Andrea Kelly

Height Adjustment in Assessing Dual Energy X- Ray Absorptiometry Measurements of Bone Mass and Density in Children

CONTEXT In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. OBJECTIVE The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). SETTING We conducted the study in five clinical centers in the United States. PARTICIPANTS We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION No interventions were used. MAIN OUTCOME MEASURES We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). RESULTS Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

An update on the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from the Cystic Fibrosis Foundation.

OBJECTIVE The objective was to develop evidence-based clinical care guidelines for the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis (CF). PARTICIPANTS The guidelines committee was comprised of physicians, registered dietitians, a pharmacist, a nurse, a parent of an individual with CF, and a health scientist, all with experience in CF. PROCESS Committee members developed questions specific to vitamin D health in individuals with CF. Systematic reviews were completed for each question. The committee reviewed and graded the available evidence and developed evidence-based recommendations and consensus recommendations when insufficient evidence was available. Each consensus recommendation was voted upon by an anonymous process. CONCLUSIONS Vitamin D deficiency is common in CF. Given the limited evidence specific to CF, the committee provided consensus recommendations for most of the recommendations. The committee recommends yearly screening for vitamin D status, preferably at the end of winter, using the serum 25-hydroxyvitamin D measurement, with a minimal 25-hydroxyvitamin D concentration of 30 ng/ml (75 nmol/liter) considered vitamin D sufficient in individuals with CF. Recommendations for age-specific vitamin D intake for all individuals with CF, form of vitamin D, and a stepwise approach to increase vitamin D intake when optimal vitamin D status is not achieved are delineated.

Update on cystic fibrosis-related diabetes

Diabetes mellitus has emerged as a common comorbidity in cystic fibrosis and is considered a clinical entity (cystic fibrosis-related diabetes, CFRD) distinct from that of type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The relevance of this diagnosis extends not only from its imposition of additional medical burden but its association with worse health outcomes in individuals with CF. This paper will review the 2010 U.S. and other international guidelines for screening and treating CFRD. It will highlight newer data regarding early glucose and insulin secretion defects, mechanisms linking CFRD to worse outcomes, and recent advances in T2DM that may provide insights for CFRD; insulin secretion will be reviewed as background for these recent developments.

Elevation of 1-Hour Plasma Glucose During Oral Glucose Tolerance Testing Is Associated With Worse Pulmonary Function in Cystic Fibrosis

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.

A cross-sectional study of vitamin D and insulin resistance in children

Objective Vitamin D deficiency is common and has been associated with several non-bone/calcium related outcomes. The objective was to determine the association between serum 25-hydroxyvitamin D (25-OH-D) and fasting glucose, insulin and insulin sensitivity in obese and non-obese children. Patients/setting/design Cross-sectional study of 85 children aged 4–18 years recruited from the local Philadelphia community and Sleep Center. Main outcomes measures Fasting blood glucose, insulin and 25-OH-D were measured. Insulin resistance was calculated using homeostasis model assessment (HOMA). Body mass index standard deviation scores (BMI-Z) and pubertal stage were determined. Multivariable linear regression was used to determine factors associated with decreased 25-OH-D and to determine the association of vitamin D with HOMA. Results Median 25-OH-D was 52 nmol/l (IQR 34–76). 26% of subjects were vitamin D sufficient (25-OH-D ≥75 nmol/l), 27% had intermediate values (50–75 nmol/l) and 47% were insufficient (25–50 nmol/l) or frankly deficient (<25 nmol/l). In the multivariable model, older age, higher BMI-Z and African–American race were all negatively associated with 25-OH-D; summer was positively associated with 25-OH-D. Lower 25-OH-D was associated with higher fasting blood glucose, insulin and HOMA after adjustment for puberty and BMI-Z. Conclusion Low 25-OH-D, common in the paediatric population at risk for diabetes (older children, African–Americans, children with increasing BMI-Z) is associated with worse insulin resistance.

Neurological aspects of hyperinsulinism–hyperammonaemia syndrome

Hyperinsulinism–hyperammonaemia syndrome (HHS) is a rare cause of congenital hyperinsulinism, due to missense mutations in the GLUD1 gene, resulting in glutamate dehydrogenase (GDH) overactivity. The aim of this study was to document the spectrum of neurological disturbances associated with HHS and to identify possible phenotype–genotype correlations. We retrospectively analyzed the neurological outcomes of 22 consecutive patients (12 males, 10 females) aged from 18 months to 40 years and diagnosed with HHS. We analyzed demographic and clinical features and neuroradiological, biochemical, and genetic findings. Fourteen patients had childhood‐onset epilepsy. Learning disability * was found in 17 patients. Two patients had pyramidal involvement and one had generalized dystonia. Seizures were observed in 11 of 19 patients with documented GLUD1 mutations, and nine of these 11 patients had a mutation in the guanosine triphosphate (GTP) binding site. Our data demonstrate that neurological disorders in HHS are more frequent than previously thought and might suggest that mutations in the GTP binding site of GDH could be associated with more frequent epilepsy.

