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1.  Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism 
The Journal of pediatrics  2000;137(2):239-246.
Objectives
To identify infants with hyperinsulinism caused by defects of the β-cell adenosine triphosphate-dependent potassium channel complex and to distinguish focal and diffuse forms of hyperinsulinism caused by these mutations.
Study design
The acute insulin response to intravenous calcium stimulation (CaAIR) was determined in 9 patients <20 years with diffuse hyperinsulinism caused by defective β-cell sulfonylurea receptor (SUR1−/−), 3 patients with focal congenital hyperinsulinism (6 weeks to 18 months), a 10-year-old with insulinoma, 5 with hyperinsulinism/hyperammonemia syndrome caused by defective glutamate dehydrogenase (6 months to 28 years), 4 SUR1+/− heterozygotes with no symptoms, and 9 normal adults. Three infants with congenital focal disease, 1 with diffuse hyperinsulinism, and the child with insulinoma underwent selective pancreatic intra-arterial calcium stimulation with hepatic venous sampling.
Results
Children with diffuse SUR1−/− disease and infants with congenital focal hyperinsulinism responded to CaAIR, whereas the normal control group, patients with hyperinsulinism/hyperammonemia syndrome, and SUR1+/− carriers did not. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling revealed selective, significant step-ups in insulin secretion that correlated anatomically with the location of solitary lesions confirmed surgically in 2 of 3 infants with congenital focal disease and in the child with insulinoma. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling demonstrated markedly elevated baseline insulin levels throughout the pancreas of the infant with diffuse hyperinsulinism.
Conclusions
The intravenous CaAIR is a safe and simple test for identifying infants with diffuse SUR1−/− hyperinsulinism or with focal congenital hyperinsulinism. Preoperative selective arterial calcium stimulation of the pancreas with hepatic venous sampling can localize focal lesions causing hyperinsulinism in children. The combination of these calcium stimulation tests may help distinguish focal lesions suitable for cure by local surgical resection.
doi:10.1067/mpd.2000.107386
PMCID: PMC4151173  PMID: 10931418
2.  Body Composition and Pulmonary Function in Cystic Fibrosis 
Background: Lower body mass index (BMI) is associated with worse pulmonary function in cystic fibrosis (CF). Hypothesis: lean body mass (LBM) is more strongly associated with pulmonary function than BMI is.
Methods: Anthropometrics, body composition by dual x-ray absorptiometry, and pulmonary function were determined in pancreatic insufficient CF (PI-CF) youth. Sex and age-adjusted Z-scores (BMI-Z, LBMI-Z, FMI-Z) were generated for CF and controls. (1) Associations of BMI-Z with LBMI-Z and FMI-Z and (2) age-adjusted associations of BMI-Z, LBMI-Z, and FMI-Z with FEV1%-predicted were tested.
Results: Two hundred eight PI-CF subjects had lower BMI-Z, LBMI-Z, and FMI-Z compared to 390 controls. BMI-Z was associated with lower LBMI-Z (p < 0.0001) in PI-CF. In females, LBMI-Z and BMI-Z were positively associated with FEV1%-predicted; this relationship did not persist for FMI-Z after adjustment for LBMI-Z. In males, only LBMI-Z and BMI-Z were associated with FEV1%-predicted.
Conclusion: In PI-CF youth, deficits in LBM were apparent. At lower BMI percentiles, BMI may not accurately depict LBM in PI-CF. In under-nourished PI-CF youth, this preservation of FM in preference to LBM is relevant since LBMI-Z, but not FMI-Z, is positively associated with FEV1%-predicted. Lean body mass index is more strongly associated with lung function compared to BMI, especially in the under-nourished child and adolescent with PI-CF.
doi:10.3389/fped.2014.00033
PMCID: PMC3995066  PMID: 24783186
body mass index; lean body mass; fat mass index; lean body mass index; pancreatic insufficient
3.  Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism 
Introduction
Hypertrophic cardiomyopathy (HCM) is a well-recognised complication in infants of diabetic mothers and is attributed to a compensatory increase in fetal insulin secretion. Infants with congenital hyperinsulinism have excessive prenatal and postnatal insulin secretion due to defects in pathways of insulin secretion (most commonly the KATP channel). HCM has been reported in a few neonates with hyperinsulinism, but its extent and risk factors for its development have not been evaluated.
