioral functioning in an understudied high-risk group, and to inform detection and treatment of OSA in this population.
Protocol #: 605bThe Sleep and Neurobehavioral Features of Health in Preteens and Teens: A Comparison Group for Obese Subjects
This study is observational, examining the effects of a medical condition on the cognitive and behavioral functioning of children. A small subgroup of children with obstructive sleep apnea will be followed over time to investigate whether cognitive or behavioral changes are observed following treatment that was prescribed on a clinical(not research) basis.
Lori Crosby, PsyD lori.crosby@cchmc.org
Protocol #: 668 Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adult Patients with Sickle Cell Disease
The purpose of this research study is to determine the extent of memory and attention problems in adults with sickle cell disease. Neurologically intact adult patient's ages 21-55 years will be enrolled. That is adults who have not experienced a stroke or other brain damage. The study will also evaluate the link between these events or conditions and abnormal MRI. These findings will be compared to healthy people with similar backgrounds. The primary objective is to determine the extent of neurocognitive dysfunction in neurologically asymptomatic adult patients with sickle cell disease. The secondary objective to determine the association between neurocognitive dysfunction and imaging abnormalities. This is a cross-sectional investigation trial designed to compare neuropsychological function of adult neurologically normal Hb SS/SB patients with matched-peer controls. A pilot intervention trial will randomize a subset of patients from the primary study to undergo either a chronic transfusion regimen or receive standard care alone, for six months. A subset of these subjects with WAIS III PIQ score greater than one standard deviation from the normative data (<85) will be eligible for randomization in the pilot transfusion trial.
Scott W Powers, PhD scott.powers@cchmc.org
Protocol #:543 Nutrition and Behavior in Young Children with Chronic Illness and Their Families
The Aims are 1) to develop the efficacy of behavioral interventions that increase dietary adherence, improve outcomes, and enhance quality of life for children with Cystic Fibrosis, Type 1 Diabetes, and Obesity, 2) to provide the candidate protected time to mentor postdoctoral fellows and junior faculty in psychology/pediatrics that are pursuing clinical investigations in behavioral nutrition. The Candidate's research has focused on behavioral factors that compromise dietary adherence and translating this into interventions that can be tested in clinical trials. For each population, the objective is to establish the efficacy of behavioral treatments through clinical outcome studies and transfer findings to improve standard care. The candidate has a track record of mentorship to fellows and junior faculty in psychology/pediatrics. The Training Plan will further the candidate's knowledge of clinical trial design and analysis of outcomes and allow him improve mentorship. The Research Plan includes two ongoing projects: an NIH funded R01 study, "Behavioral Treatment of Eating Problems in Toddlers with Cystic Fibrosis," and a novel study focusing on "Barriers to Dietary Adherence in Young Children with Type 1 Diabetes." Additionally, the candidate will continue research, on obesity prevention in low-income children. The Mentoring Plan for beginning investigators will consist of 1) mentoring of 2 fellows and a junior faculty member in psychology/pediatrics, 2) supervision of fellows in development of their research proposals, and 3) participation of fellows in didactic programs on manuscript/grant writing, design of clinical trials, and methodology and ethics in clinical research. (NIH/NIDDK funding) Brief descriptions of the objectives of the Cystic Fibrosis, Diabetes, and Obesity studies are below: Behavioral and Nutrition Treatment to Help Preschoolers with Cystic Fibrosis Grow Evidence-based nutritional interventions that achieve optimal growth in young children with cystic fibrosis (CF) do not exist, despite a need. Intervention could positively change the course of clinical lung disease and enhance survival for these children. Objective: To conduct a multi-center, randomized, controlled trial comparing a behavioral plus nutrition intervention condition to an attention control intervention condition. Specific Aims: 1. determine the impact of the behavioral intervention on energy intake and weight gain; 2. examine the durability of the behavioral intervention's impact on growth (weight and height) one year following treatment; and 3. explore the relation between physical activity and growth. Central hypothesis: Behavioral intervention will lead to better growth as measured by change in weight and height for age z scores. 100 preschoolers with CF and pancreatic insufficiency age 2 to 6 years will be randomized to one of the two conditions. The two groups will be stratified so they are similar at the initiation of treatment on weight for age z score. History of Pseudomonas aeruginosa infection and gender will be used as covariates in the statistical analysis. Outcome data (energy intake measured by 7-day diet record, weight, height) will be obtained at baseline, post-treatment (6 months), and after a 12-month follow-up (18 months post baseline). Secondary measures include BMI, body composition measured by DXA and skinfolds, and growth velocity. The long-range goal is to change the standard of nutritional care for young children with CF because behavioral intervention leads to optimal growth and ultimately improves lung health. (NIH/NIDDK funding) Factors Affecting Optimal Glycemic Control in Young Children with Type 1 Diabetes Maintaining good blood sugar control is a primary goal of modern diabetes management. Insulin pump therapy, also known as continuous subcutaneous insulin infusion (CSII), is a new and safe method of delivering insulin to people with type 1 diabetes (T1DM). Insulin pumps work by giving patients with T1DM a steady stream of insulin throughout the day. Pumps also allow for patients to get higher doses of insulin when they eat. Insulin pump therapy has transformed diabetes management. Before pumps, patients with T1DM had to follow a strict schedule of meals/snacks that matched the insulin levels in their bodies. With insulin pump therapy, patients are able to eat when they want and can eat whatever they want at meals. Insulin pump therapy has been shown to improve blood sugar control in adolescents and adults with T1DM. In young children with T1DM, insulin pump therapy has improved blood sugar control in some patients, but not in other patients. We propose to study parent and child factors that may affect blood sugar control in families of young children with T1DM who are prescribed CSII therapy. Study aims will be accomplished through a cross-sectional study of children's daily blood sugar levels, parents' behaviors for insulin administration, parents' psychosocial functioning, and children's psychosocial functioning. All data will be presented according