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1.  Periodontal Disease is Not Associated With Preeclampsia in Canadian Pregnant Women 
Journal of periodontology  2011;83(7):871-877.
The findings from the studies on the relationship between periodontal disease and preeclampsia are inconsistent. The objective of this study is to examine the relationship between periodontal disease and preeclampsia.
A multicenter case-control study was conducted in Quebec, Canada. Preeclampsia was defined as blood pressure ≥140/90 mm Hg and ≥1+ proteinuria after 20 weeks of gestation. Periodontitis was defined as the presence of ≥4 sites with a probing depth ≥5 mm and a clinical attachment loss ≥3 mm at the same sites.
A total of 92 preeclamptic women and 245 controls were analyzed. The percentage of periodontal disease was 18.5% in preeclamptic women and 19.2% in normotensive women (crude odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.52 to 1.77). After adjusting for confounding variables, periodontitis remained not associated with preeclampsia (adjusted OR = 1.13, 95% CI = 0.59 to 2.17).
This study does not support the hypothesis of an association between periodontal disease and preeclampsia.
PMCID: PMC4469482  PMID: 22191787 CAMSID: cams4723
Periodontitis; preeclampsia; pregnancy; pregnancy complications
2.  Early amniotomy and early oxytocin for prevention of, or therapy for, delay in first stage spontaneous labour compared with routine care 
Caesarean section rates are over 20% in many developed countries. The main diagnosis contributing to the high rate in nulliparae is dystocia or prolonged labour. The present review assesses the effects of a policy of early amniotomy with early oxytocin administration for the prevention of, or the therapy for, delay in labour progress.
To estimate the effects of early augmentation with amniotomy and oxytocin for prevention of, or therapy for, delay in labour progress on the caesarean birth rate and on indicators of maternal and neonatal morbidity.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (15 February 2012), MEDLINE (1966 to 15 February 2012), EMBASE (1980 to 15 February 2012), CINAHL (1982 to 15 February 2012), MIDIRS (1985 to February 2012) and contacted authors for data from unpublished trials.
Selection criteria
Randomized and quasi-randomized controlled trials that compared oxytocin and amniotomy with expectant management.
Data collection and analysis
Three review authors extracted data independently. We stratified the analyses into ’Prevention Trials’ and ’Therapy Trials’ according to the status of the woman at the time of randomization. Participants in the ’Prevention Trials’ were unselected women, without slow progress in labour, who were randomized to a policy of early augmentation or to routine care. In ’Treatment Trials’ women were eligible if they had an established delay in labour progress.
Main results
For this update, we have included a further two new clinical trials. This updated review includes 14 trials, randomizing a total of 8033 women. The unstratified analysis found early intervention with amniotomy and oxytocin to be associated with a modest reduction in the risk of caesarean section; however, the confidence interval (CI) included the null effect (risk ratio (RR) 0.89; 95% CI 0.79 to 1.01; 14 trials; 8033 women). In prevention trials, early augmentation was associated with a modest reduction in the number of caesarean births (RR 0.87; 95% CI 0.77 to 0.99; 11 trials; 7753). A policy of early amniotomy and early oxytocin was associated with a shortened duration of labour (average mean difference (MD) −1.28 hours; 95% CI −1.97 to −0.59; eight trials; 4816 women). Sensitivity analyses excluding four trials with a full package of active management did not substantially affect the point estimate for risk of caesarean section (RR 0.87; 95% CI 0.73 to 1.05; 10 trials; 5165 women). We found no other significant effects for the other indicators of maternal or neonatal morbidity.
Authors’ conclusions
In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care.
PMCID: PMC4160792  PMID: 22972098
*Labor Stage, First; Amnion [*surgery]; Cesarean Section [utilization]; Obstetric Labor Complications [prevention & control; *therapy]; Oxytocics [*administration & dosage]; Oxytocin [*administration & dosage]; Randomized Controlled Trials as Topic; Time Factors; Female; Humans; Pregnancy
3.  Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans 
Scientific Reports  2015;5:17881.
