60 % of Canadians have suboptimal vitamin D (<75 nmol/L) and 25% are obese. Obesity has been reported to be a risk factor for low vitamin D, but there is uncertainty about the magnitude of the association. Linear regression was performed using data from the nationally representative cross-sectional Canadian Health Measures Survey (2007-2009). Height, weight, waist circumference (WC), and vitamin D levels were directly measured. There were 5298 participants aged 6 to 79 years. Using a conservative p value of 0.001, body mass index (BMI) category obese / obese I was positively associated and WC was inversely associated with vitamin D level in crude analysis. WC was inversely associated with vitamin D level in multivariate analysis. The pattern of relationship is not the same as other studies, yet this was a large study with direct measurements. There may be issues with linearity of relationships or subgroups disturbing the relationship.

Objectives: Inadequate maternal vitamin D (25(OH)D) levels during pregnancy may affect primary tooth calcification predisposing enamel hypoplasia (EH), a risk factor for Early Childhood Caries (ECC). The purpose of the study was to determine the relationship between 25(OH)D status of expectant mothers and the incidence of EH and ECC among their infants. Methods: This prospective study recruited expectant mothers during their second trimester of pregnancy. A prenatal questionnaire was completed and serum sample drawn for a 25(OH)D assay. Infant dental exams, scheduled at approximately 12 months of age, determined EH and ECC, at which time the mother completed a second questionnaire. The dental examiner was blinded to each mother's prenatal vitamin D status. Results: 207 women, 90% of whom self-declared Aboriginal heritage, were enrolled at a mean age of 19.0 ± 4.7 years. The mean serum 25(OH)D was 48.1 ± 24.4 nmol/L. 35% had levels ≤ 35 nmol/L, a formerly-defined threshold of deficiency. Only 10% of women had concentrations ≥ 80 nmol/L, denoting adequacy. 135 infants were examined at 16.1 ± 7.4 months of age. EH was identified in 22% of infants, 23% had ECC and (36% ECC when white spot lesions were included). Mothers of children with EH had lower mean serum 25(OH)D concentrations during pregnancy than mothers of children without EH (43.2 ± 21.1 vs. 51.4 ± 27.4 nmol/L, p=.072). Mothers of children with ECC had lower 25(OH)D levels than mothers whose children were caries-free (41.4 ± 20.4 vs. 52.4 ± 27.4 nmol/L, p=.045). The rate of untreated decay was inversely related with maternal vitamin D concentrations (p<.001). Infants with EH were significantly more likely to have ECC (p<.001). Logistic regression identified low maternal calcium levels (p=.034), not having heard of vitamin D (p=.036), and not using margarine daily (p=.024) as being significantly associated with EH in the primary dentition of infants. Backwards logistic regression revealed that EH (p<.001), infant age (p=.002), and lower 25(OH)D levels during pregnancy (p=.019) were significantly associated with ECC. Conclusions: This study shows for the first time that maternal vitamin-D levels may influence primary dentition and the development of ECC in their babies.

1a,25-Dihydroxyvitamin D3 (1a,25(OH)2D3) is a major functional metabolic form of vitamin D. 1a,25(OH)2D3 has drawn increasing attention due to its functions in addition to maintaining calcium phosphate homeostasis. It directly regulates mineralization by osteoblasts, matrix production and remodeling by chondrocytes, and contraction of cardiomyocytes. 1a,25(OH)2D3 and its analogues have shown beneficial effects in treating multiple sclerosis, diabetes and various types of cancer. In order to maximize the pharmaceutical potential of 1a,25(OH)2D3, a better understanding its cell signaling pathway is necessary. 1a,25(OH)2D3 regulates osteoblasts through both classical nuclear vitamin D receptor (nVDR) mediated genomic effects and plasma membrane receptor-mediated rapid responses. The identity of the plasma membrane receptor for 1a,25(OH)2D3 is controversial. Protein disulfide isomerase associated 3 (Pdia3) has been hypothesized as one of the putative plasma membrane receptors for 1a,25(OH)2D3. The overall goal of this thesis was to understand the general role and the molecular mechanism of Pdia3 in 1a,25(OH)2D3-initiated rapid responses, and to determine the role of Pdia3 and its dependent signaling in osteoblast biology. The results show that Pdia3 is required for membrane-mediated responses of 1a,25(OH)2D3. Moreover, both Pdia3 and nVDR are critical components of the plasma membrane receptor complex for 1a,25(OH)2D3. Finally, Pdia3 and signaling via Pdia3 regulate osteoblast differentiation and mineralization. Taken together, this study demonstrates the role of Pdia3 in rapid responses to 1a,25(OH)2D3 and osteoblast biology, reveals the unexpected complexity of the 1a,25(OH)2D3 plasma receptor complex and opens the new target, Pdia3, for pharmaceutical application and tissue engineering.