to group means. The results of this study will be used to develop an intervention to improve blood sugar control in young children with T1DM and to improve parent functioning. (NIH/NIDDK Funding) Parenting Practices and Obesity in Low-Income African American Preschoolers This study will refine the Preschooler Feeding Questionnaire -an instrument for identifying behavioral risk factors for the development of childhood obesity - for use in low-income African Americans. A two-phase research project will be conducted. The goal of the first phase is to use qualitative research methods such as focus groups and structured individual interviews to identify differences in parenting practices between two groups of low-income African American mothers with preschoolers. The goal of the second phase is to develop and test a new version of the Preschooler Feeding Questionnaire. New items will be generated using data from phase 1 of this project and tested by cognitive interviewing. The items will be developed to define constructs about feeding and parenting that we hypothesize are related to the development of overweight in preschool children. The revised questionnaire will be administered to 300 families. Relations between questionnaire findings and child and parent weight status will be examined. The next step in our research program will investigate the relation between parental feeding restriction (measured by parent report and direct observation) and child eating (measured by energy intake and a laboratory measure of eating in the absence of hunger). We will also investigate the relation between parental feeding restriction (measured by parent report and direct observation) and child weight (measured as BMI and total fat mass based upon DEXA assessment) The long-range goal of this study is to develop obesity prevention strategies for low-income preschool aged children that focus on improving parenting skills. (NIH Funding) T32 Postdoctoral Training Grant in Child Behavior and Nutrition The T32 training program is to support postdoctoral training in child behavior and nutrition, with a specific focus on pediatric chronic illnesses. This T32 grant provides the infrastructure for a multidisciplinary training program, bringing together on a cooperative basis, behavioral, biomedical, and nutrition scientists in a manner that will enhance and extend postdoctoral training in child behavioral and nutrition sciences at Cincinnati Children's Hospital Medical Center. T32 training grant is now in its third year since funding. (NIH/NIDDK funding)
Protocol #: 683 Behavioral and Nutrition Treatment to Help Preschoolers with Cystic Fibrosis Grow
The primary objective of this NIH funded clinical trial is to conduct a multi-center, randomized, controlled trial comparing two interventions: a behavioral plus nutrition intervention to a nutrition (attention control) intervention. All subjects will receive nutritional care consistent with the 2002 CF Consensus Conference guidelines for pediatric nutrition. The specific aims are to: 1. determine the impact of the behavioral intervention on energy intake and weight gain; 2. examine the durability of the behavioral intervention's impact on growth (weight and height) one year following treatment; and 3. explore the relation between physical activity and growth. From three accredited CF Centers in Ohio (Cincinnati, Columbus, Cleveland), 100 preschoolers with CF and pancreatic insufficiency age 2 to 6 years will be randomized to one of the two conditions. The behavior plus nutrition intervention will maximize adherence to a high energy diet and enzyme replacement therapy, and motivate children to increase their energy intake. The attention control condition controls for time of contact and number of assessments conducted. Both interventions involve 7 weekly sessions followed by 4 monthly sessions. Outcome data (energy intake measured by 7-day diet record, weight, height) will be obtained at baseline, post-treatment (6 months), and after a 12-month follow-up (18 months post baseline). Secondary measures will include body mass index, body composition measured by DXA and skinfolds, and growth velocity. This study advances the investigation of early nutritional interventions for young children with CF and directly addresses the need for controlled, longitudinal assessment of behavioral intervention on growth.
Protocol #: 702 Drug and Non-Drug Treatment of Pediatric Chronic Headache
Chronic daily headache (CDH; defined as 15 or more headache days per month) is a chronic pain condition associated with a great deal of pain, suffering and disability. Over one-third of patients seen in pediatric headache clinics have CDH. Development of effective interventions for youth with CDH could potentially prevent the progression of a very debilitating and costly condition into adulthood. There are currently no randomized clinical trials evaluating the treatment of CDH in pediatric patients. The current proposal is a randomized, controlled clinical trial testing the efficacy of combined behavioral and pharmacological treatment of chronic daily headache in youth age 10 to 17. Treatments combining pharmacological interventions with behavior change have been found to be efficacious in the treatment of adults with chronic pain, including headaches, but have been understudied in pediatric populations. In this study, we will investigate whether a combination of pain coping skills training (CST) and amitriptyline (AMI) is efficacious in reducing headache frequency, functional disability, and depressive symptoms in youth with CDH. Specifically, we will test the hypothesis that coping skills training combined with amitriptyline (CST+AMI) will be superior to amitriptyline + an attention control (AMI+ATT) after 20 weeks of treatment. Further, we will test whether subjects who receive CST+AMI will have significantly less frequent headache and reduced disability and depressive symptoms at 3, 6, 9, and 12 month follow-ups. Subjects (N=132) age 10 to 17 will be randomly assigned to one of the two treatment conditions. Subjects assigned to CST will complete 8 weekly sessions of coping skills training and two monthly maintenance-promoting sessions. Sessions will focus on teaching the youth biofeedback, muscle relaxation techniques, imagery, distraction, activity pacing, problem solving and use of calming techniques using a treatment manual specifically developed and pilot tested in youth with CDH. Subjects in the manualized ATT condition will receive the same amount of therapist support and attention but not the active behavioral intervention. Booster CST or ATT sessions will occur at each follow-up time point. Amitriptyline for all subjects will be stabilized at a dose of 1 mg/kg/day. Headache frequency, functional disability, pain and headache characteristics, quality of life, and depressive symptoms will be assessed before and after treatment, and reassessed at 3, 6, 9, and 12 months. The long term objective is to establish effective treatments for CDH in youth that lead to sustained benefits in terms of clinically significant reductions in headache frequency and functional disability.
