Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 204-217).

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 225-238).

Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2003? / Includes bibliographical references (leaves 226-273.). Also available in an electronic version.

Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2002. / Includes bibliographical references. Also available in a print form.

Introdução: Uma elevada prevalência de deficiência de vitamina D (DVD) em crianças tem sido observada em todo o mundo, mas poucos são os estudos com relação ao estado nutricional da vitamina D (VD) em lactentes saudáveis. A principal causa da deficiência em crianças saudáveis é o aleitamento materno sem suplementação e a falta ou insuficiência de exposição solar. Objetivos: Determinar as concentrações séricas de VD e verificar sua associação com concentrações de paratormônio (PTH), fosfatase alcalina (FA), cálcio (Ca), fósforo (P) e albumina e uso da suplementação de VD em lactentes saudáveis com idades entre >= 6 e <= 24 meses atendidos em duas Unidades Básicas de Saúde do município de Ribeirão Preto, SP, Brasil. Métodos: Estudo transversal, observacional e analítico em que foram determinadas as concentrações séricas de 25 (OH)D, PTH, FA, Ca, P e albumina de 155 lactentes saudáveis. Informações sobre exposição solar, aspectos sociodemográficos das mães e características clínico-nutricionais dos lactentes foram obtidas por entrevistas com os responsáveis dos lactentes. Concentrações séricas de 25(OH)D maiores que 20ng/ml foram consideradas adequadas, entre 12 a 20ng/ml insuficientes e < 12ng/ml deficientes. Resultados: Dez lactentes (6,5%, Intervalo de Confiança 95% 3,5-11,4) apresentaram insuficiência de VD e nenhum apresentou DVD. Nenhuma alteração nas concentrações séricas de P, Ca e albumina foram detectadas. Apenas um lactente apresentou aumento nas concentrações séricas de PTH e 35,5% dos lactentes apresentaram FA elevada, porém nenhum apresentou DVD ou insuficiência de VD. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e as de FA, Ca e albumina. Houve associação entre concentrações séricas de 25(OH)D e PTH mesmo após ajuste para sexo, idade e Índice de Massa Corporal; também foi observada associação entre concentrações séricas de 25(OH)D e P apenas após o ajuste pelas covariáveis. Não foram verificadas associações entre insuficiência de VD, exposição solar e suplementação de VD. Conclusões: Uma baixa prevalência de concentrações insuficientes de 25(OH)D foi observada. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e PTH, FA, Ca, P e albumina. Da mesma forma, não foram encontradas associações entre de concentrações séricas de 25(OH)D, exposição solar e suplementação de VD. / Introduction: A high prevalence of vitamin D deficiency (VDD) in children has been observed worldwide, but there are few studies on the nutritional status of vitamin D (VD) in healthy infants. The main cause of deficiency in healthy children is breastfeeding without supplementation and lack or insufficiency of sun exposure. Objective: To determine serum concentrations of VD and verify its association with parathyroid hormone (PTH) levels and use of VD supplementation in healthy infants aged >= 6 to <= 24 months attended at two Basic Health Units in Ribeirão Preto city, São Paulo, Brazil. Methods: A cross-sectional, observational and analytical study was performed in which were determined serum concentrations of 25 (OH) D, PTH, alkaline phosphatase (AP), calcium (Ca), phosphorus (P) and albumin of 155 healthy infants. Information of sun exposure, sociodemographic aspects of mothers and clinical and nutritional characteristics of infants were obtained through interviews with responsible for infants. Serum concentrations of 25(OH)D greater than 20ng / ml were considered adequate, between 12 to 20ng / ml insufficient and <12ng/ml, deficient. Results: Ten infants (6.5%, 95% Confidence Interval 3.5-11.4) presented VD insufficiency and none presented DVD. Only one infant had an increase in PTH serum concentrations and 35.5% of infants had high AP but none presented DVD or VD insufficiency. No changes in serum P, Ca and albumin concentrations were detected. No associations were found between serum concentrations of 25 (OH) D and AP, Ca and albumin. There was an association between serum concentrations of 25(OH)D and PTH even after adjusting for sex, age and body mass index; an association between serum concentrations of 25(OH)D and P was observed only after adjustment for covariates. There were no associations between VD insufficiency, sun exposure and VD supplementation. Conclusions: A low prevalence of insufficient concentrations of 25 (OH)D was observed. No associations were found between serum concentrations of 25 (OH)D and PTH, FA, Ca, P and albumin. Likewise, no associations were found between serum concentrations of 25 (OH)D, sun exposure and VD supplementation.

