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Objectives: To describe rates of prediabetes among youth in Canada and the associated social and biological characteristics., Methods: We analyzed the cross-sectional data from the first (2007-2009) and second (2009-2011) cycles of the Canadian Health Measures Survey (CHMS) for youth aged 6-19 years. Prediabetes was defined using the glycated hemoglobin (A1C) guidelines set out by the American Diabetes Association (ADA) and the Canadian Diabetes Association (CDA) of A1C ranges 5.7-6.4% (38.8-46.4 mmol/mol) and 6.0-6.4% (42.1-46.4 mmol/mol), respectively., Results: An elevated A1C was observed in 22.8% of our sample (n = 3449) based on the ADA definition and 5.2% of youth using the CDA definition. Independent predictors in a fully adjusted model for prediabetes were non-White (odds ratio (OR) 2.62: 95% Confidence intervals 2.05-3.35), obese (OR 1.53: 1.19-1.96), less physically active youth (0.97: 0.95-0.99), and parents with high school education or less (1.34: 1.02-1.74). Moreover, significant regional variations were noted with higher rates for all regions except Ontario., Conclusion: Prediabetes is relatively common in Canada and associated with common biologic and socioeconomic factors. Importantly, regular physical activity was significantly associated with reduced odds of prediabetes. Targeted screening and continued emphasis on physical activity may help curb the increasing rates of prediabetes.

Objectives: Childhood obesity interventions should be family-centered and focused on lifestyle behaviours that achieve sustainable reductions in adiposity. The primary objective of this randomized controlled trial was to test a family-centered lifestyle intervention using Canada's Food and Physical Activity (PA) Guidelines to reduce body mass index-for-age z-scores (BAZ) in overweight and obese (OW/OB) children., Methods: Children (n = 78; ages 6-8.5 years) were randomized to standard (StnTx) or modified (ModTx) interventions or control (Ctrl). Measurements at baseline and every three months for one year included: anthropometry, BAZ, waist circumference (WC), and dual-energy X-ray absorptiometry scans for percent body fat (%BF), fat mass (FM) and trunk fat mass. Fatty acids measured by gas chromatography were used to assess compliance to the milk and alternatives interventions during the first six months. Six intervention sessions were based on Canada's Food and PA Guidelines and individualized to meet the needs of the family. ModTx were advised to consume four milk and alternatives/day versus the recommended two (StnTx) and to preferentially engage in daily weight-bearing PA. Ctrl were provided the guidelines., Results: Baseline anthropometry did not differ among groups. At 12 months (n = 73), all groups increased height (p < 0.001) and lean mass (p < 0.001). ModTx decreased BAZ (p < 0.001); %BF decreased in ModTx (p = 0.018), but not in StnTx (p = 0.997) or Ctrl (p = 0.998). FM, WC and trunk fat mass all significantly increased in Ctrl (p < 0.001). At baseline and three months, fatty acids did not differ among groups, however they did decrease in ModTx at six months [C14:0 (-0.07%, p = 0.053), C15:0 (-0.04%, p = 0.049), C17:0 (-0.09%, p = 0.036)]., Conclusion: Participating in a family centered-lifestyle intervention that focused on Canadian dietary and PA Guidelines and emphasized increasing milk and alternatives and weight-bearing PA had positive effects on reducing adiposity in OW/OB children. Guidelines are appropriate for the obese pediatric population but need to be individualized to meet the needs of the family. Additional studies are warranted to test the use of biochemical indices to assess compliance to milk and alternative intakes in OW/OB children participating in lifestyle interventions.

Background: Previous studies have shown an increase in the prevalence of overweight and obesity among Canadian children from 23.3% to 34.7% during 1978-2004. We examined the most recent trends by applying current definitions of overweight and obesity based on World Health Organization (WHO) body mass index (BMI) thresholds and recently validated norms for waist circumference and waist:height ratio., Methods: We examined directly measured height and weight data from the Canadian Community Health Survey (2004-2005) and the Canadian Health Measures Survey (2009-2013). We calculated z scores for BMI, height and weight based on the 2014 WHO growth charts for Canada, including the new extension of weight-for-age beyond 10 years. To calculate z scores for waist circumference and waist:height ratios, we used new charts from the reference population in the US NHANES III (National Health and Nutrition Examination Survey, 1988-1994)., Results: Data were available for 14 014 children aged 3-19 years for the period 2004-2013. We observed a decline in the prevalence of overweight or obesity, from 30.7% (95% confidence interval [CI] 29.7% to 31.6%) to 27.0% (95% CI 25.3% to 28.7%) (p < 0.001) and stabilization in the prevalence of obesity at about 13%. These trends persisted after we adjusted for age, sex and race/ethnicity. Although they declined, the median z scores for BMI, weight and height were positive and higher than those in the WHO reference population. The z scores for waist circumference and waist:height ratio were negative, which indicated that the Canadian children had less central adiposity than American children in historic or contemporary NHANES cohorts., Interpretation: After a period of dramatic growth, BMI z scores and the prevalence of overweight or obesity among Canadian children decreased from 2004 to 2013, which attests to progress against this important public health challenge., (© 2016 Canadian Medical Association or its licensors.)

