The objective of this study was to investigate the extent to which vitamin D and K are associated with bone health in pediatric cystic fibrosis (CF) patients. We hypothesized that: (1) the prevalence of vitamin D and K deficiencies would be high despite routine vitamin therapy, (2) bone health would be reduced and (3) vitamin K and D status would be associated with bone health. / Our results showed poor bone mineral mass in these CF children despite mild disease and good nutritional status. Neither vitamin K nor D was a predictor of bone health but weight and height Z-scores, fat-free mass, physical activity and lung function were all consistent predictors. / These results indicate that nutritional status as well as physical activity are key determinants of bone health in CF children and offer a unique opportunity in the prevention of CF-related bone disease. Further vitamin intervention research needs to be done in this population.

The first three studies in this thesis address the mechanism for the aberrant fall in serum 1,25-dihydroxyvitamin D$ sb3$ (1,25-(OH)$ sb2$D$ sb3 rbrack$ and increase in renal 1,25-(OH)$ sb2$D$ sb3$-24-hydroxylase(24-hydroxylase) activity in X-linked hypophosphatemic mice (Hyp). The 24-hydroxylase is the first enzyme in the C-24 oxidation pathway that degrades the vitamin D hormone to its final inactivation product, calcitroic acid. We demonstrated that: (i) the aberrant increase in 24-hydroxylase activity in Pi-deprived Hyp mice is specific to the kidney and is the result of an increase in enzyme Vmax, immunoreactive protein and mRNA abundance; (ii) the increase in 24-hydroxylase mRNA in both Pi-deprived Hyp mice and 1,25-(0H)$ sb2$D$ sb3$-treated normal littermates can be ascribed to an increase in the transcriptional activity of the 24-hydroxylase gene; (iii) 24-hydroxylase transcripts in normal mice, Pi-deprived Hyp and normal mice and 1,25-(OH)$ sb2$D$ sb3$-treated normal mice are localized to the proximal tubule by in situ hybridization; and (iv) recombinant human growth hormone administration normalizes the aberrant increase in 24-hydroxylase but that this response is not sufficient to correct serum 1,25-(OH)$ sb2$D$ sb3$ levels in Pi-deprived Hyp mice. / The fourth study addresses the mechanism whereby EB 1089, an analogue of 1,25-(OH)$ sb2$D$ sb3,$ is less calcemic than the vitamin D hormone, while being more potent in its antiproliferative action. We demonstrate that: (i) EB 1089 has a 50-fold lower affinity than 1,25-(OH)$ sb2$D$ sb3$ for the vitamin D catabolic enzyme, 24-hydroxylase; and (ii) EB 1089 and 1,25-(OH)$ sb2$D$ sb3$ exhibit tissue-specific differences in vitamin D receptor-mediated responses in vivo that may be ascribed, at least in part, to differences in binding affinities for the vitamin D receptor.

The primary function of vitamin D in humans is to maintain sufficient circulating calcium concentrations. Low vitamin D levels could result in excessive calcium resorption from bone. Vitamin deficiency may therefore decrease bone mineral density (BMD), resulting in an increased risk of fracture. This thesis sought to determine the association between vitamin D intake and bone health and to estimate circulating levels of vitamin D optimal for bone health without increasing the risk for non-bone disease. Furthermore, the thesis assessed the difference in performance between common serum vitamin D assays and the genetic influence of vitamin D status. In prospective population-based cohorts, blood concentrations <40 nmol/L (lowest 5%) increased the risk of fracture in elderly men. Low levels were further associated with a slight decrease in lumbar spine BMD. Both high (>98 nmol/L) and low (<46 nmol/L) vitamin D levels were associated with higher cancer and overall mortality. In another cohort, also of older men and women, no association was found between vitamin D levels and fracture. Low vitamin D levels were weakly associated with decreased total body BMD in men but not in women. Dietary intake of vitamin D over a 20-year period in more than 60,000 Swedish women was not associated with osteoporosis or fracture, regardless of calcium intake. During summer, dietary vitamin D intake and other life style habits are of minor importance for the variation in vitamin D levels relative to sun exposure and genes. In summer time, genes explain about half  of the variation in vitamin D levels, but none of the variance in winter time. The variability between vitamin D assays was substantial. Three assays classified 8, 22 and 43% of the same study population as vitamin D insufficient if <50 nmol/L was set as the insufficiency level. Based on the results in this thesis, low 25(OH)D levels and low dietary vitamin D intake are not a major cause of fractures in community-dwelling elderly Swedish women and men. Differences in assay performance and potential negative health outcomes of high 25(OH)D levels need to be considered.

