This investigative team has concentrated on studies in diabetes and disorders of growth & puberty.
Ongoing Projects
Dr. Mauras runs an NIH-funded project entitled “Hypoglycemia in children and adolescents with type 1 diabetes: mechanisms and prevention” (N Mauras –PI). This is part of the Diabetes research in children network (DirecNet) a five-center consortium of clinical pediatric endocrine centers plus a coordinating center of which she and her group been a part of for the last 8 years. We are conducting a series of studies on the use of continuous glucose sensor technology in very young children with diabetes (<8>Brain anatomy and function: relation to glycemia in young T1DM children which will likely get started soon. Brain MRIs and neurocognitive testing will be done in young kids with diabetes. Dr. Larry Fox and Dr. Dominique Darmaun in endocrinology, Dr. Allison Cato in neuropsychology and Dr. Debbie Merinbaum in neuroradiology are co-investigators and collaborators.
A new project is about to get started entitled “A Phase III, 3-Arm, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Investigate the Impact of Diamyd® on the Progression of Diabetes in Patients Newly Diagnosed with Type 1 Diabetes Mellitus”(N Mauras – PI) . This is funded by Diamyd, a Swedish company that has developed the 1st “vaccine” of its kind to try to slow down the demise of a cells in type 1 diabetes. We will recruit kids with new onset DM >10yrs and randomly assign them to the vaccine or placebo injections (original + 3 boosters). This is a very important trial in the quest towards a cure for diabetes.
In a project titled “Effects of therapeutic intervention on cardiovascular risk markers, insulin resistance, and intra-hepatic fat contents in obese children at risk for metabolic syndrome (syndrome X)” (N Mauras – PI),” the 1st paper on this was presented at the Endocrine meetings in the summer and was chosen for media notoriety and a press conference was given on the subject. The full paper was now accepted for publication in the Journal of Clinical Endocrinology and Metabolism and it shows that in simple obesity, i.e., that without associated glucose, lipids or blood pressure abnormalities, there is already a state of increased inflammation and prothrombosis. This is evident even in prepubertal children. This is followed by a randomized clinical trial using diet, exercise and Metformin for 6 months in patients showing these marked elevations in these markers. The results of tehse studies were presented at the international Peds Endo meetings in NY in Sept ’09.
A project entitled Continuous glucose sensors and oxidative stress” (N Mauras –PI) with Dr. Fox and Dr. Darmaun as co-investigators was completed and showed that markers of oxidative stress are elevated in kids with T1DM even in good diabetes control and that these markers are related to the variability in glucose measures. These data were presented at the ADA and Endocrine society meetings this summer and will be written and published this next year.
Another study along the same themes, also funded by the JDRF is entitled “Regulation of glutathione homeostasis in adolescents with type 1 diabetes,” (D Darmaun – PI), Dr. Mauras co-investigator, expands on earlier studies that improve the understanding of the regulation of blood glutathione, an antioxidant, in youngsters with type 1 diabetes. A series of Clinical Research Center experiments are being conducted in children in 40 with diabetes treated with antioxidants or placebo and measuring changes in the plasma markers of oxidative stress. We are almost done with the patient-care part of the study and hope to be able to present soon.
Dr. Larry Fox (PI) is conducting a study entitled “A pilot study of the effect of continuous subcutaneous insulin infusion in adolescents with newly-diagnosed type 1 diabetes on insulin resistance, beta-cell function and the honeymoon period”, funded by the Nemours Research programs. The study evaluated how insulin pump therapy (CSII) compares with multiple daily injections (MDI) in affecting the time of onset and duration of the honeymoon period, and whether differences in the honeymoon period are related to changes in insulin sensitivity and beta-cell function. Ten adolescents with new-onset type 1 diabetes have been randomized to receive either MDI or CSII, starting within four weeks after diagnosis with periodic measures of insulin sensitivity and beta-cell function. Recruitment has been completed. Patients are followed for a total of two years. The data generated in these studies will be used as pilot for a larger grant application.