Context: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance., Case Description: A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64-369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality., Conclusions: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.

Objectives: The purpose of this article was to determine the incidence and predictors of vertebral fractures (VF) during the 4 years after diagnosis in pediatric acute lymphoblastic leukemia (ALL)., Patients and Methods: Children were enrolled within 30 days of chemotherapy initiation, with incident VF assessed annually on lateral spine radiographs according to the Genant method. Extended Cox models were used to assess the association between incident VF and clinical predictors., Results: A total of 186 children with ALL completed the baseline evaluation (median age, 5.3 years; interquartile range, 3.4-9.7 years; 58% boys). The VF incidence rate was 8.7 per 100 person-years, with a 4-year cumulative incidence of 26.4%. The highest annual incidence occurred at 12 months (16.1%; 95% confidence interval [CI], 11.2-22.7), falling to 2.9% at 4 years (95% CI, 1.1-7.3). Half of the children with incident VF had a moderate or severe VF, and 39% of those with incident VF were asymptomatic. Every 10 mg/m(2) increase in average daily glucocorticoid dose (prednisone equivalents) was associated with a 5.9-fold increased VF risk (95% CI, 3.0-11.8; P < .01). Other predictors of increased VF risk included VF at diagnosis, younger age, and lower spine bone mineral density Z-scores at baseline and each annual assessment., Conclusions: One quarter of children with ALL developed incident VF in the 4 years after diagnosis; most of the VF burden was in the first year. Over one third of children with incident VF were asymptomatic. Discrete clinical predictors of a VF were evident early in the patient's clinical course, including a VF at diagnosis.

The effect of the inhaled anaesthetic isoflurane was investigated on bone biomarkers, both during maturation and on minerals and glucose postpartum. Female guinea pigs (n = 10) were anaesthetized during maturation (5 and 9 weeks) and postpartum (26 weeks of age) with isoflurane during dual-energy X-ray absorptiometry scanning. Blood collection was performed at all ages before and after anaesthesia for measurement of plasma osteocalcin (OC), total deoxypyridinoline (tDPD), and cortisol. Postpartum measurements also included: blood ions, acid-base parameters and glucose, plasma minerals, total alkaline phosphatase (tALP), and albumin. Plasma OC concentration almost doubled after exposure to isoflurane at 5 weeks (30.1 ± 5.0-57.9 ± 11.2 nmol/L, p < 0.001) and at 9 weeks (29.1 ± 7.5-62.9 ± 15.9 nmol/L, p < 0.001), but did not change postpartum (3.7 ± 3.3-4.3 ± 3.9 nmol/L, p = 0.88). There was no effect of isoflurane exposure on plasma tDPD at any age. Plasma cortisol increased after exposure to isoflurane at 9 weeks (1859.6 ± 383.2-2748.0 ± 235.3 nmol/L, p < 0.01) and postpartum (3376.7 ± 322.2-4091.6 ± 195.6 nmol/L, p < 0.001) but not at 5 weeks (2088.3 ± 326.4-2464.1 ± 538.0 nmol/L, p > 0.05). Blood ionized Ca(2+), Na(+) and plasma total Ca did not change, whereas plasma albumin decreased, and inorganic phosphate (PO4) and Cl(-) increased upon exposure to isoflurane. Isoflurane decreased tALP (43.2 ± 6.6-40.2 ± 5.9 IU/L, p = 0.01) and increased glucose (7.5 ± 0.6-10.9 ± 1.7 mmol/L, p < 0.0001) postpartum. Isoflurane inflates the assessment of a bone-derived biomarker, OC, during rapid growth, but not following pregnancy when formation is very low. Measurements prior to anaesthesia are recommended to reflect normal metabolism.