Methods
Retrospective chart review of infants, age <3 months, with congenital hyperinsulinism managed by Children’s Hospital of Philadelphia over a 3.5-year period.
Data
Gestational age, birth weight, hyperinsulinism form and treatments, echocardiogram results, cardiac/ respiratory complications.
Results
68 infants were included, 58 requiring pancreatectomy for diffuse (n=28) or focal (n=30) disease, 10 were diazoxide-sensitive. Twenty-five had echocardiograms performed. Ten had HCM, all of whom required pancreatectomy and eight of whom had confirmed ATP-sensitive potassium-hyperinsulinism. Subjects with HCM had younger gestational age 36(32, 38) than their surgical counterparts without HCM 38 (31.6, 43), p=0.02.
Discussion
HCM appears common in infants with severe hyperinsulinism. Routine echocardiogram and EKG of at-risk newborns should be considered. Fetal hyperinsulinism is the likely mediating factor for HCM in HI infants.
doi:10.1136/archdischild-2012-302546
PMCID: PMC3683355  PMID: 23377780
4.  Biospecimen Reporting for Improved Study Quality (BRISQ) 
Journal of proteome research  2011;10(8):3429-3438.
Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The BRISQ guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.
doi:10.1021/pr200021n
PMCID: PMC3169291  PMID: 21574648
5.  Biospecimen Reporting for Improved Study Quality 
Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The Biospecimen Reporting for Improved Study Quality guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.
doi:10.1089/bio.2010.0036
PMCID: PMC3142856  PMID: 21826252
6.  Acute Insulin Responses to Leucine in Children with the Hyperinsulinism/Hyperammonemia Syndrome 
Mutations of glutamate dehydrogenase cause the hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases β-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of l-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at −10, −5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min after an iv leucine bolus. The hyperinsulinism/hyperammonemia syndrome group had excessively increased insulin responses to leucine (mean ± SEM, 73 ± 21 μIU/ml) compared with the control children and adults (n = 17) who had no response to leucine (1.9 ± 2.7 μU/ml; P < 0.05). Four hyperinsulinism/hyperammonemia syndrome patients then had acute insulin responses to leucine repeated at hyperglycemia (blood glucose, 150–180 mg/dl). High blood glucose suppressed their abnormal baseline acute insulin responses to leucine of 180, 98, 47, and 28 μU/ml to 73, 0, 6, and 19 μU/ml, respectively. This suppression suggests that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption.
PMCID: PMC3313679  PMID: 11502802
7.  Elevation of 1-Hour Plasma Glucose During Oral Glucose Tolerance Testing Is Associated With Worse Pulmonary Function in Cystic Fibrosis 
Diabetes Care  2011;34(2):292-295.
OBJECTIVE
Cystic fibrosis (CF)-related diabetes (CFRD) is associated with declining pulmonary function and increased mortality. During oral glucose tolerance testing (OGTT), CFRD is defined by 2-h plasma glucose (PG2). We hypothesized PG elevations during OGTT resolving by 2 h, not meeting CFRD criteria, influence pulmonary function in CF. Thus we investigated the frequency of elevated 1-h OGTT PG (PG1) and its relationship with pulmonary function.
RESEARCH DESIGN AND METHODS
Retrospective review of OGTTs was performed between August 2005 (annual screening initiation) and June 2008 at Children’s Hospital of Philadelphia CF Center. First-time, well state OGTTs (PG0, PG1, PG2) were analyzed. Additional data collected were: percent predicted forced expiratory volume in 1 s (FEV1), BMI percentile, lung bacterial colonization, age, and sex. OGTTs were categorized as normal (PG2 <140 mg/dL), impaired glucose tolerance (IGT) (PG2 140–199 mg/dL), CFRD (PG2 ≥200 mg/dL), and indeterminate glycemia (INDET) (PG1 ≥200 mg/dL and PG2 <140 mg/dL). Frequency of PG1 ≥140 but <200 mg/dL was also noted. Multivariable linear regression was used to assess associations between percent predicted FEV1, BMI percentile, and OGTT PG.
