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Ipriflavone, a synthetic phytoestrogen, enhances intestinal calcium transport in vitro. Arjmandi BH, Khalil DA, Hollis BW. Calcif Tissue Int 2000;67:225-229. Ipriflavone (IP), a synthetic isoflavone, prevents bone loss associated with [...]

Aim: The aim of this study is to evaluate racial variation in umbilical cord blood concentration of vitamin D and to explore its correlation with markers of the insulin-like growth factor axis (IGFs) and sex steroid hormones in white and black male neonates.Methods: In 2004-2005, venous umbilical cord blood samples were collected from 75 black and 38 white male neonates, along with maternal and birth characteristics from two hospitals in Maryland, United States. 25-Hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured by radioimmunoassay and testosterone, estradiol, and sex hormone-binding globulin (SHBG) by immunoassay and IGF-1, IGF-2, and IGF-binding protein-3 by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed.Results: Mean 25(OH)D levels were lower in black than in white neonates (11.44; 95 % CI 10.10-12.95 ng/mL vs. 18.24; 95 % CI 15.32-21.72 ng/mL; p < 0.0001). Black neonates were at higher risk of suboptimal vitamin D levels [25(OH)D < 20 ng/mL] than whites (84 vs. 63 %). 25(OH)D concentrations varied by season in whites but not in blacks and were significantly inversely correlated with mother's parity (number of live births) in blacks but not in whites. Mean concentration of 1,25(OH)(2)D did not differ by race. 25(OH)D and 1,25(OH)(2)D did not correlate with IGFs, sex steroid hormones, and SHBG.Conclusions: Suboptimal vitamin D levels were prevalent especially in blacks and influenced by mother's parity and by season. The observed vitamin D differences between black and white neonates warrant further evaluation of the etiology of the disparity in chronic diseases in adulthood. [ABSTRACT FROM AUTHOR]

Background: The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease.Methods: We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided.Results: Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer.Conclusion: In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate, but the impact of various doses, and whether calcium administration jointly or independently influences vitamin D metabolite levels, is unclear.Methods: In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma, we measured the impact of vitamin D supplementation and/or calcium supplementation on plasma vitamin D metabolite concentrations. Ninety-two adult men and women living in the southeastern United States were randomized to 800 IU vitamin D(3), 2000 mg elemental calcium, both, or placebo daily for 6 months. We examined vitamin D status at baseline and postintervention and compared the change in plasma 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)(2)D levels by intervention group using general linear models.Results: Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations (<75 nmol/L) at baseline, with the lowest levels observed among African American participants. Vitamin D supplements, with or without calcium supplementation, raised plasma 25(OH)D concentrations, on average, by 25 to 26 nmol/L. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D(3) daily. Calcium alone did not influence 25(OH)D concentrations.Conclusion: In this southeastern U.S. population, half of the study participants receiving 800 IU vitamin D(3) daily had blood 25(OH)D concentrations of

PURPOSE:: Activated vitamin D (calcitriol) is a pluripotent pleiotropic secosteroid hormone. As a steroid hormone, which regulates more than 1000 vitamin D-responsive human genes, calcitriol may influence athletic performance. Recent research indicates that intracellular calcitriol levels in numerous human tissues, including nerve and muscle tissue, are increased when inputs of its substrate, the prehormone vitamin D, are increased. METHODS:: We reviewed the world's literature for evidence that vitamin D affects physical and athletic performance. RESULTS:: Numerous studies, particularly in the German literature in the 1950s, show vitamin D-producing ultraviolet light improves athletic performance. Furthermore, a consistent literature indicates physical and athletic performance is seasonal; it peaks when 25-hydroxy-vitamin D [25(OH)D] levels peak, declines as they decline, and reaches its nadir when 25(OH)D levels are at their lowest. Vitamin D also increases the size and number of Type II (fast twitch) muscle fibers. Most cross-sectional studies show that 25(OH)D levels are directly associated with musculoskeletal performance in older individuals. Most randomized controlled trials, again mostly in older individuals, show that vitamin D improves physical performance. CONCLUSIONS:: Vitamin D may improve athletic performance in vitamin D-deficient athletes. Peak athletic performance may occur when 25(OH)D levels approach those obtained by natural, full-body, summer sun exposure, which is at least 50 ng.mL. Such 25(OH)D levels may also protect the athlete from several acute and chronic medical conditions. [ABSTRACT FROM AUTHOR]

Rationale: Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.Objectives: To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.Methods: We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.Measurements and Main Results: Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log(10) unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004-0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05-0.67; P = 0.01), and increased airway responsiveness (a < or =8.58-mumol provocative dose of methacholine producing a 20% fall in baseline FEV(1) [OR, 0.15; 95% CI, 0.024-0.97; P = 0.05]).Conclusions: Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity. [ABSTRACT FROM AUTHOR]