In vitro cell model studies have shown that oxidative stress may affect beta-cell function. It is unknown whether oxidative stress may affect metabolic health in human fetuses/newborns. In a singleton pregnancy cohort (n = 248), we studied maternal (24–28 weeks gestation) and cord plasma biomarkers of oxidative stress [malondialdehyde (MDA), F2-isoprostanes] in relation to fetal metabolic health biomarkers including cord plasma glucose-to-insulin ratio (an indicator of insulin sensitivity), proinsulin-to-insulin ratio (an indicator of beta-cell function), insulin, IGF-I, IGF-II, leptin, adiponectin and ghrelin concentrations. Strong positive correlations were observed between maternal and cord plasma biomarkers of oxidative stress (r = 0.33 for MDA, r = 0.74 for total F2-isoprostanes, all p < 0.0001). Adjusting for gestational age at blood sampling, cord plasma ghrelin concentrations were consistently negatively correlated to oxidative stress biomarkers in maternal (r = −0.32, p < 0.0001 for MDA; r = −0.31, p < 0.0001 for F2-isoprostanes) or cord plasma (r = −0.13, p = 0.04 for MDA; r = −0.32, p < 0.0001 for F2-isoprostanes). Other fetal metabolic health biomarkers were not correlated to oxidative stress. Adjusting for maternal and pregnancy characteristics, similar associations were observed. Our study provides the first preliminary evidence suggesting that oxidative stress may affect fetal ghrelin levels in humans. The implications in developmental “programming” the vulnerability to metabolic syndrome related disorders remain to be elucidated.
PMCID: PMC4672324  PMID: 26643495
4.  Effect of carbohydrate feeding on the bone metabolic response to running 
Journal of Applied Physiology  2015;119(7):824-830.
Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO·kg body mass−1·h−1) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (V̇o2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P = 0.028; P1NP: P = 0.021; IL-6: P = 0.036), although there was no difference in the short-term response (β-CTX: P = 0.856; P1NP: P = 0.721; IL-6: P = 0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover.
PMCID: PMC4593812  PMID: 26251510
carbohydrate; feeding; bone metabolism; running; exercise
5.  Ambient Heat and Sudden Infant Death: A Case-Crossover Study Spanning 30 Years in Montreal, Canada 
Environmental Health Perspectives  2015;123(7):712-716.
Climate change may lead to more severe and extreme heat waves in the future, but its potential impact on sudden infant death—a leading cause of infant mortality—is unclear.
We sought to determine whether risk of sudden infant death syndrome (SIDS) is elevated during hot weather.
We undertook a case-crossover analysis of all sudden infant deaths during warm periods in metropolitan Montreal, Quebec, Canada, from 1981 through 2010. Our analysis included a total of 196 certified cases of SIDS, including 89 deaths at 1–2 months of age, and 94 at 3–12 months. We estimated associations between maximum outdoor temperatures and SIDS by comparing outdoor temperatures on the day of or day before a SIDS event with temperatures on control days during the same month, using cubic splines to model temperature and adjusting for relative humidity.
Maximum daily temperatures of ≥ 29°C on the same day were associated with 2.78 times greater odds of sudden infant death relative to 20°C (95% CI: 1.64, 4.70). The likelihood of sudden death increased steadily with higher temperature. Associations were stronger for infants 3–12 months of age than for infants 1–2 months of age, with odds ratios of 3.90 (95% CI: 1.87, 8.13) and 1.73 (95% CI: 0.80, 3.73), respectively, for 29°C compared with 20°C on the day of the event.
High ambient temperature may be a novel risk factor for SIDS, especially at ≥ 3 months of age. Climate change and the higher temperatures that result may account for a potentially greater proportion of sudden infant deaths in the future.
Auger N, Fraser WD, Smargiassi A, Kosatsky T. 2015. Ambient heat and sudden infant death: a case-crossover study spanning 30 years in Montreal, Canada. Environ Health Perspect 123:712–716;
PMCID: PMC4492261  PMID: 25748025
6.  Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS) 
Thorax  2015;70(7):617-624.
Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated.
To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity.
Human, murine and in vitro primary alveolar epithelial cell work were included in this study.
Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients.
Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed.
Trial registration
UKCRN ID 11994.
PMCID: PMC4484044  PMID: 25903964
ARDS; Innate Immunity
7.  Maternal Deworming Research Study (MADRES) protocol: a double-blind, placebo-controlled randomised trial to determine the effectiveness of deworming in the immediate postpartum period 
BMJ Open  2015;5(6):e008560.