Emerging evidence suggests that vitamin D may be associated with type 2 diabetes (T2DM), however current data are inconsistent regarding metabolic disorders underlying T2DM. The objectives of this thesis were to investigate the association of vitamin D with the primary pathophysiological disorders of type 2 diabetes: namely insulin resistance (IR) and beta (β)-cell dysfunction, and the metabolic syndrome (MetS). All studies included individuals participating in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, comprising 712 subjects 30 years and older, and at risk of T2DM at baseline. Serum 25-hydroxyvitamin D [25(OH)D] was measured to assess vitamin D nutritional status. Validated oral glucose tolerance test derived indices for IR and β-cell function were calculated. In the first cross-sectional study, multivariate linear regression analyses indicated a significant inverse association of serum 25(OH)D with IR (β=-0.003, p=0.007) and a significant positive association of 25(OH)D with β-cell function (β=0.004, p=0.03) at the baseline PROMISE clinic visit (n=712). In another cross-sectional study also conducted using data from the baseline PROMISE clinic visit, higher 25(OH)D was found to be significantly associated with a reduced presence of the MetS after multivariate adjustment (OR=0.76, 95% CI 0.62-0.93). Low serum 25(OH)D was also significantly associated with various MetS components. In light of the findings in the first cross-sectional study, the third study examined prospective associations of baseline 25(OH)D with 3-year follow-up IR and β-cell function (n=489). Although baseline 25(OH)D was not significantly associated with follow-up IR, a significant positive association of baseline 25(OH)D with β-cell function at follow-up was observed (β=0.005, p=0.015). Lastly, in a longitudinal substudy (n=127), seasonal changes in 25(OH)D over 2.5 years did not significantly affect changes in IR and β-cell function. In conclusion, results indicated that baseline serum 25(OH)D was cross-sectionally related to IR, β-cell function and the MetS, and was prospectively related to β-cell function at the 3-year follow-up. In addition, seasonal changes in 25(OH)D do not adversely affect IR and β-cell function over time. These findings suggest a potential role for higher 25(OH)D levels in reducing diabetes risk, although additional longitudinal studies are warranted.

Emerging evidence suggests that vitamin D may be associated with type 2 diabetes (T2DM), however current data are inconsistent regarding metabolic disorders underlying T2DM. The objectives of this thesis were to investigate the association of vitamin D with the primary pathophysiological disorders of type 2 diabetes: namely insulin resistance (IR) and beta (β)-cell dysfunction, and the metabolic syndrome (MetS). All studies included individuals participating in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, comprising 712 subjects 30 years and older, and at risk of T2DM at baseline. Serum 25-hydroxyvitamin D [25(OH)D] was measured to assess vitamin D nutritional status. Validated oral glucose tolerance test derived indices for IR and β-cell function were calculated. In the first cross-sectional study, multivariate linear regression analyses indicated a significant inverse association of serum 25(OH)D with IR (β=-0.003, p=0.007) and a significant positive association of 25(OH)D with β-cell function (β=0.004, p=0.03) at the baseline PROMISE clinic visit (n=712). In another cross-sectional study also conducted using data from the baseline PROMISE clinic visit, higher 25(OH)D was found to be significantly associated with a reduced presence of the MetS after multivariate adjustment (OR=0.76, 95% CI 0.62-0.93). Low serum 25(OH)D was also significantly associated with various MetS components. In light of the findings in the first cross-sectional study, the third study examined prospective associations of baseline 25(OH)D with 3-year follow-up IR and β-cell function (n=489). Although baseline 25(OH)D was not significantly associated with follow-up IR, a significant positive association of baseline 25(OH)D with β-cell function at follow-up was observed (β=0.005, p=0.015). Lastly, in a longitudinal substudy (n=127), seasonal changes in 25(OH)D over 2.5 years did not significantly affect changes in IR and β-cell function. In conclusion, results indicated that baseline serum 25(OH)D was cross-sectionally related to IR, β-cell function and the MetS, and was prospectively related to β-cell function at the 3-year follow-up. In addition, seasonal changes in 25(OH)D do not adversely affect IR and β-cell function over time. These findings suggest a potential role for higher 25(OH)D levels in reducing diabetes risk, although additional longitudinal studies are warranted.