The serum 25-hydroxyvitamin D [25(OH)D] response to daily supplementation with 20 microg cholecalciferol (D3) during winter in predominantly white premenopausal women living in Maine was measured and the effects of body composition and hormonal contraceptive use on baseline serum 25(OH)D concentrations and the response to supplementation were examined. A total of 112 women (22.2 +/- 3.7 y old) received placebo from March 2005 until September 2005 when they were randomized to receive either placebo or 20 microg/d D3 through February 2006. Eighty-six women completed the study. Actual mean D3 content of the supplements was 22 microg per capsule. In February 2005 the serum 25(OH)D concentration was 62.0 +/- 23.4 nmol/L (mean +/- SD). Serum 25(OH)D concentrations increased by 35.3 +/- 23.2 nmol/L from February 2005 to February 2006 in the treatment group, significantly more than the 10.9 +/- 16.9 nmol/L increase in the placebo group. Treatment group, magnitude of summer increase in 25(OH)D, estrogen dose, and baseline serum 25(OH)D concentrations, but not body fat, were significant predictors of the 1-y change in 25(OH)D concentrations used to assess the magnitude of the response to supplementation. Daily supplementation with 20 microg D3 during winter achieved optimal 25(OH)D concentrations (> or = 75 nmol/L) in 80% of participants, indicating that this dose is adequate to optimize vitamin D status in most young women in Maine. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neither the efficiency of the 25-hydroxylation of vitamin D nor the steady state relation between vitamin D(3) and 25-hydroxyvitamin D [25(OH)D] has been studied in humans. OBJECTIVE: We aimed to examine the relation between serum vitamin D(3) and 25(OH)D in normal subjects after either oral administration of vitamin D(3) or ultraviolet-B radiation across a broad range of inputs. DESIGN: Values for serum vitamin D(3) and (OH)D(3) were aggregated from 6 studies--1 acute and 5 near-steady state--at various vitamin D(3) inputs. In 3 of the steady state studies, vitamin D(3) had been administered for 18-26 wk in doses of 0 to 11000 IU/d; in 2 studies, subjects had received solar or ultraviolet-B irradiation. RESULTS: In the acute study, subjects receiving a single 100000-IU dose of vitamin D(3) had a rise in serum cholecalciferol to a mean of 521 nmol/L at 1 d and then a fall to near-baseline values by 7-14 d. Serum 25(OH)D peaked at 103 nmol/L on day 7 and fell slowly to baseline by day 112. In the 5 steady state studies, the relation of serum 25(OH)D to serum vitamin D(3) was biphasic and was well described by a combined exponential and linear function: Y = 0.433X + 87.81[1-exp (-0.468X)], with R(2) = 0.448. CONCLUSIONS: At physiologic inputs, there is rapid conversion of precursor to product at low vitamin D(3) concentrations and a much slower rate of conversion at higher concentrations. These data suggest that, at typical vitamin D(3) inputs and serum concentrations, there is very little native cholecalciferol in the body, and 25(OH)D constitutes the bulk of vitamin D reserves. However, at supraphysiologic inputs, large quantities of vitamin D(3) are stored as the native compound, presumably in body fat, and are slowly released to be converted to 25(OH)D. Copyright © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

The recent discovery -- from a meta-analysis of 18 randomized controlled trials -- that supplemental cholecalciferol (vitamin D) significantly reduces all-cause mortality emphasizes the medical, ethical, and legal implications of promptly diagnosing and adequately treating vitamin D deficiency. Not only are such deficiencies common, and probably the rule, vitamin D deficiency is implicated in most of the diseases of civilization. Vitamin D's final metabolic product is a potent, pleiotropic, repair and maintenance, seco-steroid hormone that targets more than 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. One of the most important genes vitamin D up-regulates is for cathelicidin, a naturally occurring broad-spectrum antibiotic. Natural vitamin D levels, those found in humans living in a sun-rich environment, are between 40-70 ng per ml, levels obtained by few modern humans. Assessing serum 25-hydroxy-vitamin D (25(OH)D) is the only way to make the diagnosis and to assure treatment is adequate and safe. Three treatment modalities exist for vitamin D deficiency: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D3 supplementation. Treatment of vitamin D deficiency in otherwise healthy patients with 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round 25(OH)D levels between 40-70 ng per mL. In those with serious illnesses associated with vitamin D deficiency, such as cancer, heart disease, multiple sclerosis, diabetes, autism, and a host of other illnesses, doses should be sufficient to maintain year-round 25(OH)D levels between 55 -70 ng per mL. Vitamin D-deficient patients with serious illness should not only be supplemented more aggressively than the well, they should have more frequent monitoring of serum 25(OH)D and serum calcium. Vitamin D should always be adjuvant treatment in patients with serious illnesses and never replace standard treatment. Theoretically, pharmacological doses of vitamin D (2,000 IU per kg per day for three days) may produce enough of the naturally occurring antibiotic cathelicidin to cure common viral respiratory infections, such as influenza and the common cold, but such a theory awaits further science. [ABSTRACT FROM AUTHOR]

Objective:With vitamin D deficiency as a serious public health problem, vitamin D status at birth was measured in neonates at latitude 32 degrees 72' (southeastern United States).Study Design:In umbilical cord blood, vitamin D status, demonstrated by circulating 25-hydroxyvitamin D, was measured and related to race and season of birth.Result:The mean+/-standard deviation of 25-hydroxyvitamin D in 100 cord blood samples was 13.5+/-8.3 ng/ml for the cohort. African-American infants, with a mean+/-standard deviation of 10.5+/-6.0 ng/ml, demonstrated significantly lower vitamin D status than Caucasian infants, with a mean+/-standard deviation of 19.5+/-9.6 ng/ml (P<0.0001). By season, the mean 25-hydroxyvitamin D level at birth in November-March compared to April-October was 11.3 ng/ml lower in Caucasian infants (from 29.0 to 17.7 ng/ml) and 3 ng/ml lower in African-American infants (from 13.1 to 10.1 ng/ml).Conclusion:The prevalence of vitamin D insufficiency is high in this cohort. African-American infants demonstrate significantly lower vitamin D status at birth than Caucasian infants. Seasonality, while significant in both groups, had a greater impact on the vitamin D status of Caucasian newborns.Journal of Perinatology (2007) 27, 568-571; doi:10.1038/sj.jp.7211796; published online 12 July 2007. [ABSTRACT FROM AUTHOR]