Another area of intense research in this group is the area of growth and pubertal disorders. In another study “A randomized, double-blind, placebo-controlled multicenter trial to assess the safety and efficacy of anastrozole TM)(Arimidex in increasing predicted adult height of adolescent males with growth hormone deficiency (N Mauras – PI),” funded as an investigator-originated grant by AstraZeneca, Dr. Mauras and colleagues at six other centers investigated the safety and efficacy of prolonged selective estrogen production using an inhibitor of this enzyme (ArimidexTM) in pubertal boys with growth-hormone deficiency. We are now seeking to follow up these patients, now young adults, and do spine films to assess long term bone health. Dr. Mauras is also competing for funding for a new study entitled: A randomized controlled trial of the use of aromatase inhibitors, alone and in combination with growth hormone in adolescent boys with idiopathic short stature (N Mauras – PI). This is a natural extension of these studies but in a different patient population.
Constitutional delay of growth and maturation (CDGM) is one of the most common causes of short stature. In another study, “Nutrients and hormones: effects in boys with disordered growth,” (N Mauras – PI) funded by the Genentech Center for Endocrinology Research. The team has conducted a randomized trial of 20 prepubertal boys with CDGM, comparing either observation for six months followed by growth hormone alone for 12 months vs. aggressive nutritional supplementation alone for six months, followed by 12 months of combined therapy. We assessed dietary intake, total energy expenditure (doubly labeled water), growth, body composition, bone mineral density, and biochemical markers of growth and nutrition. We found that adding extra calories per day also increases the total energy expenditure, hence negating any added benefit of the extra calories on growth and that using GH + extra calories does not improve growth any better than GH alone. The study suggest that there is an intrinsic imbalance of energy intake and utilization in these boys with disordered growth. Data were presented at International meetings in new York by Dr. Joan Han, previous fellow, now at NIH and is submitted for publication.
With funding from the Genentech Foundation for Endocrine Research a grant entitled: Estrogen dosing in Turner Syndrome: pharmacology & metabolism (N Mauras- PI) has been started this year. The principal am is to further define whether oral and transdermal estrogen work differently on body composition and metabolism in girls with Turner Syndrome. The study also aims to better understand whether titration of the dose of estrogen can be done using sensitive estradiol assays during treatment. We are using a new model of central recruitment done by our fellow, Dr. Martha Taboada through the Epic EMR system, recruiting subjects in Jacksonville and Philadelphia, Orlando and Pensacola. Dr Judith Ross is a co-investigator in this important work.
The assessment of growth is an important part of childhood health care. Currently, growth can only be determined by taking height measurements months apart; there is no “blood test” for growth. Recent studies have shown the C-type natriuretic peptide plays an important role in growth. The amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) is produced in equimolar amounts with CNP, and blood levels of NTproCNP correlate with growth in lambs. Preliminary studies in human show a correlation as well, suggesting that blood levels of this peptide may by a biomarker for linear growth. The study, “Amino-terminal propeptide of C-type natriuretic peptide levels in healthy children (R Olney -PI), funded by Quest Diagnostic Laboratory and Nemours Research Programs, is measuring levels of NTproCNP in a large group of healthy children to see if NT-proCNP correlates with growth velocity and to define its normal range. If it can be shown that NT-proCNP is a blood marker of growth, the laboratory will have contributed an important new tool for the evaluation of growth and overall health in children. 182 children have been studied to date and an abstract of this preliminary data was presented at the 2009 Endocrine Society Meeting in Washington D.C.
Recent data have also shown that CNP, acting through its receptor natriuretic peptide receptor-B (NPR-B, gene NPR2), plays an important role in linear growth and may play a role in IGF-I regulation. Researchers have recently shown that in a large kindred that segregates an inactivating mutation of NPR2, heterozygous carriers are significantly shorter than noncarriers. The prevalence of NPR2 mutations in the general population suggests these might be a significant cause of “idiopathic” short stature. The study “Effect on stature of genetic variations in the C-type natriuretic peptide receptor,” (R Olney –PI), funded by the Genentech Center for Endocrinology Research, is testing this hypothesis by determining the prevalence of NPR2 abnormalities in people with idiopathic short stature by sequencing NPR2 people with idiopathic short stature. This study is complete and we are just waiting on the gene sequencing results.