Brian E Saelens, PhD
Protocol #: 582 Children's Heath and Natural Growth Evaluation Study (CHANGES)
CHANGES examines the natural time course of total body fat and visceral fat (fat located around the organs within the abdominal cavity) accumulation through early puberty among already overweight youth. Visceral fat is considered the most harmful type of body fat distribution in adults, but it is unclear how, when, or why children accumulate this type of fat. This study seeks to identify specific developmental periods of relatively high and low intra-abdominal fat accretion, and to evaluate potential hormonal (e.g., leptin, insulin) and behavioral (e.g., physical activity, dietary components) precursors and consequences of changing body fat distribution. This is a 2-year prospective study being conducted among 37 overweight children who started participation at age 8. Assessments of total body fat, body fat distribution, hormonal milieu, and weight-related behaviors are conducted every six monthsThe Child Health and Natural Growth Evaluation Study (CHANGES) examines the natural time course of total body fat and visceral fat (fat located around the organs within the abdominal cavity) accumulation through middle childhood among already overweight youth. Visceral fat is considered the most harmful type of body fat distribution in adults, but it is unclear how, when, or why children accumulate this type of fat. This study seeks to identify specific developmental periods of relatively high and low intra-abdominal fat accumulation, and to evaluate potential hormonal (e.g., leptin, insulin) and behavioral (e.g., physical activity, dietary components) factors and consequences of children's changing body fat distribution. This is a 2-year prospective study being conducted among 36 overweight children who started participation at age 8. Assessments occur every six months and consistent of measurement of total body fat, body fat distribution, weight- and development-related hormones, and weight-related behaviors.
Protocol #: 698 Activity, Diet and Visceral Adiposity: New Care Emerging (ADVANCE) Project
More than 1 in 7 children in the U.S. is overweight. Clinic-based family-oriented pediatric behavioral weight control intervention has demonstrated short- and long-term efficacy, although efficacy has not necessarily been evaluated on all important indices of the health risk incurred by overweight children. For instance, among adults the pattern of body fat distribution may be more important for health risk than total body fat, with intra-abdominal or visceral fat accumulation considered among the most detrimental to long-term health. Few studies, either observational or interventional, have examined changes in children's visceral fat accumulation. Evidence from our observational Child Health and Natural Growth Evaluation Study (CHANGES; CCHMC #02-1-17) among overweight children suggests that physical activity is a strong determinant of children's visceral fat accumulation (more physical activity, less visceral fat), independent of the relation between physical activity and total body fat. This observational study was part of a K23 career development award from NIH/NIDDK. The current study is the second study that is part of this award. We propose a pilot 4-month behavioral pediatric obesity intervention trial that examines the impact on children's visceral fat of standard care intervention consisting of diet and physical activity modification (standard care intervention; SCI) versus standard care intervention with greater physical activity and enhanced strategies to increase physical activity (standard care plus physical activity; SCP). Both intervention conditions will include 1) weekly group and individual family sessions focused on behavioral strategies for dietary and activity change and 2) dietary prescriptions targeting caloric reduction, increasing healthy foods, and decreasing unhealthy foods. The activity prescription for the SCI participants will be set at 60+ minutes of physical activity each day, the current recommendation for children. The SCP participants will set goals for reaching 90+ minutes of physical activity each day and utilize various behavioral strategies to meet this elevated activity goal. Forty child-parent pairs (n=34 following expected attrition), in which both the child and parent are overweight, will participate and be randomly assigned to one of the intervention conditions. The primary outcomes will include pre-intervention to post-intervention change in child visceral fat, after adjusting for changes in total body fat. Secondary outcomes will include child weight, body fat, height, physical activity, diet, and behavioral skill adherence, as well as parent body fat and weight. This pilot study has the goals of 1) evaluating whether the SCP intervention can increase children's physical activity to desired levels and 2) estimating the initial efficacy and effect size (to inform future larger clinical trials) of visceral fat change for children provided similar dietary interventions but dissimilar physical activity interventions.
Lori J Stark, PhD lori.stark@cchmc.org
Protocol #: 540 Increasing Dietary Calcium Through Behavioral Intervention in Children with JRA
Children with JRA are at risk for low bone mass and fracture in early adulthood. The present project compares a Behavior Intervention Program (BI) to an enhanced standard of care condition (ESC) for increasing dietary calcium intake and bone mass in children with JRA. The program evaluates dietary calcium intake pre to post intervention (approximately 8 weeks later) and at 6 month intervals over 2 years. Bone mass is also examined at baseline and at 6 month intervals for 2 years post treatment. It is hypothesized that children with JRA receiving the BI will have a significantly greater dietary calcium intake per day than children with JRA receiving ESC pre to post treatment (8 weeks). It is also hypothesized that the increased calcium intake of the BI group will be maintained across 24 months post treatment and that the calcium intake of the BI group will be significantly greater than the ESC group. Finally, it is hypothesized that the BI condition will result in a significantly greater increase in bone mass than the ESC.