Normal physiological functioning is highly dependent of calcium and the concentration range is very narrow. Normal calcium levels are so crucial to survival that the body will de-mineralize bone if the levels are insufficient. A prerequisite for normal calcium uptake is a normal Vitamin D level. Insufficient levels of Vitamin D are associated to several diseases. The aims of this thesis were to study the relationship between pregnancies and hyperparathyroidism (pHPT) (I), between pHPT and pregnancy with preeclampsia (II) and also to determine if disturbances in calcium homeostasis with vitamin D deficiency are apparent in preeclamptic women (III).  The aim was also to study calciumhomeostasis in obese patients before and after bariatric surgery (IV and V) with emphasis on vitamin D status, parathyroid secretion and bone mineral density (BMD). A correlation was found between a history of pHPT and pregnancy with preeclampsia, with an odds ratio of 6,89 ( 95% CI 2.30, 20.58).  Parathyroid hormone was significantly raised in preeclamptic pregnancies but vitamin D deficiency was present both in preeclamptic and healthy pregnancies. A certain polymorphism of the Vitamin D receptor (baT haplotype), overrepresented in pHPT, was not over expressed in preeclampsia. Hypovitaminosis D was present in more than 70% of bariatric patients preoperatively, which did not change after surgery, despite great weight loss and start of Vitamin D supplementation. BMD was significantly lower in bariatric patients with a negative correlation to the time elapsed since surgery. A small increase in BMD could be noted 10-13 years after bariatric surgery, possibly due to gradual weight gain. CiCa-clamping in obese patients demonstrated a disturbed calcium homeostasis with a left-shifted calcium-PTH relationship and a lower set-point of calcium. This disturbance persisted one year postoperatively. In conclusion, derangements in calcium homeostasis with decreased levels of Vitamin D are present in preeclampsia and obesity. A history of pHPT should be viewed as a risk factor for preeclampsia. Life long follow-up is necessary after bariatric surgery, and an individually adjusted high dose Vitamin D substitute is probably needed to avoid a development of osteoporosis.

1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders.

Epidemiological studies indicate that maternal vitamin D deficiency may be a candidate developmental risk factor for schizophrenia. For example, people born in winter/spring, urban environments and dark-skinned individuals whose parents migrated to cooler climates are all at increased risk of developing schizophrenia later in life. The biological plausibility that a low prenatal level of vitamin D has an adverse impact on the developing brain has been studied using a developmental vitamin D (DVD) deficient rat model. These animals display molecular and anatomical abnormalities in brain development and alterations in behaviour as adults. Compared with control rats, neonatal DVD-deficient rat brains are different in shape; displaying a thinner cortex and larger lateral ventricles. Moreover, the brains appear to be less differentiated. At adulthood, DVD-deficient rats show an enhanced sensitivity to novelty-, antipsychotic- and psychomimetic- induced locomotion. These observations have lead to the hypothesis that dopamine and/or glutamate neurotransmission may be altered in DVD-deficient rats. Thus, the main aim of this thesis was to further characterise the dopamine and glutamate neurotransmitter systems in DVD-deficient rats. DVD-deficiency resulted in sex and age specific changes in dopamine signalling. At birth, DVD-deficient rats showed altered dopamine metabolism in the forebrain providing the first report of altered dopamine function after DVD-deficiency. Female DVD-deficient rats displayed a post-adolescent (at 3 months of age) enhanced response to amphetamine-induced locomotion. Accompanying this behavioural sensitivity were decreased levels of dopamine 1 and 2 receptor density in the nucleus accumbens. The altered behaviour in female DVD-deficient rats was not associated with increased dopamine release in the prefrontal cortex, caudate putamen or nucleus accumbens. Although a similar increase in the behavioural sensitivity to amphetamine was not observed in male DVD-deficient adult rats, increases in the density of the dopamine transporter were observed in the caudate putamen and nucleus accumbens. However, when examined at a mature adult age (6 months) neither the enhanced response to amphetamine, receptor or transporter changes persisted. These results suggest that after puberty a transient change in dopamine receptor signalling manifests as an altered response to amphetamine under certain environmental and experimental conditions. Glutamate signalling was probed with the N-methyl-D-aspartate receptor antagonist MK-801. Adult male DVD-deficient rats showed an enhanced locomotor response to MK-801 and this persisted when examined at a mature adult age. Female DVD-deficient rats showed an enhanced response but this was only observed at the mature adult age examined. No behavioral differences were observed prior to adolescence. This behavioural sensitivity did not appear to be due to altered dopamine release after MK-801 in the prefrontal cortex and caudate putamen. Taken together, male DVD-deficient rats develop a locomotor sensitivity to MK-801 at an earlier age than DVD-deficient females. This behavioural alteration is not associated with altered dopamine function. The combined results from the studies in this thesis present a complex phenotype that suggests altered dopamine and glutamate interactions in DVD-deficient rats that are dynamic; demonstrating both age and sex specific traits. I speculate that the development of these behavioural and neurochemical alterations in DVD-deficient rats follows a similar temporal profile to the symptomology observed in schizophrenia patients. Both behavioural sensitivities to amphetamine and MK-801 are observed in schizophrenia in addition to a delayed onset of symptoms in females. This provides further support for a role of vitamin D in the developing brain and suggests that a transient deficiency can result in long-term behavioural and neurochemical alterations. Together this suggests that the DVD-deficient rat model may be an informative model for exploring the developmental vitamin D deficiency hypothesis of schizophrenia.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 5 uppsatser.

Thesis (Ph.D. in Epidemiology) -- University of Colorado at Denver and Health Sciences Center, 2006. / Typescript. Includes bibliographical references (leaves 168-182). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;