Exposure to ultraviolet radiation (UV) results in both damaging and beneficial health outcomes. Excessive UV exposure has been linked to many skin and eye problems, but moderate exposure induces vitamin D production. It has been reported that humans receive 90-95% of their vitamin D from production that starts after UV exposure. Although it is possible to acquire vitamin D through dietary supplementation, the average person receives very little in this manner. Therefore, since most people acquire their vitamin D from synthesis after exposure to UV from sunlight, it is very important to understand the different environments in which people encounter UV. This project measured UV radiation and in-vitro vitamin D production in the urban canyon and at a nearby suburban location. The urban canyon is an environment consisting of tall buildings and tropospheric air pollution, which have an attenuating effect on UV. Typically, UV measurements are collected in areas outside the urban canyon, meaning that at times studies and public recommendations do not accurately represent the amount of UV reaching street-level in highly urbanized areas. Understanding of UV exposure in urban canyons becomes increasingly important as the number of people working and living in large cities steadily increases worldwide. This study was conducted in the central business district (CBD) of Brisbane, Australia, which models the urban canyons of large cities around the world in that it boasts a great number of tall buildings, including many skyscrapers, meaning that most areas only see a small amount of direct sunlight each day. During the winter of 2007 measurements of UV radiation and in-vitro vitamin D production were collected in the CBD and at a suburban site approximately 2.5km outside the CBD. Air pollution data was obtained from a central CBD measurement site. Data analysis showed that urban canyon measurements of both UV radiation and in-vitro vitamin D production were significantly lower than those collected at the suburban site. These results will aid both future researchers and policy makers in better understanding human UV exposure in Brisbane’s CBD and other urban canyons around the world.