Effects of a GTP-insensitive Mutation of Glutamate Dehydrogenase on Insulin Secretion in Transgenic Mice

Glutamate dehydrogenase (GDH) plays an important role in insulin secretion as evidenced in children by gain of function mutations of this enzyme that cause a hyperinsulinism-hyperammonemia syndrome (GDH-HI) and sensitize β-cells to leucine stimulation. GDH transgenic mice were generated to express the human GDH-HI H454Y mutation and human wild-type GDH in islets driven by the rat insulin promoter. H454Y transgene expression was confirmed by increased GDH enzyme activity in islets and decreased sensitivity to GTP inhibition. The H454Y GDH transgenic mice had hypoglycemia with normal growth rates. H454Y GDH transgenic islets were more sensitive to leucine- and glutamine-stimulated insulin secretion but had decreased response to glucose stimulation. The fluxes via GDH and glutaminase were measured by tracing 15N flux from [2-15N]glutamine. The H454Y transgene in islets had higher insulin secretion in response to glutamine alone and had 2-fold greater GDH flux. High glucose inhibited both glutaminase and GDH flux, and leucine could not override this inhibition. 15NH4Cl tracing studies showed 15N was not incorporated into glutamate in either H454Y transgenic or normal islets. In conclusion, we generated a GDH-HI disease mouse model that has a hypoglycemia phenotype and confirmed that the mutation of H454Y is disease causing. Stimulation of insulin release by the H454Y GDH mutation or by leucine activation is associated with increased oxidative deamination of glutamate via GDH. This study suggests that GDH functions predominantly in the direction of glutamate oxidation rather than glutamate synthesis in mouse islets and that this flux is tightly controlled by glucose.

Infant BMI or Weight-for-Length and Obesity Risk in Early Childhood.

BACKGROUND: Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity. METHODS: Anthropometrics were extracted from electronic medical records for well-child visits for 73 949 full-term infants from a large pediatric network. World Health Organization WFL and BMI z scores (WFL-z and BMI-z, respectively) were calculated up to age 24 months. Correlation analyses assessed the agreement between WFL-z and BMI-z and within-subject tracking over time. Logistic regression determined odds of obesity at 2 years on the basis of adiposity classification at 2 months. RESULTS: Agreement between WFL-z and BMI-z increased from birth to 6 months and remained high thereafter. BMI-z at 2 months was more consistent with measurements at older ages than WFL-z at 2 months. Infants with high BMI (≥85th percentile) and reference WFL (5th–85th percentiles) at 2 months had greater odds of obesity at 2 years than those with high WFL (≥85th percentile) and reference BMI (5th–85th percentiles; odds ratio, 5.49 vs 1.40; P < .001). At 2 months, BMI had a higher positive predictive value than WFL for obesity at 2 years using cut-points of either the 85th percentile (31% vs 23%) or 97.7th percentile (47% vs 29%). CONCLUSIONS: High BMI in early infancy is more strongly associated with early childhood obesity than high WFL. Forty-seven percent of infants with BMI ≥97.7th percentile at 2 months (versus 29% of infants with WFL ≥97.7th percentile at 2 months) were obese at 2 years. Epidemiologic studies focused on assessing childhood obesity risk should consider using BMI in early infancy.

Transitory Expression of Alpha Cardiac Myosin Heavy Chain in a Subpopulation of Secondary Generation Muscle Fibers in the Pig

Unlike the random distribution of fiber types seen in skeletal muscles of most mammals, pig muscle exhibits a rosette pattern consisting of islets of slow fibers surrounded by concentric circles of type IIA and IIB fibers. Within each islet of slow fibers, one of the central fibers is a primary myofiber, whereas all others are secondary fibers. The present study demonstrates that a subpopulation of the slow secondary fibers transiently expresses α‐myosin heavy chain (MHC). Two cDNA libraries were made from longissimus dorsi skeletal muscle of 14‐day‐old piglet and adult pig atrium; the latter muscle is mainly composed of α‐MHC. Screening of the libraries with a human anti‐α‐MHC mAb (F8812F8) demonstrated the presence of positive MHC clones in both libraries; the nucleotide sequence of the 3′‐untranslated region (3′‐UTR) was identical in both libraries. As this MHC 3′‐UTR had 75% homology with the human α‐MHC, it was identified as pig α‐MHC. Using specific cRNA probes and mAbs against pig α‐cardiac and β/slow/type I MHC, we studied the expression of these MHCs in developing pig semitendinosus muscle by combining in situ hybridization and immunocytochemistry on serial sections at 90 days of gestation, and at 1, 6, 35 days and 6 months of age. The results showed that a subpopulation of secondary fibers that directly abut primary fibers, transiently produced α‐MHC, both at the levels of the protein and its transcript. Subsequently, these fibres expressed β‐MHC. At 1 day, immunocytochemistry showed that 16% of the secondary fibers expressed α‐MHC, among which 20% did not yet express β‐MHC. At 6 days, α‐ and β‐MHCs were mostly present in the same fibers, i.e., 23% of the secondary fibers. Thereafter, the proportion of secondary fibers reacting with α‐MHC mAb decreased to 10% at 5 weeks and 0% at 6 months, whereas β‐MHC was still accumulating in about 38% of the secondary fibers. During the period studied, the distribution of α‐ and β‐MHC transcripts closely matched that of the corresponding proteins. Expression of α‐MHC was not detected in primary type I muscle fibers and slow type I secondary fibers at the periphery of the rosettes of slow fibers. This study is the first unequivocal demonstration of a transitory expression of α‐MHC in a subpopulation of secondary fibers in a limb skeletal muscle during mammalian development. Dev. Dyn. 1997;210:106–116.

Hypocalcemia in the critically ill patient

Hypocalcemia is common in the critically ill patient. In this population, however, the diagnosis of hypocalcemia is complicated by limitations in the interpretation of the total plasma calcium concentration. These limitations are principally the result of the effects of hypoalbuminemia and disorders of acid-base balance on the total calcium concentration. Thus, measurement of ionized calcium can be critical in determining an individual’s true serum calcium status. In this review, we first describe the regulation of normal calcium metabolism and then focus on the various etiologies of hypocalcemia, including congenital and acquired disorders of parathyroid hormone and vitamin D, which are encountered in the neonatal, pediatric, and adult critical care settings. The approach to the treatment of hypocalcemia and the current consensus on treatment of hypocalcemia in the critically ill patient is also presented.