Objectives: Our objectives were to assess the magnitude of the disparity in lumbar spine bone mineral density (LSBMD) Z-scores generated by different reference databases and to evaluate whether the relationship between LSBMD Z-scores and vertebral fractures (VF) varies by choice of database., Patients and Design: Children with leukemia underwent LSBMD by cross-calibrated dual-energy x-ray absorptiometry, with Z-scores generated according to Hologic and Lunar databases. VF were assessed by the Genant method on spine radiographs. Logistic regression was used to assess the association between fractures and LSBMD Z-scores. Net reclassification improvement and area under the receiver operating characteristic curve were calculated to assess the predictive accuracy of LSBMD Z-scores for VF., Results: For the 186 children from 0 to 18 years of age, 6 different age ranges were studied. The Z-scores generated for the 0 to 18 group were highly correlated (r ≥ 0.90), but the proportion of children with LSBMD Z-scores ≤-2.0 among those with VF varied substantially (from 38-66%). Odds ratios (OR) for the association between LSBMD Z-score and VF were similar regardless of database (OR = 1.92, 95% confidence interval 1.44, 2.56 to OR = 2.70, 95% confidence interval 1.70, 4.28). Area under the receiver operating characteristic curve and net reclassification improvement ranged from 0.71 to 0.75 and -0.15 to 0.07, respectively., Conclusions: Although the use of a LSBMD Z-score threshold as part of the definition of osteoporosis in a child with VF does not appear valid, the study of relationships between BMD and VF is valid regardless of the BMD database that is used.

Background: Glycogen storage disease type III is caused by mutations in both alleles of the AGL gene, which leads to reduced activity of glycogen-debranching enzyme. The clinical picture encompasses hypoglycemia, with glycogen accumulation leading to hepatomegaly and muscle involvement (skeletal and cardiac). We sought to identify the genetic cause of this disease within the Inuit community of Nunavik, in whom previous DNA sequencing had not identified such mutations., Methods: Five Inuit children with a clinical and biochemical diagnosis of glycogen storage disease type IIIa were recruited to undergo genetic testing: 2 underwent whole-exome sequencing and all 5 underwent Sanger sequencing to confirm the identified mutation. Selected DNA regions near the AGL gene were also sequenced to identify a potential founder effect in the community. In addition, control samples from 4 adults of European descent and 7 family members of the affected children were analyzed for the specific mutation by Sanger sequencing., Results: We identified a homozygous frame-shift deletion, c.4456delT, in exon 33 of the AGL gene in 2 children by whole-exome sequencing. Confirmation by Sanger sequencing showed the same mutation in all 5 patients, and 5 family members were found to be carriers. With the identification of this mutation in 5 probands, the estimated prevalence of genetically confirmed glycogen storage disease type IIIa in this region is among the highest worldwide (1:2500). Despite identical mutations, we saw variations in clinical features of the disease., Interpretation: Our detection of a homozygous frameshift mutation in 5 Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect., (© 2015 Canadian Medical Association or its licensors.)