Protocol #: 563 Behavior Treatment and Nutrition in Pediatric Chronic Disease
Children and adolescents with inflammatory bowel disease (IBD; ulcerative colitis and Crohn's Disease) are at risk for low bone mass and fracture in early adulthood. The present project compares a Behavior Intervention Program (BI) to a standard of care condition (STC) for increasing dietary calcium intake and bone mass in children with IBD. The program evaluates calcium intake pre to post intervention (approximately 8 weeks later) and at 6 month intervals over 2 years. Bone mass will also be examined at baseline and at 6 month intervals for 2 years post treatment. It is hypothesized that children with IBD receiving the BI will have a significantly greater dietary calcium intake per day than children with IBD receiving STC pre to post treatment (8 weeks). It is also hypothesized that the increased calcium intake of the BI group will be maintained across 24 months post treatment and that the calcium intake of the BI group will be significantly greater than the STC group. Finally, it is hypothesized that the BI condition will result in a significantly greater increase in bone mass than the STC.
Nicolay C Walz, PhD nicolay.walz@cchmc.org
Protocol #: 631 Social Development Following Pre-School Brain Injury
The research plan is designed to examine short- and long-term social outcomes and to test a model of the development of social competence following TBI during the preschool years. Deficits in social competence, social information processing (SIP) skills, and core neuropsychological abilities are predicted outcomes of preschool TBI. The theoretical model to be tested rests on the assumption that TBI causes dysfunction of the brain networks responsible for the development of neuropsychological abilities needed for effective SIP and good social adjustment. The model proposes that the SIP deficits are at least partially responsible for the emergence of poor social competence. The influences of pre-injury child characteristics, injury parameters, and pre- and post-injury parenting practices will also be investigated to isolate the effects of TBI on social competence.
Margaret H Zeller, PhD margaret.zeller@cchmc.org
Protocol #: 608b Health Related Quality of Life and Family Functioning for Youth Pursuing Weight Management Intervention
The prevalence of pediatric obesity has increased dramatically in the past three decades with current estimates indicating that approximately 15.5% of children and adolescents are obese. There is a growing literature documenting the health consequences of obesity, however, the greater immediate costs of pediatric obesity may be psychosocial. The primary purpose of this study is to validate both a self-report and parent-proxy measure of obesity-specific health-related quality of life (HRQOL) for youth (ages 5-18). Additional aims are to examine the relation between parent HRQOL and parent-proxy reports of their child's HRQOL and parent and child factors associated with HRQOL in obese treatment-seeking youth. The proposed study has two phases. Phase 1. We plan to collect data from 150 children/adolescents and their primary caregiver(s) referred to the CCHMC HealthWorks! weight management program. Phase 2. Participants in Phase 1 will be approached for Phase 2. We plan to collect test-retest data on 50 children ages 5-13 and 50 adolescents ages 14-18 and their parents in their home environment. Preliminary data analyses on the psychometric properties of the obesity-specific measures will include several phases, including item reduction, assessing scale reliabilities, test-retest reliability, and convergent and discriminant validity. Additional analyses will be conducted examining the relations between parent HRQOL, parent-proxy HRQOL, child HRQOL, perceived social support, and parenting stress..
Protocol #: 624 Extreme Obesity in African American and Caucasian Adolescents
The rising epidemic of pediatric obesity has become a national health care priority due to the cumulative medical and psychosocial consequences across the lifespan. The degree of overweight has also increased at an alarming rate making the adolescent with extreme obesity (BMI > 40 kg/m ) a growing population for which there is increasing concern. Empirically supported treatments for adolescent obesity and, in particular, extreme obesity are lacking. However, in adult populations, bariatric surgery has become a viable intervention option for extreme obesity and now surgical weight loss procedures are being critically evaluated for adolescents. Given adolescence is often marked by significant emotional, cognitive, and interpersonal growth, the fluidity of this developmental period may present unique challenges for the adolescent surgical patient. However, there is a critical gap in our understanding of the psychosocial functioning of this unique youth population pursuing this aggressive mode of weight reduction. The primary aims of this pilot study are to document the feasibility and utility of the proposed methods. The study will involve the administration of a battery of psychological measures assessing psychological adjustment, relationship to food, and quality of life in adolescents with extreme obesity pre- and post-bariatric surgery at 3-, 6-, months and thus provide preliminary data about the short-term outcomes of bariatric surgery on these psychological and quality of life factors.
Return to top Pulmonary Biology
Bruce Trapnell, MD bruce.trapnell@cchmc.org
Protocol #: 641 Donation of Blood for Use in Experiments Involving Measurement of Anticytokine Autoantibodies and Growth Factors in Rare Lung Diseases
The purpose of the research study is to collect blood from normal, healthy donors. The blood collected is studied to determine how certain antibodies and other factors found in the blood can play a role in the development of rare lung diseases by comparing normal, healthy blood to the blood found in individuals with these diseases. Approximately 50 subjects will be recruited annually for three years. The study is a minimal risk study without potential direct benefit. Normal healthy donors aged 18 to 40 that meet criteria to donate blood are eligible to participate. Donors complete a medical health and blood donor questionnaire, which are reviewed prior to participation to verify eligibility. The blood is drawn by nurses in the General Clinical Research Center. A sterile, single use needle is used to collect approximately 30 ml of blood. Donors are compensated for their participation.