Soil-transmitted helminth infections are endemic in 114 countries worldwide, and cause the highest burden of disease among all neglected tropical diseases. The WHO includes women of reproductive age as a high-risk group for infection. The primary consequence of infection in this population is anaemia. During lactation, anaemia may contribute to reduced quality and quantity of milk, decreasing the duration of exclusive breastfeeding and lowering the age at weaning. To date, no study has investigated the effects of maternal postpartum deworming on infant or maternal health outcomes.
Methods and analysis
A single-centre, parallel, double-blind, randomised, placebo-controlled trial will be carried out in Iquitos, Peru, to assess the effectiveness of integrating single-dose 400 mg albendazole into routine maternal postpartum care. A total of 1010 mother-infant pairs will be randomised to either the intervention or control arm, following inhospital delivery and prior to discharge. Participants will be visited in their homes at 1, 6, 12 and 24 months following delivery for outcome ascertainment. The primary outcome is infant mean weight gain between birth and 6 months of age. Secondary outcomes include other infant growth indicators and morbidity, maternal soil-transmitted helminth infection and intensity, anaemia, fatigue, and breastfeeding practices. All statistical analyses will be performed on an intention-to-treat basis.
Ethics and dissemination
Research ethics board approval has been obtained from the McGill University Health Centre (Canada), the Asociación Civil Impacta Salud y Educación (Peru) and the Instituto Nacional de Salud (Peru). A data safety and monitoring committee is in place to oversee study progression and evaluate adverse events. The results of the analyses will be published in peer-reviewed journals, and presented at national and international conferences.
Trial registration number NCT01748929.
PMCID: PMC4480032  PMID: 26084556
albendazole; helminthiasis; PARASITOLOGY; postpartum; randomised controlled trials; intervention study
8.  The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1) 
Endocrinology  2015;156(9):3114-3121.
Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder.
PMCID: PMC4541614  PMID: 26052899
9.  Exposure to Free and Conjugated Forms of Bisphenol A and Triclosan among Pregnant Women in the MIREC Cohort 
Environmental Health Perspectives  2014;123(4):277-284.
Bisphenol A (BPA) and triclosan (TCS) are two nonpersistent chemicals that have been frequently measured in spot urine samples from the general population but less so in pregnant women; however, data are limited on the free (bioactive) and conjugated forms of these phenols.
The Maternal-Infant Research on Environmental Chemicals (MIREC) Study addressed these data gaps by utilizing stored maternal urine samples from a large multicenter cohort study of Canadian pregnant women.
Concentrations of free and conjugated forms of BPA and TCS were measured in about 1,890 first-trimester urine samples by ultra performance liquid chromatograpy–tandem mass spectrometry using isotope dilution.
The glucuronides of BPA and TCS were the predominant forms of these chemicals measured (detected in 95% and 99% of samples, respectively), whereas the free forms were detected in 43% and 80% of samples, respectively. The geometric mean urinary concentrations for glucuronides of BPA and TCS were 0.80 μg/L (95% CI: 0.75, 0.85) and 12.30 μg/L (95% CI: 11.08, 13.65), respectively. Significant predictors of BPA included maternal age < 25 vs. ≥ 35 years, current smoking, low vs. high household income, and low vs. high education. For TCS, urinary concentrations were significantly higher in women ≥ 25 years of age, never vs. current smokers, and women with high household income and high education.
The results from this study represent the largest national-level data on urinary concentrations of free and conjugated forms of BPA and TCS in pregnant women and suggest that maternal characteristics predicting elevated urinary concentrations of these phenols largely act in opposite directions.
Arbuckle TE, Marro L, Davis K, Fisher M, Ayotte P, Bélanger P, Dumas P, LeBlanc A, Bérubé R, Gaudreau É, Provencher G, Faustman EM, Vigoren E, Ettinger AS, Dellarco M, MacPherson S, Fraser WD. 2015. Exposure to free and conjugated forms of bisphenol A and triclosan among pregnant women in the MIREC cohort. Environ Health Perspect 123:277–284;
PMCID: PMC4384201  PMID: 25494523
10.  Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study 
Cancer Causes & Control  2014;26:205-218.
Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0500-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
11.  A birth cohort study to investigate the association between prenatal phthalate and bisphenol A exposures and fetal markers of metabolic dysfunction 
Environmental Health  2014;13:84.