This study examined the associations between vitamin D status, bone mineral content (BMC), areal bone mineral density (aBMD), and markers of calcium homeostasis in preschool-aged children. Children (n=488; age range: 1.8-6.0 y) were randomly recruited from Montreal. The distal forearm was scanned using a peripheral dual-energy X-ray absorptiometry scanner (Lunar PIXI; GE Healthcare, Fairfield, CT). A subset (n=81) had clinical dual-energy X-ray absorptiometry (cDXA) scans (Hologic 4500A Discovery Series) of lumbar spine (LS) 1-4, whole body, and ultradistal forearm. All were assessed for plasma 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone concentrations (Liaison; Diasorin), ionized calcium (ABL80 FLEX; Radiometer Medical A/S), and dietary vitamin D and calcium intakes by survey. Age (p<0.001) and weight-for-age Z-score (p<0.001) were positively associated with BMC and aBMD in all regression models, whereas male sex contributed positively to forearm BMC and aBMD. Having a 25(OH)D concentration of >75 nmol/L positively associated with forearm and whole body BMC and aBMD (p<0.036). Sun index related to (p<0.029) cDXA forearm and LS 1-4 BMC and whole-body aBMD. Nutrient intakes did not relate to BMC or aBMD. In conclusion, higher vitamin D status is linked to higher BMC and aBMD of forearm and whole body in preschool-aged children., (Copyright © 2015 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: Whether there is a dose-dependent effect of maternal dietary cholecalciferol during pregnancy on maternal glucose tolerance is unknown. In addition, circulating osteocalcin is increased by 1,25-dihydroxyvitamin D [1,25(OH)2D] and may improve glucose homeostasis., Objective: This study was designed to test whether dietary cholecalciferol during pregnancy dose-dependently affects maternal glucose tolerance and maternal and neonatal glucose concentrations in relation to plasma osteocalcin and body composition., Methods: Female guinea pigs (n = 45; 4 mo old) were randomly assigned to 5 doses of cholecalciferol (0, 0.25, 0.5, 1, or 2 IU/g diet) fed from mating to delivery. Plasma vitamin D metabolites, minerals, and osteocalcin, and blood glucose were measured before mating, at midgestation (day 42), and at day 2 postpartum in sows and in 2-d-old pups. At day 50 of pregnancy (early third trimester), a 3-h oral-glucose-tolerance test (OGTT) (2 g/kg) was conducted. Body composition was measured before mating and at day 2 postpartum in sows and in pups., Results: A positive dose-response to dietary cholecalciferol was observed for change in maternal plasma 25-hydroxyvitamin D [25(OH)D] through pregnancy (P < 0.0001), with 1,25(OH)2D increasing by 198% in the 1-IU/g group by midgestation vs. a reduction of 43.6% in the 0-IU/g group (P = 0.05). Twenty-four (54.5%) sows had gestational diabetes mellitus (GDM) on the basis of nonfed glucose and 39 (88.6%) had GDM on the basis of 2-h OGTT glucose concentrations. There were no group differences in maternal OGTT or changes in glucose, minerals, osteocalcin concentrations, and body composition. Pre-mating 25(OH)D was inversely related to 3-h area under the curve for blood glucose from the OGTT (r = -0.31, P = 0.05). In guinea pig pups, although both 25(OH)D (P < 0.0001) and 1,25(OH)2D (P < 0.0001) followed a dose-response to maternal diet, glucose, osteocalcin, minerals, and body composition were not altered., Conclusions: Dietary vitamin D intake during pregnancy in guinea pigs does not affect the already high rate of GDM, whereas higher prepregnancy vitamin D status appears to be protective., (© 2014 American Society for Nutrition.)

Background: The effects of vitamin D during pregnancy on maternal and neonatal bone health remain unclear., Objective: This study was designed to test whether dietary vitamin D dose-dependently affects maternal and neonatal bone health., Methods: Female guinea pigs (n = 45; 4 mo old) were randomly assigned at mating to receive 1 of 5 doses of vitamin D3 (cholecalciferol; 0, 0.25, 0.5, 1, or 2 IU/g diet) throughout pregnancy. Plasma vitamin D metabolites, mineral homeostasis, bone biomarkers, and bone mass were tested in sows throughout pregnancy and in 2-d-old pups. Microarchitecture and histology of excised bone were conducted postpartum., Results: By 3 wk of pregnancy, plasma 25-hydroxyvitamin D [25(OH)D] followed a positive dose-response, whereas 1,25-dihydroxyvitamin D [1,25(OH)2D] reached a plateau if vitamin D was ≥0.5 IU/g diet. Weight gain, areal bone mineral density (aBMD), volumetic bone mineral density (vBMD), and bone biomarkers did not differ among maternal groups. A positive dose-response was observed for mean ± SEM pup plasma concentrations of 25(OH)D (10.5 ± 1.50 to 113 ±11.6 nmol/L) and 1,25(OH)2D (123 ± 13.8 to 544 ± 53.3 pmol/L). Pup weight, plasma minerals, and osteocalcin were not different; plasma deoxypyridinoline was lower in the 1- and 0.25-IU/g groups than in all other groups. Pup femur aBMD was higher (9.2-13%; P = 0.04) in the 2-IU/g group than in all other groups except for the 0-IU/g group. Tibia and femur vBMD of pups responded to maternal diet in a U-shaped pattern. The femoral growth plate was 7.9% wider in the 0-IU/g group than in the 1-IU/g group., Conclusions: Maternal vitamin D supplementation dose-dependently altered pup long bone architecture and mineral density in a manner similar to vitamin D deficient rickets whereas maternal bone was stable. These data reinforce that inadequate maternal vitamin D intake may compromise neonatal bone health and that exceeding recommendations is not advantageous., (© 2014 American Society for Nutrition.)