Return to top Pulmonary Medicine
Raouf Amin, MD raouf.amin@cchmc.org
Protocol #: 590 Mechanisms Mediating Cardiovascular Disease in Children with Obstructive Sleep Apnea
The goal of this study is to understand the effect of sleep apnea on the heart and blood pressure by studying the differences in control of blood pressure and the size and function of the heart in children with obstructive sleep apnea. We are also studying the effect of treatment of obstructive sleep apnea on these changes in blood pressure control and the size and function of the heart in comparison to children without obstructive sleep apnea. This is a one-year study that will involve a screening visit and four study visits spaced at visit 1, 6 weeks post treatment, 6 months post treatment, and 1 year post treatment. For subjects who qualify, each subject will have 3-4 overnight stays (depending on which study group the subject is placed) that includes a polysomnography (sleep study),three echocardiographs, and four home 24-hour ambulatory blood pressure tests. Our study involves measuring breathing, blood pressure, sleep quality, and heart size and function. Participants are recruited from children ages 6-13 years with suspected obstructive sleep apnea (OSA) and who still have their tonsils or adenoids. These children will be matched with a control group of children ages 6-13 who do not snore or have symptoms of OSA and who have not had their tonsils or adenoids removed within the past two years.
Protocol #: 634a Vascular Function in Children with Obstructive Sleep Apnea
The pediatric syndrome of sleep disordered breathing encompasses children with simple snoring, obstructive hypoventilation and varying degrees of obstructive sleep apnea. The syndrome occurs in more than 12% of children, with most having mild to moderate involvement. Without knowledge of the long-term cardiovascular morbidity with less severe forms of SDB, adequate management of children with the disorder and prevention of cardiovascular disease during adulthood cannot be assessed. We hypothesize that in children with SDB, increased systemic levels of inflammatory cytokines and acute phase reactants correlate with severity of the disorder and with vascular and myocardial remodeling. We have reported left ventricular changes in children with SDB occurring independently of hypertension and obesity. The mechanism of left ventricular remodeling remains undefined. Our data show that in children with SDB there is a strong association between plasma levels of acute phase reactants and left ventricular mass. Similarly, levels of plasma cytokines correlate with carotid artery intima thickness. The goals of this study are threefold: 1) to compare inflammatory cardiovascular disease mechanisms in 5- to 13-year-old children with varying degrees of SDB to those in normal controls; 2) to determine how cytokine levels in plasma relate to those in tonsils; 3) to examine the relationship between inflammatory markers and carotid intima thickness, carotid compliance, pulse pressure, aortic stiffness and left ventricular mass and function before and after adenotonsillectomy.
Protocol #: 634b Vascular Function in Children with OSA
This study is designed to investigate the changes in blood vessels compliance and stiffness in children ages 5 to 13 years with the syndrome of obstructive breathing during sleep. It is designed to examine the relationship of the severity of the syndrome to vascular functions and to specific inflammatory mediators related to early stages of arterial stiffness and their effect on cardiovascular endpoints, namely twenty-four hour ambulatory blood pressure and left ventricular mass. This study will also examine the relationship between plasma and tonsillar tissue levels of inflammatory cytokines. Our aim is to identify vascular risk factors in childhood and to determine whether sleep disordered breathing in children represents an independent risk factor for cardiovascular disease which, if left inadequately identified, could track into adult years.
Paul Boesch, DO paul.boesch@cchmc.org
Protocol #: 687 Diagnosis of Chronic Aspiration of Saliva in Children
Chronic aspiration of saliva causes permanent lung injury due to the persistent accumulation of oral microbes and enzymes stimulating chronic airway inflammation. There is no gold standard test for the diagnosis of salivary aspiration and the diagnosis currently depends on the combination of a suggestive history and physical exam coupled with a positive diagnostic test. Current tests for salivary aspiration evaluate children for aspiration at a single point in time. Identification of oral flora on culture of bronchoalveolar lavage fluid (BAL) may also signify aspiration of saliva and may have an advantage by reflecting accumulation of oral contents in the lower airways over time. Quantitative BAL cultures for oral flora are widely available but have not been evaluated as a test for aspiration. The purpose of this pilot study is to evaluate quantitative BAL culture as a novel test for the diagnosis of salivary aspiration by determining its ability to prospectively differentiate between children clinically diagnosed with chronic salivary aspiration and controls. Amongst children undergoing clinically indicated flexible bronchosocpy with BAL, subjects are enrolled as cases of salivary aspiration based on a combination of risk factors involving symptomatology, underlying diagnoses, and a positive diagnostic test. Controls are those undergoing bronchoscopy strictly for evaluation of structural airway lesions. Quantitative cultures of BAL for oral flora are compared between these two groups and are correlated to a semi-quantitative score of lung injury by CT scan.