Obesity and type-2 diabetes are on the rise and in utero exposure to environmental contaminants is a suspected contributing factor. Our objective was to examine associations between prenatal exposure to potential endocrine disrupting chemicals and markers of fetal metabolic dysfunction.
The Maternal-Infant Research on Environmental Chemicals Study (MIREC) recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. First trimester maternal urine was measured for 11 phthalate metabolites and bisphenol A (BPA). Leptin and adioponectin measured in 1,363 available umbilical cord blood samples served as markers of metabolic function. Restricted cubic spline curves were used to assess the relationship between continuous measures of phthalate and BPA levels and cord blood adipokines. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between phthalates and BPA and both high (≥90th percentile) and low (≤10th percentile) fetal adiponectin and leptin, adjusting for confounding factors. Analyses were conducted for all subjects, overall, and separately by fetal sex.
Leptin was significantly higher in female than male infants. We observed an inverse, non-linear relationship between BPA and adiponectin among males in the restricted cubic spline and linear regression analysis. Mono-(3-carboxypropyl) (MCPP) was associated with increased odds of high leptin among males in the polytomous logistic regression models (4th quartile OR = 3.5 95% CI: 1.1-11.6).
Our findings contribute to the growing body of evidence examining the influence of early life exposure on metabolic regulation and function. Associations between maternal exposure to chemicals and markers of metabolic function appear to be potentially sex specific. However, further investigation is required to determine whether in utero and childhood exposure to BPA and phthalates are associated with metabolic dysfunctions later in life.
PMCID: PMC4271497  PMID: 25336252
Phthalates; Bisphenol A; Leptin; Adiponectin; Pregnancy; Cohort study; Canada
12.  Does Bone Resorption Stimulate Periosteal Expansion? A Cross‐Sectional Analysis of β‐C‐telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway, and Periosteal Circumference as Measured by pQCT 
Journal of Bone and Mineral Research  2014;29(4):1015-1024.
We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β‐C‐telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC). CTX and mid‐tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength‐strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single‐nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF‐κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut‐off) (n = 2379). Subsequently, we performed a meta‐analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut‐off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
PMCID: PMC4138988  PMID: 24014423
13.  Birth weight is positively related to bone size in adolescents but inversely related to cortical bone mineral density: Findings from a large prospective cohort study 
Bone  2014;65(100):77-82.
To examine the influence of intrauterine environment on subsequent bone development, we investigated the relationship between birth weight and cortical bone parameters, and the role of puberty, bone resorption and insulin as possible mediators. Bone outcomes were obtained from mid-tibial pQCT scans performed at age 15.5 years in 1960 males and 2192 females from the ALSPAC birth cohort. Birth weight was positively related to periosteal circumference (PC) [beta = 0.40 (0.34, 0.46)], which was largely but not completely attenuated after adjustment for height and weight [beta = 0.07 (0.02, 0.12)] (SD change in outcome per 1 kg increase in birth weight with 95% CI). Based on our height and weight adjusted model, the association was stronger in females compared to males (P = 0.02 for gender interaction), and persisted in 2842 participants with equivalent results at age 17.7 years. Conversely, birth weight was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after adjusting for height and weight [beta = − 0.18 (− 0.23, − 0.13)], with a stronger association in males compared to females (P = 0.01 for gender interaction), but an equivalent association was not seen at 17.7 years. In further analyses performed on data from age 15.5 years, the association between birth weight and PC was unaffected by adjustment for puberty (Tanner stage at age 13.5 years), bone resorption (fasting beta-carboxyterminal cross linking telopeptide (βCTX) at age 15.5 years) or insulin (fasting insulin at age 15.5 years). In contrast, the association with BMDC was attenuated by approximately 30% after adjustment for puberty or bone resorption, and by 50% after adjustment for both factors combined. We conclude that the inverse relationship between birth weight and BMDC is in part mediated by effects of puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.
•Birth weight (BW) was positively related to periosteal circumference (PC) at age 15, even after height and weight adjustment.•The association of BW with PC was stronger in females, and was also seen at age 17.7 years.•BW was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after height and weight adjustment.•The inverse association of BW with BMDC was stronger in males, but there was no association at 17.7 years.•The association of BW with BMDC was attenuated by approximately 50% after adjustment for puberty and bone resorption.