Background: Low vitamin D status has long been implicated in colorectal carcinogenesis. We investigated this relationship in a nested case-control study within the Health Professionals Follow-up Study (HPFS), a large ongoing study of male health professionals living in the United States.Methods: Between 1993 and 2002, 179 colorectal cancer patients were diagnosed and matched to 356 control subjects by age and by month and year of blood collection. Results were also pooled with previously published results from the Nurses' Health Study (NHS) cohort, a large female cohort. Conditional logistic regression was used to analyze the association between plasma 25-hydroxyvitamin D [25(OH)D] and colorectal cancer, and pooled estimates were calculated using the method of DerSimonian and Laird. All statistical tests were two-sided.Results: In the HPFS, we observed a non-statistically significant inverse association between higher plasma 25(OH)D concentration and risk of colorectal cancer and a statistically significant inverse association for colon cancer (highest versus lowest quintile: odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.24 to 0.89; P(trend) = .005). After pooling the results from the HPFS and NHS, higher plasma 25(OH)D concentrations were statistically significantly associated with decreased risks of both colorectal cancer (highest versus lowest quintile, OR = 0.66, 95% CI = 0.42 to 1.05; P(trend) = .01) and colon cancer (highest versus lowest quintile, OR = 0.54, 95% CI = 0.34 to 0.86; P(trend) = .002). Inverse associations with plasma 25(OH)D concentration did not differ by location of colon cancer (proximal versus distal), but the number of patients was small and none of the associations was statistically significant. Opposite relationships between plasma 25(OH)D levels and risk of rectal cancers were found among men (positive) and women (inverse).Conclusion: Our data provide additional support for the inverse association between vitamin D and colorectal and, in particular, colon cancer risk. [ABSTRACT FROM AUTHOR]

Concerns about vitamin D have resurfaced in medical and scientific literature because the prevalence of vitamin D deficiency in the United States, particularly among darkly pigmented persons, has increased. The primary goals of this review were to discuss past and current literature and to reassess the dietary reference intake for vitamin D in adults, with particular focus on women during pregnancy and lactation. The appropriate dose of vitamin D during pregnancy and lactation is unknown, although it appears to be greater than the current dietary reference intake of 200-400 IU/d (5-10 microg/d). Doses of < or =10 000 IU vitamin D/d (250 microg/d) for up to 5 mo do not elevate circulating 25-hydroxyvitamin D to concentrations > 90 ng/mL, whereas doses < 1000 IU/d appear, in many cases, to be inadequate for maintaining normal circulating 25-hydroxyvitamin D concentrations of between 15 and 80 ng/mL. Vitamin D plays no etiologic role in cardiac valvular disease, such as that observed in Williams syndrome, and, as such, animal models involving vitamin D intoxication that show an effect on cardiac disease are flawed and offer no insight into normal human physiology. Higher doses of vitamin D are necessary for a large segment of Americans to achieve concentrations equivalent to those in persons who live and work in sun-rich environments. Further studies are necessary to determine optimal vitamin D intakes for pregnant and lactating women as a function of latitude and race. Copyright © 2004 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

This report briefly reviews existing methods for analyzing the vitamin D content of fortified and unfortified foods. The existing chemical methods are similar; all are time consuming, require experienced technicians, and have only been validated for a few materials (eg, dairy products or animal feed materials). This report also describes the lack of standard reference materials with certified values for vitamin D that laboratories need to guarantee the accuracy of existing analytic methods. Recently, the US Department of Agriculture, as part of a project to update the vitamin D values in the National Nutrient Database of Standard Reference, established an analytic methods committee to compare several existing vitamin D methods and to characterize 5 control materials (skim milk, processed cheese, cereal, orange juice, and salmon). Initial relative SDs for the 5 materials ranged from 35% to 50%. Elimination of systematic biases related to the methods and the standards yielded much more satisfactory relative SDs of 7% to 12%. This research has shown that existing methods for analyzing the vitamin D content in foods can produce accurate results. A new, simpler, and faster method, however, would greatly benefit the field. To guarantee accuracy, we need certified reference materials for foods. © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

