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1.  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February 2012), CINAHL (1982 to 15 February 2012), MIDIRS (1985 to February 2012) and contacted authors for data from unpublished trials.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
2.  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
3.  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(1):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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures
We measured fat mass, by DXA, and bone turnover markers.
Among women, fat mass was inversely related to age in controls (P=.01), but not in HBM cases (P=.96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P<.001). Increased fat mass in male HBM cases was less marked (gender interaction P=.03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2,5.4] kg; P<.002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P<.001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P=.04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P<.001).
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
PMCID: PMC3589712  PMID: 23337721
17.  Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5 
PLoS ONE  2013;8(1):e55412.
Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5682P/+) and homozygous (Trpv5682P/682P) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5682P/+ and Trpv5682P/682P mice consistent with a trafficking defect. In addition, Trpv5682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria.
PMCID: PMC3559602  PMID: 23383183
18.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants:
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures:
We measured fat mass, by DXA, and bone turnover markers.
Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001).
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
PMCID: PMC3589712  PMID: 23337721
19.  Seasonal Variation in 25(OH)D at Aberdeen (57°N) and Bone Health Indicators– Could Holidays in the Sun and Cod Liver Oil Supplements Alleviate Deficiency? 
PLoS ONE  2013;8(1):e53381.
Vitamin D has been linked with many health outcomes. The aim of this longitudinal study, was to assess predictors of seasonal variation of 25-hydroxy-vitamin D (25(OH)D) (including use of supplements and holidays in sunny destinations) at a northerly latitude in the UK (57°N) in relation to bone health indicators. 365 healthy postmenopausal women (mean age 62.0 y (SD 1.4)) had 25(OH)D measurements by immunoassay, serum C-telopeptide (CTX), estimates of sunlight exposure (badges of polysulphone film), information regarding holidays in sunny destinations, and diet (from food diaries, including use of supplements such as cod liver oil (CLO)) at fixed 3-monthly intervals over 15 months (subject retention 88%) with an additional 25(OH)D assessment in spring 2008. Bone mineral density (BMD) at the lumbar spine (LS) and dual hip was measured in autumn 2006 and spring 2007 (Lunar I-DXA). Deficiency prevalence (25(OH)D<25 nmol/L) was reduced in women who went on holiday to sunny destinations 3 months prior to their visit, compared to women who did not go on holidays [5.4% vs. 24.6% in Spring (p<0.001) and 3.8% vs. 25.6% in Winter (p = 0.001), respectively]. Similarly deficiency was lower amongst those who took CLO supplements compared to women that did not consume these supplements [2.0% vs. 23.7% in Spring (p = 0.001) and 4.5% vs. 24.8% in winter (p = 0.005), respectively]. There was no seasonal variation in CTX; 25(OH)D predicted a small proportion (1.8% variation) of LS BMD in spring 2007 [unstandardized β (SE): 0.039 (0.016), p = 0.017]. Seasonal variation of 25(OH)D had little effect on BMD and no effect on CTX. It appears that small increments in vitamin D (e.g. those that can be achieved by cod liver oil supplements of 5 µg/day) are sufficient to ensure that 25(OH)D is above 25 nmol/L for most people throughout the year. Similarly, holidays in sunny destinations show benefit.
PMCID: PMC3540094  PMID: 23308207
20.  Effect of supplementation with vitamin D2-enhanced mushrooms on vitamin D status in healthy adults 
Vitamin D deficiency is emerging worldwide and many studies now suggest its role in the development of several chronic diseases. Due to the low level of vitamin D naturally occurring in food there is a need for supplementation and use of vitamin D-enhanced products. The aim of the present study was to determine if daily consumption of vitamin D2-enhanced mushrooms increased vitamin D status in free-living healthy adults or affected markers of the metabolic syndrome. A total of ninety volunteers (aged 40–65 years) were randomly assigned to one of two 4-week studies: mushroom study (15 µg vitamin D2 or placebo mushroom powder) and capsule study (15 µg vitamin D3 or placebo capsules). Consumption of vitamin D2-enhanced mushrooms increased serum 25-hydroxyvitamin D2 (25(OH)D2) by 128 % from baseline (3·9 (sd 1·9) nmol/l; P < 0·05). Serum 25(OH)D3 increased significantly in the vitamin D3 capsule group (a 55 % increase from a baseline of 44.0 (sd 17·1) nmol/l; P < 0·05). Vitamin D status (25(OH)D) was affected only in the vitamin D3 group. Plasminogen activator inhibitor-1 was lowered by vitamin D2 intake. Vitamin D2 from enhanced mushrooms was bioavailable and increased serum 25(OH)D2 concentration with no significant effect on 25(OH)D3 or total 25(OH)D.