Agirios Dinopoulos, MD agirios.dinopoulos@cchmc.org
Protocol #: 677 Sleep Disorders in Children with Tuberous Sclerosis Complex
Background: TSC is a genetically determined multi-system disorder that may affect any human organ. The incidence of TSC is estimated to be as high as 1 in 5,800 births and most cases present during childhood. When the brain is involved, abnormalities of neuronal migration, cellular differentiation, and excessive cell proliferation contribute to the formation of the various brain lesions (subependymal nodules, cortical tubers, subependymal giant cell astrocytoma "SEGA"). The location and number of cortical tubers vary from patient to patient and they are easily demonstrated by MRI. Seizures are a frequent neurological symptom of TSC. The prevalence of sleep disorders and their relation with seizures and the extent of the intracranial pathology (type and location) have not been evaluated in depth in TSC. Purpose: The purpose of this study is to determine the prevalence of sleep disorders, to detect sleep architecture and sleep-related breathing problems in patients with TSC and to correlate these problems with the epileptic activity and with the extent of intracranial pathology as it is depicted on brain MRI. Hypothesis: We hypothesize that patients with Tuberous sclerosis complex (TSC) have a high prevalence of sleep disorders and sleep architecture abnormalities related to epileptic activity and to the extent of intracranial pathology. We also hypothesize that, a subgroup of patients with specific intracranial manifestations (SEGA and/or cerebellar tubers) have a high prevalence of sleep-disordered breathing. Material and Method: To determine the prevalence of sleep disorders in TSC patients a packet consist of an age-based validated questionnaire, known as "The Children's Sleep Habits Questionnaire (CSHQ), will be mailed to parents or caregivers of children with TSC and parents or caregivers of an age and gender-matched control group without chronic medical problem. To detect and measure sleep architecture abnormalities as well as sleep-disordered breathing problems a dedicated polysomnography study (full EEG with quantitation of the electrographic epileptic activity and full polysomnography) will be performed in a sample of children with TSC. The study population will be recruited from an initial cohort of patients with TSC ages 4-18 years that followed in TSC clinic in CCHMC. The cohort will be stratified in 3 groups according to the type and location of the brain lesions and 10 patients from each group will be randomly selected to undergo the dedicated polysomnography study. Clinical significance: The identification of sleep disorders in patients with TSC has important treatment implications. If sleep architecture disruption is related to uncontrolled seizures or undetected subclinical epileptic activity then additional treatment aimed at better seizure control will be of patients benefit. The identification and treatment of sleep-disordered breathing problems such as sleep apnea in certain patients with TSC is important because these conditions, if untreated, may precipitate symptoms such as headaches and seizures. In addition TSC patients with their prototype brain pathology and focal epilepsy is a group that can serve as model of studying associations between sleep organization and ictal and interictal epileptic activity.
Maninder Kalra, MD maninder.kalra@cchmc.org
Protocol #: 635 Assessment of Pharyngeal Collapsibility in Obese Children with OSA by Volume Segmentation of Cine MR Data
Over the past decade, the prevalence of childhood obesity has dramatically escalated, reaching epidemic proportion. Despite the fact that obstructive sleep apnea (OSA) is widely associated with cognitive deficits, metabolic, and cardiovascular sequelae, the underlying mechanistic basis for the disease in obese adolescents is unknown. Because of this, early identification and treatment of OSA in obese children remains unachievable. The proposed research will fill important gaps in our knowledge base and set the stage for future research on predisposing factors for OSA in obese children. Awareness of these factors will enable early intervention and ultimately result in reduced morbidity in this group of children. The primary objective of the candidate's research is to test the hypothesis that central adiposity is strongly associated with increased pharyngeal wall motion in obese adolescents. A second objective of this research is to determine the relationship between increased pharyngeal wall motion and OSA. The third objective is to study the effect of body composition change on pharyngeal wall motion in obese adolescents with OSA. Pharyngeal wall motion will be determined in awake subjects by change in coefficient of variation of pharyngeal volume, as measured by MR cine imaging, after topical pharyngeal anesthesia. The proposed research is innovative in that it utilizes a new approach to the study of airway dynamics, which is the non-invasive and precise method of volume segmentation of cine MR data. The simultaneous assessment of airway structure and dynamics by this method allows the assessment of pharyngeal dynamics independent of airway size.
Mohannad Mannaa, MD mohannad.mannaa@cchmc.org
Protocol #: 667 Vascular Function in Morbidly Obese Children with Obstructive Sleep Apnea Undergoing Bariatric Surgery
Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper airways obstruction during sleep that result in partial or complete cessation of airflow leading to intermittent episodes of hypoxia. A large number of studies have recently shown that atherosclerotic blood vessel disease is not simply due to lipid deposition along the blood vessels, but is the result of a chronic local inflammatory reaction. The association between cardiovascular disease and markers of systemic inflammation has been repeatedly demonstrated in several adult studies. Results show a strong correlation between high levels of inflammatory cytokines, adhesion molecules, and the risk of having or dying from cardiovascular disease. Based on this knowledge, we anticipate finding elevated levels of inflammatory markers in obese children with OSA in comparison with obese children without OSA, and later on, decrease in the level of inflammatory markers after the resolution of the OSA. The study of carotid blood vessels provides important knowledge about the elastic and structural properties of the vessel wall. In adults, carotid artery intima thickness is a strong predictor of coronary artery disease. Based on preliminary data showing that children with OSA have abnormal vascular function, we anticipate finding that children with obstructive breathing during sleep develop structural abnormalities of blood vessels which can place them at a greater risk for future cardiovascular disease. So, we are measuring the intima-thickness by carotid ultrasound in the obese children with OSA in comparison to Non-OSA. Then re-measure it after improvement or resolution of OSA.
Return to top Rehabilitation
Shari L Wade, PhD shari.wade@cchmc.org
Protocol #: 630 Child and family sequelae of preschool brain injury
The purpose of this research study is to learn more about what happens to young children with injuries. The goals are to find out how children with injuries learn and behave after they leave the hospital, and how their injuries affect them and their families. To answer these question, children, aged 3 to 6, with moderate to severe head injuries will be compared to children with injuries that do not involve the head (such as broken bones).