PMCID: PMC4073227  PMID: 24840816
pQCT; Periosteal circumference; Tibia; Puberty; Bone resorption
14.  Associations of childhood 25-hydroxyvitamin D2 and D3 and cardiovascular risk factors in adolescence: prospective findings from the Avon Longitudinal Study of Parents and Children 
Studies of the associations of circulating total 25-hydroxyvitamin D (25(OH)D) with cardiovascular disease risk factors in adults have reported inconsistent findings. We aimed to compare prospective associations of two analogues of childhood 25(OH)D (25(OH)D2 and 25(OH)D3) with cardiovascular risk factors measured in adolescence.
Methods and results
We examined associations of childhood (ages 7–12 years) 25(OH)D2 and 25-25(OH)D3 with a range of cardiovascular risk factors (blood pressure, fasting lipids, glucose, insulin and C-reactive protein (CRP)) determined in adolescence (mean age 15.4 years). Data were from 2470 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based cohort. After adjustments for age, gender, socioeconomic position and BMI, there were no associations of 25(OH)D2 with cardiovascular risk factors. There was a positive association of season-adjusted (and unadjusted) 25(OH)D3 with high-density lipoprotein cholesterol (HDL-C) (mean change per doubling of 25(OH)D3: 0.03 mmol/l; 95% confidence interval (CI): 0.001 to 0.05, p = 0.02) and an inverse association with fasting insulin (relative difference of −4.59% per doubling; 95% CI: −8.37 to −0.59, p = 0.03). Participants with total 25(OH)D concentration <50 nmol/l had 0.04 mmol/l lower HDL-C (95% CI: −0.07 to −0.01) and 5.54% higher fasting insulin (95% CI: 0.82 to 10.47) compared with participants with total 25(OH)D ≥72 nmol/l.
In the first prospective study of children/adolescents, we have shown that higher 25(OH)D3 concentrations in childhood are associated with higher levels of HDL-C and lower fasting insulin in adolescence.
PMCID: PMC3931583  PMID: 23185083
Vitamin D; cardiovascular diseases; paediatrics; ALSPAC
15.  Elevated Circulating Sclerostin Concentrations in Individuals With High Bone Mass, With and Without LRP5 Mutations 
The role and importance of circulating sclerostin is poorly understood. High bone mass (HBM) caused by activating LRP5 mutations has been reported to be associated with increased plasma sclerostin concentrations; whether the same applies to HBM due to other causes is unknown.
Our objective was to determine circulating sclerostin concentrations in HBM.
Design and Participants:
In this case-control study, 406 HBM index cases were identified by screening dual-energy x-ray absorptiometry (DXA) databases from 4 United Kingdom centers (n = 219 088), excluding significant osteoarthritis/artifact. Controls comprised unaffected relatives and spouses.
Main measures:
Plasma sclerostin; lumbar spine L1, total hip, and total body DXA; and radial and tibial peripheral quantitative computed tomography (subgroup only) were evaluated.
Sclerostin concentrations were significantly higher in both LRP5 HBM and non-LRP5 HBM cases compared with controls: mean (SD) 130.1 (61.7) and 88.0 (39.3) vs 66.4 (32.3) pmol/L (both P < .001, which persisted after adjustment for a priori confounders). In combined adjusted analyses of cases and controls, sclerostin concentrations were positively related to all bone parameters found to be increased in HBM cases (ie, L1, total hip, and total body DXA bone mineral density and radial/tibial cortical area, cortical bone mineral density, and trabecular density). Although these relationships were broadly equivalent in HBM cases and controls, there was some evidence that associations between sclerostin and trabecular phenotypes were stronger in HBM cases, particularly for radial trabecular density (interaction P < .01).
Circulating plasma sclerostin concentrations are increased in both LRP5 and non-LRP5 HBM compared with controls. In addition to the general positive relationship between sclerostin and DXA/peripheral quantitative computed tomography parameters, genetic factors predisposing to HBM may contribute to increased sclerostin levels.