PMCID: PMC4153019  PMID: 25191578
Food enhancement; Metabolic syndrome; Mushrooms; Vitamin D status; 25(OH)D, 25-hydroxyvitamin D; hsCRP, high-sensitivity C-reactive protein; MetS, metabolic syndrome; PAI-1, plasminogen activator inhibitor-1; PTH, parathyroid hormone
21.  Associations of Circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade 
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with PSA-detected prostate cancer in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs localized) and Gleason grade (high-grade (≥7) vs low-grade (<7)). Pre-determined categories of total 25(OH)D were defined as: high: ≥30ng/mL; adequate: 20-<30ng/mL; insufficient: 12-<20ng/mL; deficient: <12ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a two-fold increased risk of advanced versus localized cancer (OR for deficient vs adequate total 25(OH)D=2.33, 95% CI: 1.26,4.28) and high-grade versus low-grade cancer (OR for deficient vs adequate total 25(OH)D=1.78, 95% CI: 1.15,2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low- Gleason grade), but there was no evidence of an association with overall prostate cancer risk.
PMCID: PMC3378478  PMID: 22033893
Prostate cancer; vitamin D; 25-hydroxyvitamn D
22.  Serum 25-Hydroxyvitamin D3 and D2 and Non-Clinical Psychotic Experiences in Childhood 
PLoS ONE  2012;7(7):e41575.
Non-clinical psychotic experiences are common and distressing. It has been hypothesized that early life vitamin D deficiency may be a risk factor for psychosis-related outcomes, but it is not known if circulating concentrations of 25-hydroxyvitamin D (25(OH)D) during childhood are associated with psychosis-related outcomes or whether the two different forms of 25(OH)D, (25(OH)D3 and 25(OH)D2, have similar associations with psychosis-related outcomes.
We investigated the association between serum 25(OH)D3 and 25(OH)D2 concentrations and psychotic experiences in a prospective birth cohort study. Serum 25(OH)D3 and 25(OH)D2 concentrations were measured at mean age 9.8 years and psychotic experiences assessed at mean age 12.8 years by a psychologist (N = 3182).
Higher 25(OH)D3 concentrations were associated with lower risk of definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.75–0.95)). Higher concentrations of 25(OH)D2 were associated with higher risk of suspected and definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 1.26 (1.11, 1.43)). Higher 25(OD)D2 concentrations were also weakly associated with definite psychotic experiences (adjusted OR (95% CI) 1.17 (0.96, 1.43), though with wide confidence intervals including the null value.
Our findings of an inverse association of 25(OH)D3 with definite psychotic experiences is consistent with the hypothesis that vitamin D may protect against psychosis-related outcomes.
PMCID: PMC3405076  PMID: 22848531
23.  The Association of 25-Hydroxyvitamin D3 and D2 with Behavioural Problems in Childhood 
PLoS ONE  2012;7(7):e40097.
Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D3 (the active vitamin D3 metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans.
We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D3 and 25(OH)D2– and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D3 and 25(OH)D2 concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome.
Higher 25(OH)D3 concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D3 or 25(OH)D2 concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D.
Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans.
PMCID: PMC3393748  PMID: 22808099
24.  Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets 
The Journal of Endocrinology  2004;183(3):R1-R9.
MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemic-rickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renal-tubules. Using a specific competitive ELISA we measured a five fold increase (P=0·007) of serum ASARM-peptide(s) in human HYP patients (normal subjects 3·25 μM n=9; S.E.M.=0·51 and HYP-patients 15·74 μM, n=9; S.E.M.=3·32). A 6·23 fold increase (P=0·008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3·73 μM, S.E.M.=0·57, n=3; and hyp-mice 23·4 μM, n=3, S.E.M.=4·01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.
PMCID: PMC3357083  PMID: 15590969
25.  Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women 
The P2X7 receptor gene (P2RX7) is highly polymorphic with five previously described loss-of-function (LOF) single-nucleotide polymorphisms (SNP; c.151+1G>T, c.946G>A, c.1096C>G, c.1513A>C and c.1729T>A) and one gain-of-function SNP (c.489C>T). The purpose of this study was to determine whether the functional P2RX7 SNPs are associated with lumbar spine (LS) bone mineral density (BMD), a key determinant of vertebral fracture risk, in post-menopausal women. We genotyped 506 post-menopausal women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) for the above SNPs. Lumbar spine BMD was measured at baseline and at 6–7 year follow-up. P2RX7 genotyping was performed by homogeneous mass extension. We found association of c.946A (p.Arg307Gln) with lower LS-BMD at baseline (P=0.004, β=−0.12) and follow-up (P=0.002, β=−0.13). Further analysis showed that a combined group of subjects who had LOF SNPs (n=48) had nearly ninefold greater annualised percent change in LS-BMD than subjects who were wild type at the six SNP positions (n=84; rate of loss=−0.94%/year and −0.11%/year, respectively, P=0.0005, unpaired t-test). This is the first report that describes association of the c.946A (p.Arg307Gln) LOF SNP with low LS-BMD, and that other LOF SNPs, which result in reduced or no function of the P2X7 receptor, may contribute to accelerated bone loss. Certain polymorphic variants of P2RX7 may identify women at greater risk of developing osteoporosis.
PMCID: PMC3330223  PMID: 22234152
P2RX7; LS-BMD; single-nucleotide polymorphisms

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