Return to top Rheumatology
Hermine I Brunner, MD hermine.brunner@cchmc.org
Protocol #: 604 Long-Term Outcomes and Gonadal Function in Childhood Onset Systemic Lupus Erythematosus
The Automated Neuropsychological Assessment Metrics (ANAM) is a software program that utilizes measures and specifications developed in various branches of the Armed Forces to create a performance battery sensitive to cognitive change [6-10] . Several studies have demonstrated the ability of the ANAM to capture subtle cognitive change associated with mild traumatic brain injury (MTBI) [11, 12] . Performance decrements on the ANAM were observed even in those individuals with MTBI without decrement on traditional neuropsychological tests. Recent findings demonstrate the ANAM's ability to track deterioration and recovery of cognitive functioning following sports-related concussion injury in young adult males [11, 12] . The ANAM has been used for the assessment of cognitive impairment in adult SLE [13] . The pediatric adaptation of the ANAM has been recently developed and initial validation studies have been performed. Whether this battery is useful for pediatric NPSLE will be studied in this protocol. In this study, patient self reports of neuropsychiatric symptoms will be compared with the results of formal neurocognitive testing. In adults, there is a significant association between higher subjective complaint scores and lower cognitive function as determined by formal neurocognitive testing [14]. Similar studies have not yet been done in childhood onset systemic lupus erythematosus and are a focus of the presented research study. A Self Assessment Neuropsychiatric Questionnaire (NSAQ) similar to the one described in the studies above used in adults, was adapted for children and will be used to determine if self reports of cognition are comparable to the current standard of formal neurocognitive testing.
Protocol #: 626 Triptorelin for Ovary Protection in Childhood Onset Lupus
Approximately 30,000 children in the US are diagnosed with Systemic Lupus Erythematosus (SLE), a multiorgan autoimmune disease with striking female preponderance. For severe disease manifestations of SLE intravenous chemotherapy using cyclophosphamide is required, whose side effects include gonadotoxicity. No drugs have been approved to protect patients with SLE from chemotherapy associated gonadal damage. The gonadotoxic effects of cyclophosphamide are most apparent among males and women over the age of 30 years who have a 70% risk of premature ovarian failure after cyclophosphamide therapy, likely because they have an age-related smaller ovarian reserve.. The risks of developing overt ovarian failure among young females is much smaller at around 11%.. Gonadotropin releasing hormone agonists (GNRH-a),such as triptorelin, may significantly decrease the incidence of premature ovarian failure (POF) after cyclophosphamide in adult SLE. The biologic basis for protecting ovaries is that, after a brief episode of increased ovarian activity, likely leading to increased vulnerability to gonadotoxins, triptorelin can induce complete ovarian suppression (COS), making ovaries relatively resistant to cyclophosphamide gonadotoxicity. The safety of triptorelin in SLE has not been well examined. Previous case reports suggest that GnRH-a may worsen SLE disease activity and promote autoimmunity.. The optimal dose of triptorelin for ovarian protection and the exact time interval necessary to induce a COS in children with SLE are unknown. It is uncertain whether adolescent females with their decreased incidence of POF would also benefit from triptorelin
Protocol #: 653 Safety and Efficacy of Lipitor (atorvastatin) in Reducing the Progression of Carotid IMT in Early Childhood SLE: Atherosclerosis Prevention in Pediatric Lupus Erythematosus
This research study is being done to find out whether or not a drug called atorvastatin, also known as Lipitor\'ae, will lower cholesterol levels, decrease inflammation, and lessen heart, stroke and circulatory problems in children with SLE between the ages of 10 through 21 years. Many people with SLE have high levels of lipids (fats) in their blood. Cholesterol is a special type of blood lipid. When blood vessels become hardened, inflamed (thickening of the walls of the vessel) and blocked by these fats, this condition is called atherosclerosis. Adults with SLE are at especially high risk for developing atherosclerosis. Atherosclerosis can occur in people with SLE even if they do not have high cholesterol levels in their blood. Atherosclerosis increases the risk of heart attack, stroke, problems with circulation, and may shorten one's life. Atorvastatin belongs to a family of drugs called 'statins' which are cholesterol lowering medications. These drugs have been proven to reduce cholesterol levels, slow the process of atherosclerosis and improve quality and length of life in adults with high blood cholesterol levels. Atorvastatin has been approved by the United States Food and Drug Administration (FDA) to treat high cholesterol in adults. Atorvastatin was recently approved by the FDA to treat children with dangerously high cholesterol caused by an inherited disease. It is not approved for use in children with normal cholesterol levels or in those with SLE, or other conditions. This study will test whether or not Atorvastatin will work better than a placebo (sugar pill) that looks like the study drug but has no effect on the body) at slowing the process of atherosclerosis in children with normal and abnormal cholesterol levels and adolescents with SLE when used with other cholesterol-lowering strategies.
Protocol #: 685 Meaningful Outcomes for Pediatric Lupus Clinical Trials
Systemic Lupus Erythematosus (SLE) is a severe autoimmune disease with rising mortality that targets primarily young women of US minorities and 20% of all patients are diagnosed during childhood (cSLE). Children with cSLE have a worse prognosis than adults. There are only 3 medications (aspirin, hydroxychloroquine, gluco-corticoids) that have ever been fully approved for adult SLE by the U.S. Food and Drug Administration, but there are none for cSLE. Lack of testing new drugs is likely one of the main reasons why the 10-year survival of SLE and cSLE patients at 85% has not improved for over a decade. Randomized clinical trials (RCTs) in SLE, but especially cSLE, are hindered by the lack of standardized high-quality surrogate markers to verify the effects of new drugs within the short time frames considered in RCTs. The central hypothesis of this application is that modified RCT outcomes parameters (surrogate markers) of adult SLE can be used to assess treatment responses of children with cSLE. We propose to enroll 100 children with cSLE from 5 pediatric rheumatology centers organized in Childhood Arthritis & Rheumatology Research Alliance; 40 childrne will be recruited at CCHMC. Subjects will be assessed every 3 months (follow-up: 1.5 yrs). Previously developed RCT software will be used for web-based data entry and study management. To test the central hypothesis of the application the following 3 specific aims are pursued: 1: To assess the proposed American College of Rheumatology Ad-hoc Committee criteria for minimal important differences in disease activity of adults with SLE for their validity when used in cSLE. 2: To prospectively validate the preliminary definitions of improvement for cSLE that have been proposed by the Pediatric Rheumatology International Trial Organization (PRINTO) and the Prediatric Rheuamtology Collaborative Study Group (PRCSG). 3: To newly develop preliminary criteria of disease flare in cSLE based on the set of cSLE core response variables that have been previously developed by PRINTO/PRCSG.