The number of assessments of circulating 25-hydroxyvitamin D [25(OH)D] for diagnostic purposes has increased significantly during the past 5 y. Over the years, techniques for quantifying 25(OH)D have increased and evolved. Some changes have been for the better and some have not. Most current methods appear to provide valid results as long as the operator of the given technique is properly trained and motivated. In addition, any laboratory that assesses circulating 25(OH)D for clinical diagnosis needs to participate in the Vitamin D External Quality Assessment Scheme. Finally, research has shown that circulating 25(OH)D is extremely stable in stored serum or plasma samples; this characteristic makes accurate, long-term epidemiologic studies of circulating 25(OH)D possible. In this article, I provide an overview of the techniques available for measuring 25(OH)D, compare these techniques with one another, and assess their clinical utility. I also briefly discuss the stability of 25(OH)D in biological media and present an overview of the Vitamin D External Quality Assessment Scheme. © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Scientific data pertaining to vitamin D supplementation during lactation are scarce. The daily recommended intake for vitamin D during lactation has been arbitrarily set at 400 IU/d (10 microg/d). This recommendation is irrelevant with respect to maintaining the nutritional vitamin D status of mothers and nursing infants, especially among darkly pigmented individuals. Our objective was to examine the effect of high-dose maternal vitamin D2 supplementation on the nutritional vitamin D status of mothers and nursing infants. Fully lactating women (n = 18) were enrolled at 1 mo after birth to 1 of 2 treatment arms, ie, 1600 IU vitamin D2 and 400 IU vitamin D3 (prenatal vitamin) or 3600 IU vitamin D2 and 400 IU vitamin D3, for a 3-mo study period. High-dose (1600 or 3600 IU/d) vitamin D2 supplementation for a period of 3 mo safely increased circulating 25-hydroxyvitamin D [25(OH)D] concentrations for both groups. The antirachitic activity of milk from mothers receiving 2000 IU/d vitamin D increased by 34.2 IU/L, on average, whereas the activity in the 4000 IU/d group increased by 94.2 IU/L. Nursing infant circulating 25(OH)D2 concentrations reflected maternal intake and the amount contained in the milk. With limited sun exposure, an intake of 400 IU/d vitamin D would not sustain circulating 25(OH)D concentrations and thus would supply only limited amounts of vitamin D to nursing infants in breast milk. A maternal intake of 2000 IU/d vitamin D would elevate circulating 25(OH)D concentrations for both mothers and nursing infants, albeit with limited capacity, especially with respect to nursing infants. A maternal intake of 4000 IU/d could achieve substantial progress toward improving both maternal and neonatal nutritional vitamin D status. Copyright © 2004 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: Few studies evaluate the effects of vitamin D status and supplementation on maternal bone mineral density (BMD) during lactation and further lack inclusion of diverse racial/ethnic groups, body mass index (BMI), or physical activity. Objective: Determine the effects of vitamin D treatment/status, feeding type, BMI, race/ethnicity, and physical activity on postpartum women's BMD to 7 months. Methods: Women with singleton pregnancies beginning 4-6 weeks' postpartum were randomized into two treatment groups (400 or 6400 IU vitamin D/day). Participant hip, spine, femoral neck, and whole-body BMD using Dual-energy X-ray absorptiometry (DXA Hologic), serum 25-hydroxyvitamin D [25(OH)D] (RIA; Diasorin), BMI, and physical activity were measured at 1, 4, and 7 months postpartum. A general linear mixed modeling approach was undertaken to assess the effects of vitamin D status [both serum 25(OH)D concentrations and treatment groups], feeding type, race/ethnicity, BMI, and physical activity on BMD in postpartum women. Results: During the 6-month study period, lactating women had 1-3% BMD loss in all regions compared with 1-3% gain in nonlactating women. Higher maternal BMI was associated with less bone loss in femoral neck and hip regions. Black American women had less BMD loss than White/Caucasian or Hispanic lactating women in spine and hip regions. Exclusively breastfeeding women in the 6400 IU vitamin D group had less femoral neck BMD loss than the 400 IU group at 4 months sustained to 7 months. Physical activity was associated with higher hip BMD. Conclusion: While there was BMD loss during lactation to 7 months, the loss rate was less than previously reported, with notable racial/ethnic variation. Breastfeeding was associated with loss in BMD compared with formula-feeding women who gained BMD. Higher BMI and physical activity independently appeared to protect hip BMD, whereas higher vitamin D supplementation appeared protective against femoral neck BMD loss.