Adequate vitamin D status plays an important role in bone health and may also protect against Type 1 Diabetes (T1D), multiple sclerosis and certain cancers. Vitamin D is obtained from two sources; diet and through skin synthesis through the action of ultraviolet (UV) light. Dietary intakes of vitamin D are low in New Zealand (NZ) and the majority of our vitamin D comes from UV exposure. The NZ population may be at risk of low vitamin D status because of low dietary intakes, the country�s latitude (35-46 �S), and high proportion of darker skinned Maori and Pacific People. While case reports have described the occurrence of rickets, predominantly in immigrant groups, there are currently no national data on the vitamin D status of the NZ population. Reports of low vitamin D status in countries of similar latitude to NZ justify an examination of New Zealanders� vitamin D status. The best method to assess of vitamin D status is to measure circulating 25-hydroxyvitamin D concentrations. This thesis comprises three main studies. The first two had the following aims: to measure 25-hydroxyvitamin D concentrations and their determinants in a national sample (n=1585) of NZ children aged 5-14 y and to measure serum 25-hydroxyvitamin D concentrations and their determinants in a national sample (n=2948) of New Zealanders aged 15 y and over. The 2002 Children�s Nutrition Survey CNS02 was a year long (December, March-November) cross-sectional survey of a nationally representative sample of NZ school children 5-14 y. Over-sampling of Maori and Pacific children allowed ethnic specific analyses. The 1997 National Nutrition Survey (NNS97) participants were recruited over one year according to an area-based sampling frame with a 3 stage stratified design consisting of primary sampling units, households within each unit, and one randomly selected respondent from each household. Mean (99% CI) serum 25-hydroxyvitamin D concentrations were similar in children and adults (both 50 nmol/L). Among Maori, Pacific and NZEO children respectively, prevalence (%, 99% CI) of serum 25-hydroxyvitamin D deficiency (< 17.5 nmol/L) was 5% (2, 12), 8% (5, 14), and 3% (1,7). Based on a cutoff of < 37.5 nmol/L, prevalence of insufficiency was 41% (29, 53), 59% (42, 75) and 25% (15, 35), respectively. Based on a cutoff of 50 nmol/L, 56% of children were insufficient. Three percent of adult New Zealanders had serum 25-hydroxyvitamin D concentrations indicative of deficiency ([less than or equal to] 17.5 nmol/L); 48% and 84% were insufficient based on cutoffs of [less than or equal to] 50 and [less than or equal to] 80 nmol/L The main determinants of vitamin D status in NZ children were season, ethnicity and sex. After adjustment for other factors and covariates, boys had an adjusted mean (99% CI) 25-hydroxyvitamin D concentration 5 (1, 9) nmol/L higher than girls, Maori children were 7 (2, 11) and Pacific children 15 (11, 20) nmol/L lower than NZ European and Other (NZEO) children. Obese children were 7 (2, 11) nmol/L lower than overweight or �normal� weight. Children�s mean 25-hydroxyvitamin D concentrations (adjusted for other variables) peaked in March (69 nmol/L) and was at its lowest in August (36 nmol/L). In adults, there were effects of a similar magnitude of ethnicity and season on serum 25-hydroxyvitamin D concentrations. Obesity, latitude and age were determinants of vitamin D status in women but not men. Obese (BMI > 30) women had an adjusted mean vitamin concentration 6 (3, 10) nmol/L lower than women with BMI < 25. Women living in the South Island were 6 (3, 9) nmol/L lower than women living in the North Island. Additionally, adjusted mean serum 25-hydroxyvitamin D was 13 (8, 18) higher in women 15 -18 y than women 65 y or older. The third and final study aimed to determine whether the higher rates of vitamin D inadequacy reported in the winter than summer months in NZ also result in higher PTH concentrations, which would provide evidence for functional effect of inadequate vitamin D status. We also aimed to objectively explore the effect of natural skin colour on vitamin D status, given the higher prevalence of vitamin D insufficiency in dark-skinned groups living far from the equator. Skin colour measurements were taken with a hand-held light reflectometer (Datacolor Mercury[TM] 1000 colorimeter, Lawrenceville, NJ). In the 342 residents of Invercargill and Dunedin, mean serum 25-hydroxyvitamin D concentrations were lower in the late summer versus early spring (79 vs 51 nmol/L; P< 0.001). The lower serum 25-hydroxyvitamin D in early spring versus summer was associatedwith a 2 pg/mL (P< 0.001) higher parathyroid hormone (PTH) concentration. Interestingly, no significant effect of natural skin colour, based on light reflectance at the inside of the upper arm, was discovered, though there was a positive effect of tanning, based on light reflectance at the upper forearm, on serum 25-hydroxyvitamin D concentrations. Ethnicity and season are major determinants of serum 25-hydroxyvitamin D in New Zealanders. There is a high prevalence of vitamin D insufficiency in NZ children and adults, which may contribute to increased risk of osteoporosis and other chronic disease. While there is a pressing need for more convincing evidence with regards to the health risks associated with the low vitamin D status in children, evidence from the study of adults, where higher PTH concentrations were found during spring versus summer, suggests that the low 25-hydroxyvitamin D concentrations are having an adverse effect on bone health of adults. The high prevalence of vitamin D insufficiency in New Zealanders, warrants serious consideration of strategies such as fortification, to improve the vitamin D status of the population.

The metabolism of vitamin D commences with exposure of the skin to sunlight. The growing recognition of its role in insulin resistance, autoimmune disorders, infections, cancer, as well as the health of cells that influence physical and mental function have profound implications on how we define vitamin D requirements and why we should care whether they are met or not. Most of the actions of vitamin D are mediated by the vitamin D receptor (VDR), a protein whose gene sequence can vary, giving rise to polymorphic forms which are potent enough to affect the binding capacity of this protein to vitamin D. Some of these polymorphic forms of VDR gene may be associated with reduced effectiveness of vitamin D and hence predispose individuals to diseases such as type 2 diabetes and insulin resistance. An earlier study, the Surya Study, looked at the responsiveness of the South-Asian women living in Auckland to vitamin D. The research described here is an extension of this study and its focus was to identify the associations/linkages between certain polymorphic forms of the VDR gene and the disease conditions and intervention responsiveness in the same women. The first objective was to compare two well known techniques for genotyping single nucleotide polymorphisms (SNPs) of the VDR gene at the 3’ end, namely BsmI, ApaI and TaqI: the newer real-time polymerase chain reaction (qPCR) and the traditional restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) techniques. This comparison was performed to evaluate alternative methods for genotyping which consumed less time than RFLP-PCR. When the presence of each polymorphism by both the techniques was compared in this cohort of South-Asian women, it was found that RFLP-PCR proved to be a more reliable technique than qPCR for genotyping the VDR gene. Another objective of this project was to investigate the prevalence of the above three polymorphisms along with Cdx-2 and FokI SNPs which are present at the 5’ end of the VDR gene, in the population under study and their possible association with phenotypes such as vitamin D responsiveness and insulin resistance. These women were screened and biochemical data was collected during the earlier Surya Study. Of these, eighty-one women were then selected for intervention based on them having high insulin resistance (HOMA-IR>1.93) and serum 25(OH)D<50 nmol/L. Out of these eighty-one women, forty-two were given vitamin D supplement and thirty-nine were given a placebo for six months. Baseline and endpoint measurements included insulin resistance (HOMA-IR), insulin sensitivity (HOMA2%S) etc. How each individual responded to treatment in the intervention group was analysed in the context of the polymorphisms that they had. An association of insulin resistance with BsmI, ApaI and TaqI SNPs was observed in this cohort of 239 women. The response to insulin resistance in the vitamin D supplemented group significantly differed for FokI genotype compared to other genotypes. This explained why certain women responded to treatment better than the others. When the frequencies of the genotypes of these five SNPs of the VDR gene were compared to other studies of different ethnicities, the results of this study were consistent with few studies but contradictory to others. The possible reasons for these differences could be because of small sample size and different ethnicities under study due to which the frequency of alleles and hence the genotypes differed.