Daniel J Lovell, MD daniel.lovell@cchmc.org
Protocol #: 703 Biology in Response to TNF Blockade in JIA
BACKGROUND. 35% of children with Polyarticular Juvenile Rheumatoid Arthritis (P-JRA) treated with anti-TNF monoclonal antibody therapy (infliximab or adalimumab) demonstrate clinically inactive disease (CID). The proper time to stop anti-TNF monoclonal antibody therapy in a child demonstrating CID is unknown. These therapies can be associatied with short-and medium- term side effects in children with JRA. Long term effects in both adults and children are unknown. SPECIFIC AIMS. 1. Perform a pharmacokinetic (PK) study in P-JRA on either infliximab or adalimumab to determine proper sampling time for an in vivo cytokine capture assay (IVCCA) that quantitates in vivo TNF production. 2. Perform cross sectional study in P-JRA to determine ability of the IVCCA to distinguish between levels of in vitro production of TNF. METHODS. Timed PK sampling in 6 children with P-JRA on infliximab and 6 on adalimumab will determine the most informative time point for sampling for the IVCCA. A cross sectional study in 3 P-JRA groups on infliximab or adalimumab will be performed (active disease, partial response and inactive arthritis). SIGNIFICANCE. This is first human study of a novel biomarker of in vivo TNF production. If effective, it could lead to safer and more cost effective use of infliximab and adalimumab in a variety of diseases in adults and children.
Return to top Surgery
Thomas Inge, MD thomas.inge@cchmc.org
Protocol #: 659 Collection and Banking of Biological Specimens from Patients with Obesity
The purpose of this research protocol is to help researchers learn more about pediatric obesity. Blood, fat, gastrointestinal tissue and liver tissue collected from this unique group of patients who are undergoing bariatric surgery may harbor clues to the pathophysiologic mechanisms that lead to extreme pediatric obesity and the mechanisms by which massive weight loss benefits the health of these individuals. The mechanism by which this occurs is unclear, but likely involves fundamental alterations in the endocrinologic function of the human foregut as well as energy balance pathways. A detailed understanding of the mechanisms by which bariatric surgical therapy produces such dramatic morphologic and biochemical changes can be explored for the potential development of alternative treatment paradigms that do not require invasive, risky procedures. This protocol allows for the acquisition of key samples to create a long-term repository of biological specimens from patients both before and after surgery. In addition, past medical history, demographic, anthropometric, surgical, and laboratory information is collected to permit selection of specimens to be used in hypothesis-driven research studies of obesity and related disorders.
Protocol #: 663 Adolescent Gastric Bypass and Diabetic Precursors
This project will begin a detailed study of insulin resistance, beta cell function, anthropometrics, nutrition, and physical activity in morbidly obese adults compared to adolescents undergoing bariatric surgery in relation to carbohydrate metabolism. While it is known that gastric bypass causes the weight loss necessary to correct some metabolism problems, not much is known about when these changes need to happen to provide the best long term outcome. Evidence suggests that if left untreated for too long the pancreas can "burn out" and then the metabolism problems may be less completely reversed. The effects of gastric bypass on the metabolism of adults and adolescents will be compared to try to determine whether there are greater metabolic and health advantages of performing gastric bypass earlier in life versus waiting until adulthood.
Gregory Tiao, MD gregory.tiao@cchmc.org
Protocol #: 596 Comparison of Intravenous Methylprednisolone Vs. Oral Prednisolone in the Treatment of Acute Rejection in Pediatric Liver Transplant Recipients
The trial comparing intravenous methlyprednisolone versus oral prednisolone in the treatment of acute rejection in pediatric liver transplant recipients continues. We are comparing the effect of oral versus iv steroids in an effort to improve the patients quality of life and to reduce medical costs. In the past, all children who had acute rejection following liver transplantation required one week hospitalization. This is disruptive to their day to day life and has an impact on medical costs. The bioavailability of orally administered steroids is similar to those given intravenously therefore we hypothesized both treatments are effective. To ensure patient safety, we began this small study to test that hypothesis. Our study endpoints are control of acute rejection, improved quality of life as assessed by an outcomes questionnaire and decreased medical cost.
Return to top Translational Research
Patrick Kelly, MD
Protocol #: 643 Collection of Hematopoietic Cells from Patients with Fanconi Anemia for Future Autologous Reinfusion and Research
The purpose of this research study is to collect, purify, study, and store a large amount of CD34+ cells collected from either the bone marrow or the peripheral blood from patients with Fanconi anemia before severe bone marrow failure occurs. Subjects will be enrolled on the study for approximately one to three weeks, depending upon the harvest condition. After a bone marrow harvest or the cytokine mobilized peripheral blood collection, CD34+ cells will be purified using an experimental device called the CliniMACS. Some of the purified CD34+ cells will be used for study in the laboratory. The majority of cells (85% or more) will be frozen and stored indefinitely for future use, including reinfusion back into the subject as part of other studies designed to help treat Fanconi anemia.
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