Objective: This article aims to determine the association between maternal 25-hydroxy-vitamin D [25(OH)D] status and intake of hormonal oral contraceptive pills (OCPs) in women who are lactating., Study Design: Women who were exclusively breastfeeding participated in a randomized controlled trial assessing vitamin D supplementation at 400, 2,400, or 6,400 international unit (IU)/d from 1 month through 7 months postpartum. This observational, secondary analysis assessed whether OCPs were associated with maternal 25(OH)D concentrations in women who are lactating. Multivariate regression models were used to predict 25(OH)D concentrations and create parameter estimates for each variable., Results: In a bivariate analysis, the use of OCPs at 4 months was associated with increased serum 25(OH)D ( p  = 0.02). OCPs' use at 7 months was associated with a higher trend in 25(OH)D, but this finding was not statistically significant ( p  = 0.1). In a multivariate regression model at 4 months, independent positive predictors of 25(OH)D concentrations were the use of OCPs ( p  = 0.03) and treatment with vitamin D at 6,400 IU/d ( p ≤ 0.0001). Negative predictors were Black ( p  = 0.001) and Hispanic ( p  = 0.0001) race and ethnicity, and body mass index (BMI) greater than 30 ( p  = 0.0002). The same pattern occurred at 7 months, with more southern latitude as a positive independent predictor ( p  = 0.04) of 25(OH)D concentration., Conclusion: The use of OCPs was associated with greater 25(OH)D in women who are lactating. Additionally, treatment with vitamin D at 6,400 IU/d and southern latitude was associated with greater 25(OH)D in women who are lactating. Black and Hispanic race and ethnicity, and BMI greater than 30, were independently associated with lower 25(OH)D in women who are lactating., Key Points: · The association of OCP with serum 25(OH)D concentrations during postpartum lactation is unknown.. · OCPs' use was associated with higher 25(OH)D concentrations in postpartum women who are lactating.. · Treatment with vitamin D and southern latitude was associated with greater 25(OH)D in women who are lactating.. · Black and Hispanic, and BMI > 30 were associated with lower 25(OH)D in women who are lactating.. · Practitioners can counsel women who are lactating on OCPs' use and the positive effects on their 25(OH)D status.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Our objective was to conduct a secondary, post hoc analysis of the National Institute of Child Health and Human Development (NICHD) vitamin D (vitD) pregnancy study by Hollis et al, which reported on the effect of vitD supplementation in pregnant women and determine the potential interaction between intact parathyroid hormone (iPTH) concentrations, vitD status, and various comorbidities associated with pregnancy. Women with low 25-hydroxy vitamin D (25(OH)D) concentrations and high iPTH concentrations during pregnancy, known as functional vitamin-D deficiency (FVDD), were more likely to acquire complications also affecting their neonates., Study Design: This post hoc analysis of data collected from a diverse group of pregnant women participating in the NICHD vitD pregnancy study was applied to investigate the applicability of the concept of FVDD in pregnancy (Hemmingway, 2018) in identifying potential risks for certain comorbidities of pregnancy. This analysis defines FVDD as maternal serum 25(OH)D concentrations below 20 ng/mL and iPTH concentrations above 65 pg/mL creating a definitive ratio number, 0.308, to classify mothers as having FVDD prior to delivery (PTD). Statistical analyses were performed using SAS 9.4 (Cary, NC)., Results: In total, 281 women (85 African American, 115 Hispanic, and 81 Caucasian) with 25(OH)D and iPTH concentrations measured at monthly visits were included in this analysis. No statistically significant association was found between mothers classified as having FVDD at baseline or 1-month PTD and hypertensive disorders of pregnancy, infection, or admittance to the neonatal intensive care unit. When combining all comorbidities of pregnancy in this cohort, results showed those with FVDD at baseline, 24 weeks' gestation, and 1-month PTD were more likely to experience a comorbidity ( p  = 0.001; p  = 0.001; p  = 0.004, respectively). Those with FVDD 1-month PTD were 7.1 times (confidence interval [CI]: 1.71-29.81) more likely to have preterm birth (<37 weeks) than women without FVDD., Conclusion: Participants were more likely to have experienced preterm birth if they met the criteria for FVDD. This study supports the importance of FVDD during pregnancy., Key Points: · Functional vitamin D deficiency (FVDD) is defined as the ratio of 25(OH)D divided by iPTH concentration ≤0.308.. · At a minimum, it is recommended that vitamin D status be kept in the healthy range based on current recommendations for pregnant individuals.. · FVDD is a more sensitive predictor of pregnancy risk than 25(OH)D alone.. · FVDD identified those with greater risk of preterm birth in this cohort.., Competing Interests: None declared., (Thieme. All rights reserved.)