The metabolism of vitamin D commences with exposure of the skin to sunlight. The growing recognition of its role in insulin resistance, autoimmune disorders, infections, cancer, as well as the health of cells that influence physical and mental function have profound implications on how we define vitamin D requirements and why we should care whether they are met or not. Most of the actions of vitamin D are mediated by the vitamin D receptor (VDR), a protein whose gene sequence can vary, giving rise to polymorphic forms which are potent enough to affect the binding capacity of this protein to vitamin D. Some of these polymorphic forms of VDR gene may be associated with reduced effectiveness of vitamin D and hence predispose individuals to diseases such as type 2 diabetes and insulin resistance. An earlier study, the Surya Study, looked at the responsiveness of the South-Asian women living in Auckland to vitamin D. The research described here is an extension of this study and its focus was to identify the associations/linkages between certain polymorphic forms of the VDR gene and the disease conditions and intervention responsiveness in the same women. The first objective was to compare two well known techniques for genotyping single nucleotide polymorphisms (SNPs) of the VDR gene at the 3’ end, namely BsmI, ApaI and TaqI: the newer real-time polymerase chain reaction (qPCR) and the traditional restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) techniques. This comparison was performed to evaluate alternative methods for genotyping which consumed less time than RFLP-PCR. When the presence of each polymorphism by both the techniques was compared in this cohort of South-Asian women, it was found that RFLP-PCR proved to be a more reliable technique than qPCR for genotyping the VDR gene. Another objective of this project was to investigate the prevalence of the above three polymorphisms along with Cdx-2 and FokI SNPs which are present at the 5’ end of the VDR gene, in the population under study and their possible association with phenotypes such as vitamin D responsiveness and insulin resistance. These women were screened and biochemical data was collected during the earlier Surya Study. Of these, eighty-one women were then selected for intervention based on them having high insulin resistance (HOMA-IR>1.93) and serum 25(OH)D<50 nmol/L. Out of these eighty-one women, forty-two were given vitamin D supplement and thirty-nine were given a placebo for six months. Baseline and endpoint measurements included insulin resistance (HOMA-IR), insulin sensitivity (HOMA2%S) etc. How each individual responded to treatment in the intervention group was analysed in the context of the polymorphisms that they had. An association of insulin resistance with BsmI, ApaI and TaqI SNPs was observed in this cohort of 239 women. The response to insulin resistance in the vitamin D supplemented group significantly differed for FokI genotype compared to other genotypes. This explained why certain women responded to treatment better than the others. When the frequencies of the genotypes of these five SNPs of the VDR gene were compared to other studies of different ethnicities, the results of this study were consistent with few studies but contradictory to others. The possible reasons for these differences could be because of small sample size and different ethnicities under study due to which the frequency of alleles and hence the genotypes differed.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 2005. / Bibliyografya var.

Zugl.: München, Univ., Diss., 2008

Diss. (sammanfattning) Göteborg : Univ. , 2009. / Härtill 4 uppsatser.