Marfan syndrome is a common genetic syndrome that effects the bones, heart, lungs, and eyes. The skeletal features include tall stature and are primarily due to bone overgrowth. Recent studies have shown that the heart and lung effects are due to high levels of the protein transforming growth factor-beta (TGF-b). Other studies have shown that TGF-b can increase the production of CNP and CNP can cause bone overgrowth. This may be the reason that people with Marfan syndrome are tall. The study, “C-Type Natriuretic Peptide and Marfan Syndrome: A Pilot Study” (R Olney –PI), funded by Nemours Research Programs, is measuring a fragment of CNP in the blood of people and mice with Marfan syndrome to see if it is elevated. This study was completed in 2009 and we did not find increased levels of CNP. an abstract of this data was presented at the 2009 Endocrine Society Meeting in Washington D.C.
“C-Type Natriuretic Peptide and Skeletal Growth: Impact of Thyroid Dysfunction in Prepubertal Children” is run by Dr. Mitch Geffner at Childrens Hospital of Los Angeles (R. Olney –CoI), and funded as an investigator-initiated project by Pfizer, Inc., is another study of blood levels of CNP and its related protein NTproCNP, in children with abnormal rates of growth. The children in this study will have abnormal growth rates because of a newly diagnosed thyroid disorders, either hypo-(too little) or hyper-(too much) thyroidism. Following treatment of the thyroid disorder and correction of growth rates to normal, we will evaluate CNP and NTproCNP at regularly scheduled intervals. By doing this, we hope to determine the relationship between these blood levels and growth rates in children with thyroid disorders following treatment. This study will help to further clarify the important role of CNP in skeletal growth. Recruitment for this study is complete and in the follow-up phase. An abstract of this preliminary data was presented at the 2009 Endocrine Society Meeting in Washington D.C.
Klinefelter syndrome is a syndrome in which boys are born with two X chromosomes, in addition to a Y chromosome. One characteristic of this syndrome is tall stature. Recent studies show that a gene on the X chromosome called SHOX regulates B-type natriuretic peptide (BNP) production. We hypothesized that increased BNP production might reduce CNP clearance, causing overgrowth. The study “C-Type Natriuretic Peptide and Klinefelter Syndrome: A Pilot Study” (R Olney –PI, Judy Ross NCC-D – Co-I) is also funded by Nemours Research Program and has looked at this. Twenty-four boys with Klinefelter syndrome have been studied and the results do show an abnormality in the CNP production, but not the abnormality expected. We are developing new hypotheses to explain this data for a possible new study.
Vitamin D deficiency is a common problem, even in developed countries, and in infants can lead to rickets, poor growth and skeletal deformities. Matthew Benson, MD, a fellow in the endocrine division, has designed a study to look at a simple urine test to screen for vitamin D deficiency in at risk infants and toddlers. This study, “Utility of the Urine Calcium-to-Creatinine Ratio as a Screening Tool for Vitamin D Deficiency in Infants and Toddlers” (R Olney – PI, M. Benson – Co-I) has been approved by the Nemours CRRC and is awaiting funded from the Nemours Research Programs. It has also been submitted for external funding from the NIH and the Thrasher Research Fund.
Another study entitled: Effects of a Fruit and Vegetable Juice Concentrate (FVJC) In-Vivo On Retinol Binding Protein 4 and Antioxidant Capacity in Lean and Overweight Boys– A Pilot Randomized Placebo Controlled Study was started this year in the division (JA Canas – PI, Balagopal B – co-investigator). It is a study of the role of natural antioxidants in childhood obesity. The recruitment is ongoing and will be completed in 2010.
The second study is entitled “An open-label non-comparative, multi-centre study to assess the efficacy and safety of bicalutamide when used in combination with anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis. (BATT-bicalutamide anastrozole treatment for testotoxicosis) (N Mauras – PI). Testotoxicosis is a very rare form of precocious puberty in boys that presents with striking virilization, tall stature and advanced bone age typically at age 4-5 yrs. One of our patients with this condition is getting bicalutamide, a drug that blocks the virilizing effects of testosterone (the principal male hormone), and anastrozole, a drug that blocks the conversion of androgens to estrogens, hence slowing down the closure of the growth plates. The paper is under review at present.