Pregnancy is a unique time when amplified sex steroid concentrations promote an escalation in vitamin D binding protein (DBP) synthesis, associated with increased total vitamin D and metabolites, including 25-hydroxyvitamin D (25(OH)D). Free 25(OH)D concentration increases disproportionately to total 25(OH)D during pregnancy, likely an adaptation to supply the woman and fetus with readily available 25(OH)D. Highlighting the importance of the calcium metabolic stress during pregnancy, the interactional relationship between serum 25(OH)D and PTH has been evaluated. Maternal total 25(OH)D and total 25(OH)D/iPTH are measures of vitamin D status and biomarkers for potential pregnancy complications. It has been proposed that free 25(OH)D and free 25(OH)D/iPTH could be better indicators of vitamin D status and predictors of pregnancy complications such as gestational diabetes (GDM), hypertensive disorders of pregnancy, and preterm delivery. This study aims to determine if free 25(OH)D and its association with PTH are more accurate predictors of comorbidities of pregnancy than total 25(OH)D and its association with PTH. In this post hoc analysis of the Kellogg Pregnancy Study, a double-blind randomized placebo-controlled trial, participants included 297 women with singleton pregnancies: 191 participants were randomized into a group receiving a daily prenatal (400 IU vitamin D 3 ) while 196 received a prenatal plus extra supplementation (4400 IU vitamin D 3 ). Blood and urine samples were collected monthly. 297 participants' serum total 25(OH)D concentrations were measured using radioimmunoassay at baseline (visit 1) and 5-7 months' gestation (visit 6-7). 93 participants' serum free 25(OH)D and PTH concentrations were measured using ELISA and immunoradiometric assay, respectively, at visit 1 and 6-7; 66 participants had paired samples and were included in this analysis. Data were analyzed using SAS 9.4, Cary, N.C. or SPSS v28, IBM Corporation, Armonk, N.Y. Results were considered significant with a p < 0.05. A significant relationship exists between the ratio of total 25(OH)D/iPTH and free 25(OH)D/iPTH grouped by total 25(OH)D ≥ 30 ng/mL and < 30 ng/mL as an indicator of maternal vitamin D status. There was a statistically significant relationship between lower mean free 25(OH)D/iPTH and the development of GDM at visit 1 (p = 0.0003) and at visit 6-7 (p = 0.001) while total 25(OH)D/iPTH and GDM were significantly related only at visit 1 (p = 0.029). In this exploratory cohort, neither free 25(OH)D/iPTH nor total 25(OH)D/iPTH were significantly associated with increased incidence of preterm delivery, hypertensive disorders, or combined comorbidities of pregnancy. An univariate logistic regression evaluating the outcome of gestational diabetes while independently controlling for independent factors showed the ratio of free 25(OH)D/iPTH was more closely associated with gestational diabetes than the ratio of total 25(OH)D/iPTH, although neither were significant. This proof-of-concept analysis suggests that the ratio of free 25(OH)D/iPTH is associated with the development of gestational diabetes throughout pregnancy while total 25(OH)D/iPTH is only associated with the outcome early in pregnancy. Further investigation is warranted to explore this relationship between calcium metabolic stress during pregnancy with a larger cohort to improve validity,reproducibility, and relevance to other pregnancy comorbidities., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Vitamin D (VitD) has been shown to impact neurodevelopment. Studies have shown that higher 25-hydroxy-vitamin D (25(OH)D) concentrations (the indicator of vitD status) may be associated with better neurodevelopmental outcomes, although current data are conflicting. This study examined the relationship between total circulating 25(OH)D concentrations and neurodevelopmental outcomes in 3-5-year-old (3-5 yo) children., Methods: In this study, pregnant women were randomized to receive 400 (standard dose), 2000, or 4000 IU vitD 3 /day. Offspring then underwent the Brigance Screen at 3-5 yo. The 25(OH)D concentration was measured at birth and 3-5 yo. Relationships between Brigance scores and 25(OH)D and Brigance scores and vitamin D binding protein (VDBP) genotype were examined., Results: Higher 25(OH)D at the time of testing was associated with better overall performance on neurodevelopmental testing as measured by the Brigance quotient (B = 0.208, p = 0.049). Scores were then broken down into sub-scores. Children born to mothers in the 2000 IU/day group scored higher on the Brigance language component of the assessment versus the standard dose group (B = 4.667, p = 0.044). The group of children who had the Gc1f-1s or Gc1f-2 genotypes scored higher on the Brigance academic component (B = 9.993, p < 0.001) and lower on the Brigance language component versus the 1f1f genotype (B = -9.313, p < 0.001). Children with the Gc1s-1s, Gc1s-2, or Gc2-2 genotypes also scored lower than the Gc1f-1f genotype (B = -6.757, p = 0.003)., Conclusion: These results suggest that higher 25(OH)D concentrations early in life and higher doses of maternal vitamin D supplementation during pregnancy may have a positive association with neurodevelopmental outcomes. This study also suggests that the VDBP genotype is associated with neurodevelopment and differentially affects various fields of neurodevelopment.