Objective: The purpose of this study was to investigate circulating concentrations of osteocalcin, a bone-derived protein, while accounting for 25-hydroxyvitamin D (25(OH)D) throughout pregnancy, and whether early gestation concentrations and changes in osteocalcin predict the subsequent diagnosis of gestational diabetes mellitus (GDM)., Methods: This was a nested case-control study involving 48 GDM and 48 control pregnant Caucasian women (matched for age, season of conception, pre-pregnancy body mass index and pregnancy length). Maternal serum osteocalcin was measured by enzyme-linked immunosorbent assay and 25(OH)D by chemiluminescence throughout pregnancy (11-13 weeks, 24-28 weeks and predelivery). Differences between groups were compared by mixed model analysis of variance. Predictors of diagnosis of GDM were explored using generalized estimating equation models. Neonatal general health outcomes were also compared between groups., Results: Serum osteocalcin was higher across pregnancy (p=0.006) in women with GDM vs. controls, whereas serum 25(OH)D was not different (p=0.80). Both biomarkers increased with time across pregnancy (p<0.0001). However, serum osteocalcin during early pregnancy and changes in its concentration from early to mid gestation did not predict the development of GDM. There were no significant differences in anthropometry and APGAR (appearance, pulse, grimace, activity, respiration) scores in neonates of controls and cases., Conclusions: Serum osteocalcin is elevated in Caucasian women with GDM throughout pregnancy, but was not predictive of the onset of GDM. Larger trials evaluating the role of osteocalcin and the development of GDM appear warranted., (Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Dual-energy X-ray absorptiometry (DXA) measures of bone mineral density (BMD) are generally not feasible in fieldwork. The present study determined the agreement between BMD measured by DXA and portable peripheral DXA in preschool aged children. Fifty-seven children (4.2 ± 1.0 yr) had their nondominant distal forearm scanned using a peripheral DXA scanner (PIXI; GE Medical Systems Lunar, Madison, WI) at their daycare and a DXA (4500A Discovery Series; Hologic Inc., Bedford, MA) at our research clinic. Correlation analysis, one-way analysis of variance, and Bland-Altman plots were performed to examine the agreement between measurements. Data were also divided into tertiles for cross-classification analysis and calculation of kappa coefficients. Distal forearm BMD measured by PIXI was significantly correlated with DXA measures of total forearm BMD (r > 0.51; p < 0.001), proximal 1/3 BMD (r > 0.41; p < 0.001), mid-BMD (r > 0.37; p < 0.001), and ultradistal (UD) BMD (r > 0.57; p < 0.001). Cross-classification in the same or adjacent tertile between measures (UD forearm: 96.5%; UD radius: 94.4%; total forearm: 87.7%; total radius: 84.2%) resulted in weighted kappa coefficients of 0.46, 0.58, 0.42, and 0.43, respectively. Bland-Altman plots further clarified these agreements as all had low bias (UD forearm: bias = 0.003 ± 0.002; UD radius: -0.015 ± 0.021; total forearm: -0.062 ± 0.027; total radius: -0.077 ± 0.026). These results demonstrate that portable DXA measures of forearm BMD agree moderately with DXA., (Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids (GC) are a standard treatment for pediatric rheumatic disease. Recent literature highlights skeletal vulnerability in children with rheumatic illness, including vertebral and peripheral fractures and reductions in bone mineral density in longitudinal follow-up. Annual vertebral fracture incidence of 4-6 % in those recently diagnosed and prevalence of 7-28 % in those several years post diagnosis have been reported. The fractures are often asymptomatic, often thoracic in location, and usually of mild, anterior wedge morphology. Diseases with more systemic involvement and severe inflammation (SLE, JDM) seem to be at higher risk. Neither BMD nor GC dose are ideal predictors for risk of fractures. These children also seem to have an increased incidence of long-bone fractures, particularly in the forearm and wrist; in the scant literature, long-bone fractures are not predictive of vertebral fractures. Bone mass accrual is typically suboptimum across time, although the use of potent steroid-sparing anti-inflammatory agents may counteract the effects of GC and active disease. Vitamin D insufficiency warrants ongoing monitoring. Additional targeted studies are justified to increase understanding of bone health risks in this population.