PMCID: PMC4207929  PMID: 24606091
16.  Associations of 25-Hydroxyvitamin D2 and D3 with Cardiovascular Risk Factors in Childhood: Cross-Sectional Findings from the Avon Longitudinal Study of Parents and Children 
Studies in adults have reported associations of low circulating total 25-hydroxyvitamin D with increased cardiovascular disease and risk factors. Evidence of associations in children, however, is limited, and it is unknown whether associations with risk factors differ for each 25-hydroxyvitamin D analog [25-hydroxyvitamin D2 (25[OH]D2) and 25-hydroxyvitamin D2 (25[OH]D3)].
The objective of the study was to compare associations of 25(OH)D2 and 25(OH)D3 with cardiovascular risk factors in children.
The design of the study was a cross-sectional study of 4274 children (mean age 9.9 yr) from the Avon Longitudinal Study of Parents and Children.
Main Outcomes
The main outcomes included blood pressure, lipids [triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C)], apolipoproteins (Apo-A1 and Apo-B), adiponectin, leptin, C-reactive protein, and IL-6.
In confounder-adjusted models, 25(OH)D2 was inversely associated with Apo-A1 (change per doubling of exposure: −0.74mg/dl; 95% confidence interval −0.14, −0.04) and triglycerides (relative percentage change per doubling of exposure: −1.64%; −3.27, 0.01) and positively associated with C-reactive protein (8.42%; 3.40, 13.58) and IL-6 (5.75%; 1.83, 9.25). 25(OH)D3 was positively associated with HDL-C (0.04 mmol/liter; 0.02, 0.06), Apo-A1 (1.96 mg/dl; 0.65, 3.24), and adiponectin (0.47 μg/ml; 0.15, 0.79). There was statistical evidence that associations of 25(OH)D2 and 25(OH)D3 with HDL-C, Apo-A1, and IL-6 differed from each other (all P values for differences ≤0.02).
Higher circulating 25(OH)D3 was associated with cardioprotective levels of HDL-C, Apo-A1, and adiponectin in children. Associations of 25(OH)D2 with cardiovascular risk factors were in mixed directions. It is necessary to see whether these associations are replicated in large prospective studies.
PMCID: PMC3927053  PMID: 22344194
17.  Circulating Docosahexaenoic Acid Levels Are Associated with Fetal Insulin Sensitivity 
PLoS ONE  2014;9(1):e85054.
Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies.
Methods and Principal Findings
In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity.
Low circulating DHA levels are associated with compromised fetal insulin sensitivity, and may be involved in perinatally “programming” the susceptibility to type 2 diabetes in the offspring of gestational diabetic mothers.
PMCID: PMC3890289  PMID: 24454790
18.  Influence of Vitamin D Metabolites on Plasma Cytokine Concentrations in Endurance Sport Athletes and on Multiantigen Stimulated Cytokine Production by Whole Blood and Peripheral Blood Mononuclear Cell Cultures 
ISRN Nutrition  2014;2014:820524.
Aim. Our aims were to determine the influence of plasma total 25-hydroxy vitamin D (25(OH)D) status on the plasma cytokine concentrations in athletes and the in vitro effects of different doses of 1, 25 dihydroxyvitamin D3 (1, 25(OH)2D3) on multiantigen stimulated cytokine production by whole blood and peripheral blood mononuclear cell (PBMC) cultures. Methods. Plasma samples from 43 athletes with high and low levels of 25(OH)D were assayed for the concentrations of cytokines. The whole blood samples and PBMCs from healthy subjects were incubated in vitro with a multi-antigen vaccine and different doses of added 1, 25(OH)2D3. The circulating cytokines and stimulated whole blood and PBMC culture production of cytokines were determined using a biochip assay. Results. The circulating interleukin-(IL-)10 and interferon-(IFN-) γ concentrations were significantly higher in the vitamin D sufficient athletes. Furthermore, the production of tumour necrosis factor-(TNF-) α, IL-6, IFN-γ, IL-2, and IL-10 by whole blood culture was significantly inhibited by 1, 25(OH)2D3 concentrations of 1000 pmol/L or 10000 pmol/L. Conclusions. We found that the influence of vitamin D on circulating cytokines might be different in athletes compared with nonathletes and cytokines production by whole blood culture was not influenced by 1, 25(OH)2D3 in concentrations within the normal healthy range.
PMCID: PMC4045303  PMID: 24967273
19.  An N-Ethyl-N-Nitrosourea Induced Corticotropin-Releasing Hormone Promoter Mutation Provides a Mouse Model for Endogenous Glucocorticoid Excess 
Endocrinology  2013;155(3):908-922.
Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion is stimulated by CRH, and we report a mouse model for Cushing's syndrome due to an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at −120 bp of the promoter region, which significantly increased luciferase reporter activity and was thus a gain-of-function mutation. Crh−120/+ mice, when compared with wild-type littermates, had obesity, muscle wasting, thin skin, hair loss, and elevated plasma and urinary concentrations of corticosterone. In addition, Crh−120/+ mice had hyperglycemia, hyperfructosaminemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia but normal adiponectin. Crh−120/+ mice also had low bone mineral density, hypercalcemia, hypercalciuria, and decreased concentrations of plasma PTH and osteocalcin. Bone histomorphometry revealed Crh−120/+ mice to have significant reductions in mineralizing surface area, mineral apposition, bone formation rates, osteoblast number, and the percentage of corticoendosteal bone covered by osteoblasts, which was accompanied by an increase in adipocytes in the bone marrow. Thus, a mouse model for Cushing's syndrome has been established, and this will help in further elucidating the pathophysiological effects of glucocorticoid excess and in evaluating treatments for corticosteroid-induced osteoporosis.
PMCID: PMC4192286  PMID: 24302625
20.  Associations of maternal 25-hydroxyvitamin D in pregnancy with offspring cardiovascular risk factors in childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children 
Heart  2013;99(24):1849-1856.
Lower maternal vitamin D status in pregnancy may be associated with increased offspring cardiovascular risk in later life, but evidence for this is scant. We examined associations of maternal total 25-hydroxyvitamin D (25(OH)D) in pregnancy with offspring cardiovascular risk factors assessed in childhood and adolescence.
A longitudinal, prospective study.
The study was based on data from mother–offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective population-based birth cohort (N=4109).
Outcome measures
Offspring cardiovascular risk factors were measured in childhood (mean age 9.9 years) and in adolescence (mean age 15.4 years): blood pressure, lipids, apolipoproteins (at 9.9 years only), glucose and insulin (at 15.4 years only), C reactive protein (CRP), and interleukin 6 (at 9.9 years only) were measured.
After adjustments for potential confounders (maternal age, education, body mass index (BMI), smoking, physical activity, parity, socioeconomic position, ethnicity, and offspring gestational age at 25(OH)D sampling; gender, age, and BMI at outcome assessment), maternal 25(OH)D was inversely associated with systolic blood pressure (−0.48 mm Hg difference per 50 nmol/L increase in 25(OH)D; 95% CI −0.95 to −0.01), Apo-B (−0.01 mg/dL difference; 95% CI −0.02 to −0.001), and CRP (−6.1% difference; 95% CI −11.5% to −0.3%) at age 9.9 years. These associations were not present for risk factors measured at 15.4 years, with the exception of a weak inverse association with CRP (−5.5% difference; 95% CI −11.4% to 0.8%). There was no strong evidence of associations with offspring triglycerides, glucose or insulin.
Our findings suggest that fetal exposure to 25(OH)D is unlikely to influence cardiovascular risk factors of individuals later in life.
PMCID: PMC3841764  PMID: 24125739
21.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
22.  Measurement of Circulating 25-Hydroxy Vitamin D Using Three Commercial Enzyme-Linked Immunosorbent Assay Kits with Comparison to Liquid Chromatography: Tandem Mass Spectrometry Method 
ISRN Nutrition  2013;2013:723139.
Aim. The purpose of this study was to compare the accuracy and clinical implications of three commercial enzyme-linked immunosorbent assay (ELISA) kits (Eagle Biosciences, Immundiagnostik, and MicroVue) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum 25(OH)D concentration. Methods. Blood samples were obtained from 225 healthy individuals who were recruited as subjects from Loughborough University, UK. Plasma samples were measured for 25(OH)D concentration by means of LC-MS/MS and ELISA kits from Eagle Biosciences, Immundiagnostik, and MicroVue. Results. The 25(OH)D concentration measured by the Eagle Biosciences, Immundiagnostik, and MicroVue ELISAs biased −50.9 ± 79.1 nmol/L, −14.2 ± 91.0 nmol/L, and −7.2 ± 18.9 nmol/L (bias ± SD) from the LC-MS/MS method, respectively. We found that 52% (Eagle Biosciences), 48% (Immundiagnostik), and 38% (MicroVue) of participants were misclassified, and the results showed the poor agreement (Kappa: −0.201~0.251) in classification of participants defined as vitamin D sufficiency and insufficiency between each method and LC-MS/MS. Conclusions. The present study demonstrated that there were negative biases and considerable misclassification of participants using the cut-off point (50 nmol/L) for vitamin D insufficiency and sufficiency using the Eagle Biosciences, Immundiagnostik, and MicroVue ELISAs compared with the LC-MS/MS assay.