Introduction: Positive effects of vitamin D (vitD) supplementation on comorbidities of pregnancy (COP) have been explored; however, few studies have elucidated the pathophysiology behind the development of these COP and the potential relationship with derangements in placental development and morphology. Additionally, it is known that placentas weighing 10th-90th % for gestational age are associated with better outcomes. Therefore, the objective of this study was to assess the impact of resulting circulating serum 25(OH)D concentrations associated with intake of high or low doses of supplementary vitD on placental development and morphology in women who participated in a randomized double blind, placebo-controlled trial of vitD supplementation. We hypothesized that if maternal serum 25(OH)D concentration (vitD status marker) is insufficient/deficient, then placental weight and % for gestational age (GA) will be smaller and will correlate with increased vascular and inflammatory placental pathologic findings., Methods: The findings of the present study are a secondary analysis of data generated from a previously reported randomized controlled trial (RCT), the Kellogg Vitamin D Pregnancy Study. Pregnant women (n = 297) in this RCT (January 2013 - April 2018) were randomly assigned to 400 IU vs. 4400 IU vitD/day (10-14 weeks' gestational age) and followed to delivery. 132 placentas were analyzed by pathologists blinded to treatment, and the 2016 Amsterdam Consensus Criteria were used to categorize grouping/grading of placental pathology and weight. Total [25(OH)D] was measured using radioimmunoassay (ng/mL). Chi-square and Student's t-test were used to show the difference in maternal characteristics by treatment group and by placental weight. Chi-square analysis was used to determine differences between the percent pathology findings by treatment group. Students t-test was used to determine the differences in vitD status and the frequency of placental lesions. Association between [25(OH)D] area under the curve (AUC) and placental morphology were determined in a regression model that included maternal BMI ≥ 30 kg/m 2 , race/ethnicity, and vitD treatment group allocation. Data were analyzed using SAS v9.4 (Cary, NC) and statistical significance was indicated by p < 0.05., Results: The percent pathology findings by treatment group were not significantly different for each of the placental pathology categories as defined by the 2016 Amsterdam Consensus Criteria including placental weight. However, when using 25(OH)D as a biomarker for vitD status, linear regression model showed maternal serum [25(OH)D] AUC was significantly associated with greater placental weight (p = 0.023). Logistic regression models showed mothers with BMI ≥ 30 kg/m 2 had larger placental weight (p = 0.046), and Hispanic and white/Caucasian mothers had greater placental weights than Black American mothers (p = 0.025). When placentas ≥ 90th % for GA, n = 7, were removed from the placental pool, Pearson correlation still showed a positive association between maternal serum 25(OH)D AUC and placental weight (p = 0.011). In a second linear regression model of placentas ≥ 90th % for GA (n = 7) vs. placentas < 90th % (n = 108), maternal serum 25(OH)D AUC was significantly greater in those placentas ≥ 90th % (p = 0.03); however, this was not associated with increased perinatal mortality. CONCLUSION FINDINGS: suggest increasing maternal serum [25(OH)D] via vitamin D supplementation during pregnancy did not adversely affect placental morphology; trends showed those in the treatment group had fewer placental lesions. Placental weight was found to be significantly associated with [25(OH)D] AUC, which represents maternal vitamin D status over the course of pregnancy; 7 placentas ≥ 90th % for GA were not associated with perinatal mortality., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: It is documented that vitamin D may have a role in erythropoiesis as its deficiency is accompanied by an increased risk of anemia. Aim: This study aimed to examine whether improvement of vitamin D status through daily consumption of either fortified foods or supplements could impinge on certain hematologic parameters in adults. Methods: We pooled data from our two separate clinical trials and made five experimental groups. As part of their usual diet, one group consumed 500 mL/day of yogurt drink fortified with 1000 IU of vitamin D (D-yogurt, n  = 27) whereas one group consumed 500 mL/day of the plain yogurt drink (P-yogurt, n  = 27). In addition three other groups consumed either 50 g/day bread fortified with 1000 IU of vitamin D (D-bread) or supplement containing 1000 IU vitamin D (D-supplement, n  = 27) or placebo (placebo, n  = 27). Biochemical measurements were performed before and after the intervention. Results: In all three vitamin D-supplemented groups, serum 25(OH)D concentration increased after the intervention period, which was interestingly accompanied by a significant increment of hemoglobin (D-yogurt, p  < 0.001, D-bread, p  = 0.003, D-supplement, p  < 0.001). Analyses indicated that among participants in vitamin D-intervention groups, being in D-yogurt group was more favourable predictor of improvement in hemoglobin concentrations compared with the placebo ( p  < 0.001), D-bread ( p  = 0.045) and P-yogurt ( p  = 0.001). Conclusion: Improvement of vitamin D status via regular intake of either vitamin D-fortified food products or supplements can result in a significant increment of hemoglobin in adult subjects. This finding has very important clinical as well as public health implications.

Background: Vitamin D (vitD) plays a major role in maintenance of bone mineral homeostasis. It is unknown if bone mineral content (BMC) and bone mineral density (BMD) differ between infants who receive direct vitD supplementation and those who receive vitD indirectly via their mother's breast milk, while she received a high dose of vitD. It is hypothesized that there would be no differences in BMC or BMD by treatment group. Design/Methods: Randomized, double-blind trial to compare BMD and BMC of infants who received direct vitD (400 IU vitD 3 /day) in addition to their mother receiving standard dosage (400 IU vitD 3 /day) versus infants whose mothers were their only source of vitD and were given high-dose supplementation (6,400 IU vitD 3 /day). Participants were exclusively breastfeeding mothers and their infant consuming only human milk. Infant BMC and BMD were measured by dual-energy X-ray absorptiometry (DXA) scans of the infant's total body using Hologic Discovery A Densitometer and analyzed using Hologic Infant software at 1, 4, and 7 months of age. Results: Infant BMC and BMD did not differ significantly at 1, 4, or 7 months of age between direct and indirect supplementation arms. The mean difference in BMC from 1 to 7 months was 1.624 and 1.464 g for the 400 and 6,400 IU groups, respectively, ( p  = 0.5); the mean difference in BMD over this same period was 0.042 and 0.032 g/cm 2 for the 400 and 6,400 IU groups, respectively ( p  = 0.2). Although some differences among races were observed, this did not reflect changes in bone growth between the treatment arms. Conclusion: High-dose vitD supplementation of mothers during lactation provided an efficacious alternative to direct supplementation of infants, as evidenced by noninferior infant BMD and BMC. Clinical Trial Registration number: NCT00412074.