RESULTS
OGTTs (101) were available (59 male/42 female; age 5.8–22 years, percent predicted FEV1 = 94.5 ± 18%, BMI percentile = 52 ± 25%). With the use of PG2, 91 OGTT were normal, eight were IGT, and two were CFRD. With the use of PG1 (n = 89), 39 OGTT were normal, 36 were PG1 ≥140 <200 mg/dL, and 14 were PG1 ≥200 mg/dL. PG1 was negatively associated with percent predicted FEV1, adjusting for BMI percentile (P = 0.009, R2 0.13). Percent predicted FEV1 was not associated with PG0, PG2, age, sex, or lung bacterial colonization.
CONCLUSIONS
PG elevations at nontraditional OGTT times are common in CF. The association of increasing PG1 with worse pulmonary function suggests early PG abnormalities may be deleterious or an early marker for worsening disease and will be missed if CFRD diagnosis focuses on PG2.
doi:10.2337/dc10-1604
PMCID: PMC3024336  PMID: 21228248
8.  A Review of International Biobanks and Networks: Success Factors and Key Benchmarks 
Biopreservation and Biobanking  2009;7(3):143-150.
Biobanks and biobanking networks are involved in varying degrees in the collection, processing, storage, and dissemination of biological specimens. This review outlines the approaches that 16 of the largest biobanks and biobanking networks in Europe, North America, Australia, and Asia have taken to collecting and distributing human research specimens and managing scientific initiatives while covering operating costs. Many are small operations that exist as either a single or a few freezers in a research laboratory, hospital clinical laboratory, or pathology suite. Larger academic and commercial biobanks operate to support large clinical and epidemiological studies. Operational and business models depend on the medical and research missions of their institutions and home countries. Some national biobanks operate with a centralized physical biobank that accepts samples from multiple locations. Others operate under a “federated” model where each institution maintains its own collections but agrees to list them on a central shared database. Some collections are “project-driven” meaning that specimens are collected and distributed to answer specific research questions. “General” collections are those that exist to establish a reference collection, that is, not to meet particular research goals but to be available to respond to multiple requests for an assortment of research uses. These individual and networked biobanking systems operate under a variety of business models, usually incorporating some form of partial cost recovery, while requiring at least partial public or government funding. Each has a well-defined biospecimen-access policy in place that specifies requirements that must be met—such as ethical clearance and the expertise to perform the proposed experiments—to obtain samples for research. The success of all of these biobanking models depends on a variety of factors including well-defined goals, a solid business plan, and specimen collections that are developed according to strict quality and operational controls.
doi:10.1089/bio.2010.0003
PMCID: PMC4046743  PMID: 24835880
9.  Deficits in Bone Mineral Content in Children and Adolescents with Cystic Fibrosis Are Related to Height Deficits 
Objective
Despite reports of decreased bone density, children with mild to moderate cystic fibrosis (CF)-associated pulmonary disease do not have increased fracture rates. Short stature and delayed puberty complicate interpretations of bone mineral status in many children with chronic diseases. This study sought to characterize bone mineral content (BMC) in children with CF and determine its relationship to growth, body composition, and disease severity.
Design
Dual energy x-ray absorptiometry measurements of whole body BMC (WB-BMC), spine BMC (Sp-BMC), and lean body mass (LBM) were converted to Z-scores in 82 CF and 322 healthy children. Effects of growth, body composition, and CF-disease characteristics upon BMC were determined using linear regression.
Results
Children with CF had lower weight, height (HT), BMI, and LBM-Z. Females with CF had lower (p<0.001) WB-BMC-Z (−1.1±1.1) and Sp-BMC-Z (−0.9±1.1) than controls. Following adjustment for HT-Z, deficits were absent. Males with CF had lower (p<0.001) WB-BMC-Z (−1.3±0.9) and Sp-BMC-Z (−0.9±1.3). Following adjustment for HT-Z, WB-BMC-Z deficits were attenuated and Sp-BMC-Z deficits absent. HT-Z, LBM-Z, and pulmonary function had independent effects upon WB-BMC-Z and Sp-BMC-Z.
Conclusion
BMC deficits are related to altered body size, reduced LBM, and pulmonary function in children with CF. Interventions targeting improved growth, muscle mass, and pulmonary function may benefit bone health in CF.
doi:10.1016/j.jocd.2008.07.002
PMCID: PMC2633715  PMID: 18757221
bone density; bone mineral content; cystic fibrosis; DXA; children

Results 1-10 (10)