Another study funded by Abbott is entitled: A Phase 3, Randomized, Multi-Center, Open-Label Study to Evaluate the Efficacy and Safety of Leuprolide Acetate 11.25 mg and 30 mg Formulation in Children with Central Precocious Puberty (N Mauras-PI, Gagliardi –co-investigator). This is a straightforward efficacy study on different doses of Lupron in children with precocious puberty. Twelve children were recruited and will be followed for 2 years.
A study entitled: A multicenter, randomized, double-blind, placebo-controlled, single-dose study to assess the pharmacokinetics, safety, and tolerability of sitagliptin in 10 to 17-year-old subjects with type 2 diabetes (L Fox – PI) examines the PK. PD of this new class of drugs for the treatment of children with T2 diabetes. So far 8 kids have been studied at NCC-Jacksonville without any side effects noted.
A collaboration between Dr. Fox, Dr. Walsh and Dr. Merimbaum has developed in a Nemours-funded study entitled Dynamic Contrast Medium-Enhanced Magnetic Resonance Imaging in Preoperative Diagnosis of Thyroid Cancer in Children and Adolescents (L Fox –PI) that investigates better ways to image thyroid nodules and determine whether they are cancerous or not. The project is now getting started.
Database Projects
Dr. Mauras’ group is also currently involved in two databases:
- postmarketing surveillance of growth hormone-treated children, NCGS – Genentech (Mauras N – PI), and
- Genesis – Eli Lilly (Olney R – PI).
This summary does not include the endocrine division’s collaboration with other groups, solely the work originated in our division at Nemours.
Invited Meetings & Presentations
Dr. Mauras continues to travel presenting her research with invitations in Venezuela, abstract presentations at the Endocrine Society, ADA and LWPES/ESPE meetings. Dr. Fox had abstract presentations at ADA and Dr. Olney at Endocrine and LWPES/ESPE meetings.
Nemours, WCH & UFL Committees
Dr. Mauras Chairs the Division of Endocrinology & Metabolism and Chairs the Clinical Research Review Committee for the whole enterprise, and now directs the Nemours Research Conferences and co-directs with Dr. Arn the newly created Educational Conferences. Dr. Fox is the Medical Director of the NE Florida Pediatric Diabetes Center, and Dr. Gagliardi is the Associate Director of the Clinical Program. Dr. Olney is a member of the Nemours IRB & Graduate Medical Education Committee as well as the UFL Pediatrics Education committee. Dr. Canas is a member of the EMR committee.
National & International Committees
Dr. Mauras is a member of the program committee for the LWPES/PAS meeting, a council member of the Growth Hormone Research Society, a Nemours-approved consultant for AstraZeneca. Dr. Fox is a member of governor Charlie Crist's diabetes advisory panel for the state of Florida, the Medical Director of the local Juvenile Diabetes Camp, Camp JADA, member of the National Youth Strategy Committee & Youth Information and Resource Team for the American Diabetes Association, and member of the local Jacksonville ADA executive council. Dr. Canas is a member of the task force on childhood obesity at Nemours.
Journal Reviews
The group has extensively reviewed for JCEM, Diabetes Care, Pediatric Diabetes, Pediatrics, J Peds, Pediatric Endocrinology & Metabolism, Metabolism and The New England Journal of Medicine (NM).
Other Achievements
- Camp JADA – for children with diabetes, run and directed by Dr. Larry Fox, and staff by our diabetes team, great success
- ADA recognition certification – obtained for our diabetes program. This is a National recognition of excellence in diabetes education
- Night with Nemours Gala – a fund raising event for our division attended by >350 peple, great success
- ADA CARE award for excellence in community work in diabetes - Dr. Larry Fox
- Alumni Hall of Fame Achievement Award by the Santa Ana College Foundation on June 5, 2009 California, Dr. Thanh Nguyen
- Distinguished Alumni Award by the Community College League of California on November 21, 2009, Dr. Thanh Nguyen