Background: To ensure the safety of higher dose vitamin D supplementation in pregnant and lactating mothers, and urinary calcium/creatinine (UCa/Cr) ratios, serum calcium, and serum 25(OH)D concentrations are closely monitored. To achieve optimal maternal and infant vitamin D status, while avoiding hypercalcemia, safety measures assessing vitD supplementation must be reliable. Whether or not this holds true for infants before 7 months of age, remains unknown. Objective: Analyze the association among UCa/Cr ratio, serum calcium, intact serum parathyroid hormone (iPTH), 25(OH)D, and 25(OH)D/iPTH ratio in infants to determine whether evidence supports the use of these parameters as valuable measures of hypervitaminosis D or toxicity in infants. Methods: A series of analyses were performed on the cohort of infants who participated in the National Institute of Child Health and Human Development lactation vitD supplementation trial to determine the association among UCa/Cr ratio, serum calcium, iPTH, 25(OH)D, and 25(OH)D/iPTH ratio. Results: Upon multivariate analysis, serum calcium was significantly associated with 25(OH)D ( p  = 0.0441), iPTH ( p  = 0.0017), and 25(OH)D/iPTH ratio ( p  = 0.0001). Infant UCa/Cr did not associate with 25(OH)D but did associate with iPTH ( p  = 0.0008) and 25(OH)D/iPTH ratio ( p  = 0.0001). The correlation between UCa/Cr and 25(OH)D/iPTH ratios was significantly stronger than the association between UCa/Cr ratio and iPTH. Serum calcium more strongly correlated with 25(OH)D/iPTH ratio versus 25(OH)D and iPTH. Conclusion: In this healthy cohort of infants 1 to 7 months old, UCa/Cr and serum calcium are more valid indicators of 25(OH)D/iPTH ratio than either 25(OH)D or iPTH alone. Moreover, serum calcium (and not UCa/Cr) is a valid indicator of infant total circulating 25(OH)D and should be measured if vitamin D toxicity is a concern. Clinical Trial Registration number: FDA IND Number: 66,346; ClinicalTrials.gov Number: NCT00412074.

The placenta plays an important role in how vitamin D is metabolized and supplied to the fetus., Competing Interests: CW, BH No competing interests declared, (© 2022, Wagner and Hollis.)

We investigated the effect of daily intake of yogurt drink fortified with either vitamin D alone or with added calcium on resting metabolic rate (RMR), thyroid hormones and homeostatic model assessment for insulin resistance in subjects with type 2 diabetes (T2D). A total of 75 adult subjects with T2D were randomly assigned to 1 of the 3 groups to receive either D-fortified yogurt drink (DY; 1000 IU vitamin D/day), Ca-D-fortified yogurt drink (CDY; 1000 IU vitamin D plus 500 mg calcium), or plain yogurt drink for 12 weeks. All assessments were done at the baseline and after the intervention. The concentrations of anti-thyroid peroxidase antibody (anti-TPO-Ab), intact parathyroid hormone (iPTH) and thyroid stimulating hormone (TSH) had declined significantly compared with baseline values only in the CDY group. The mean RMR increased in both DY and CDY groups ( p  < 0.001 for both). Also, changes of serum concentrations of 25-hydroxycalciferol (B = 2.96, 95% confidence interval (CI) = 1.3 to 4.6, p  = 0.001) and iPTH (B = -2.41, 95% CI = -4.5 to -0.31, p  = 0.025) remained significant predictors of RMR changes even after adjustment for changes of serum concentrations of TSH (B = -18.2, 95% CI = -61.7 to 25.2, p  = 0.406). Daily intake of vitamin D together with calcium at physiological doses has attenuating effect on anti-TPO-Ab and TSH. Also, vitamin D with or without added calcium causes a significant thyroid-independent increase in RMR in euthyroid subjects with T2D. Registered at clinicaltrials.gov as NCT01229891. Novelty: Daily intake of vitamin D with calcium at physiological doses has attenuating effect on anti-TPO-Ab and TSH. Vitamin D with or without added calcium causes a thyroid-independent increase in RMR in euthyroid subjects with T2D.

Background: Some evidence suggests indirect ameliorating effects of vitamin D in diabetes via adiponectin and sirtuins. This study aimed to evaluate the effects of daily intake of vitamin D-fortified yogurt drink, either with or without added calcium, on serum adiponectin, sirtuins (SIRT)1 and 6., Methods: Briefly, 75 adults aged 30-60 years from both sexes with type 2 diabetes were randomly allocated to one of the three groups: (i) D-fortified-yogurt drink (DY; containing 1000 IU vitamin D and 300 mg calcium), (ii) Ca+D-fortified-yogurt drink (CDY; containing 1000 IU vitamin D and 500 mg calcium) and (iii) plain yogurt drink (PY; containing no detectable vitamin D and 300 mg calcium). All assessments were performed initially and after 12 weeks., Results: A significant within-group increment in serum adiponectin concentrations was observed in both DY and CDY groups (+60.4 ± 8.6, +57.5 ± 6.4 µg/L, respectively; p < 0.001 for both). The concentrations of SIRT1 and SIRT6 had a significant within-group increment only in the CDY group (p = 0.003, p = 0.001 respectively). Being in CDY group was more favorable predictor of improvement in SIRT6 concentrations. Changes of 25(OH)D were a significant predictor of changes of adiponectin. However, this association disappeared following adjustment for changes of SIRT1. In contrast, the association between changes of 25(OH)D and HbA1c remained significant even after adjustment for SIRT1., Conclusions: Daily consumption of vitamin D-fortified yogurt drink for 12 weeks resulted in an increase in circulating concentrations of SIRT1 and SIRT6 in T2D subjects and D+Ca-fortified yogurt drink was more in favor of SIRT6 increment., (© 2021. The Author(s).)

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O 2 ), followed by hypothermia alone or with N -acetylcysteine (25 mg/kg) and vitamin D (1,25(OH) 2 D 3 , 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

Background: For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations., Methods: Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D 3 /day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined., Results: Baseline TGF-β and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-β, VEGF and IL-10 and with IL-10 at second and third trimesters., Conclusions: Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-β and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy., Impact: In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-β and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-β, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-β, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.