PMCID: PMC4045297  PMID: 24967259
23.  Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study 
Lancet  2013;381(9884):2176-2183.
Maternal vitamin D status in pregnancy is a suggested determinant of bone-mineral content (BMC) in offspring, but has been assessed in small studies. We investigated this association in a large prospective study.
Eligible participants were mother-and-singleton-offspring pairs who had participated in the Avon Longitudinal Study of Parents and Children, and in which the mother had recorded measurements of 25(OH)D concentration in pregnancy and the offspring had undergone dual-energy x-ray absorptiometry at age 9–10 years. 25(OH)D concentrations in pregnancy were assessed per 10·0 nmol/L and classified as sufficient (more than 50·00 nmol/L), insufficient (49·99–27·50 nmol/L), or deficient (lower than 27·50 nmol/L). Associations between maternal serum 25(OH)D concentrations and offspring total body less head (TBLH) and spinal BMC were assessed by trimester.
3960 mother-and-offspring pairs, mainly of white European origin, were assessed (TBLH BMC n=3960, spinal BMC n=3196). Mean offspring age was 9·9 years. 2644 (67%) mothers had sufficient, 1096 (28%) insufficient, and 220 (6%) deficient 25(OH)D concentrations in pregnancy, but TBLH and spinal BMC did not differ between offspring of mothers in the lower two groups versus sufficient 25(OH)D concentration. No associations with offspring BMC were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH BMC confounder-adjusted mean difference −0·03 g per 10·0 nmol/L, 95% CI −1·71 to 1·65; spinal BMC 0·04 g per 10·0 nmol/L, 95% CI −0·12 to 0·21).
We found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood.
UK Medical Research Council, Wellcome Trust, and University of Bristol.
PMCID: PMC3691477  PMID: 23518316
24.  Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial 
Trials  2013;14:100.
Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function.
The ‘Vitamin D to prevent lung injury following oesophagectomy trial’ is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres.
This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy.
Trial registration
Current Controlled Trials ISRCTN27673620
PMCID: PMC3680967  PMID: 23782429
Acute lung injury; One lung ventilation; Oesophagectomy; Vitamin D
25.  Birth outcomes and infant mortality among First Nations Inuit, and non-Indigenous women by northern versus southern residence, Quebec 
In circumpolar countries such as Canada, northern regions represent a unique geographical entity climatically, socioeconomically and environmentally. There is a lack of comparative data on birth outcomes among Indigenous and non-Indigenous subpopulations within northern regions and compared with southern regions.
A cohort study of all births by maternal mother tongue to residents of northern (2616 First Nations (North American Indians), 2388 Inuit and 5006 non-Indigenous) and southern (2563 First Nations, 810 643 non-Indigenous) Quebec, 1991–2000.
Compared with births to southern non-Indigenous mother tongue women, births to northern women of all three mother tongue groups were at substantially elevated risks of infant death (adjusted OR (aOR) 1.7–2.9), especially postneonatal death (aOR 2.2–4.4) after controlling for maternal education, age, marital status and parity. The risk elevation in perinatal death was greater for southern First Nations (aOR 1.6) than for northern First Nations (aOR 1.2). Infant macrosomia was highly prevalent among First Nations in Quebec, especially in the north (31% vs 24% in the south). Within northern regions, Inuit births were at highest risk of preterm delivery (aOR 1.4) and infant death (aOR 1.6).
All northern infants (First Nations, Inuit or non-Indigenous) were at substantially elevated risk of infant death in Quebec, despite a universal health insurance system. Southern First Nations newborns have not benefited from the more advanced perinatal care facilities in southern regions. Environmental influences may partly account for the very high prevalence of macrosomia among First Nations in northern Quebec.
PMCID: PMC3133748  PMID: 21051777 CAMSID: cams1702

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