Introduction Vitamin D status is an important public health issue due to the high prevalence of vitamin D insufficiency and deficiency, especially in high latitude areas. Furthermore, it has been reported to be associated with a number of diseases. In a previous umbrella review of meta-analyses of randomized clinical trials (RCTs) and of observational studies, it was found that plasma/ serum 25-hydroxyvitamin D (25(OH)D) or supplemental vitamin D has been linked to more than 130 unique health outcomes. However, the majority of the studies yielded conflicting results and no association was convincing. Aim and Objectives The aim of my PhD was to comprehensively explore the association between vitamin D and multiple outcomes. The specific objectives were to: 1) update the umbrella review of meta-analysis of observational studies or randomized controlled trials on associations between vitamin D and health outcomes published between 2014 and 2018; 2) conduct a systematic literature review of previous Mendelian Randomization studies on causal associations between vitamin D and all outcomes; 3) conduct a systematic literature review of published phenome wide association studies, summarizing the methods, results and predictors; 4) create a polygenic risk score of vitamin D related genetic variants, weighted by their effect estimates from the most recent genome wide association study; 5) encode phenotype groups based on electronic medical records of participants; 6) study the associations between vitamin D related SNPs and the whole spectrum of health outcomes, defined by electronic medical records utilising the UK Biobank study; 7) explore the causal effect of 25- hydroxyvitamin D level on health outcomes by applying novel instrumental variable methods. Methods First I updated the vitamin D umbrella review published in 2015, by summarizing the evidence from meta-analyses of observational studies and meta-analyses of RCTs published between 2014 and 2018. I also performed a systematic literature review of all previous Mendelian Randomizations studies on the effect of vitamin D on all health outcomes, as well as a systematic review of all published PheWAS studies and the methodology they applied. Then I conducted original data analysis in a large prospective population-based cohort, the UK Biobank, which includes more than 500,000 participants. A 25(OH)D genetic risk score (weighted sum score of 6 serum 25(OH)D-related SNPs: rs3755967, rs12785878, rs10741657, rs17216707, rs10745742 and rs8018720, as identified by the largest genome wide association study of 25(OH)D levels) was constructed to be used as the instrumental variable. I used a phenotyping algorithm to code the electronic medical records (EMR) of UK Biobank participants into 1853 distinct disease categories and I then ran the PheWAS analysis to test the associations between the 25(OH)D genetic risk score and 950 disease outcome groups (i.e. outcomes with more than 200 cases). For phenotypes found to show a statistically significant association with 25(OH)D levels in the PheWAS or phenotypes which were found to be convincing or highly suggestive in previous studies, I developed an extended case definition by incorporating self-reported data collected by UK Biobank baseline questionnaire and interview. The possible causal effect of vitamin D on those outcomes was then explored by the MR two-stage method, inverse variance weighted MR and Egger's regression, followed by sensitivity analyses. Results In the updated systematic literature review of meta-analyses of observational studies or RCTs, only studies on new outcomes which had not been covered by the previous umbrella review were included. A total of 95 meta-analyses met the inclusion criteria. Among the included studies there were 66 meta-analyses of observational studies, and 29 meta-analyses of RCTs. Eighty-five new outcomes were explored by meta-analyses of observational studies, and 59 new outcomes were covered by meta-analyses of RCTs. In the systematic review of published Mendelian Randomization studies on vitamin D, a total of 29 studies were included. A causal role of 25(OH)D level was supported by MR analysis for the following outcomes: type 2 diabetes, total adiponectin, diastolic blood pressure, risk of hypertension, multiple sclerosis, Alzheimer's disease, all-cause mortality, cancer mortality, mortality excluding cancer and cardiovascular events, ovarian cancer, HDL-cholesterol, triglycerides and cognitive functions. For the systematic literature review of published PheWAS studies and their methodology, a total of 45 studies were included. The processes for implementing a PheWAS study include the following steps: sample selection, predictor selection, phenotyping, statistical analysis and result interpretation. One of the main challenges is the definitions of the phenotypes (i.e., the method of binning participants into different phenotype groups). In the phenotyping step, an ICD curated phenotyping was widely used by previous PheWAS, which I also used in my own analysis. By applying the ICD curated phenotyping, 1853 phenotype groups were defined in the participants I used. In PheWAS, only phenotype groups with more than 200 cases were analysed (920 phenotypes). In the PheWAS, only associations between rs17216707 (CYP24A1) and "calculus of ureter" (beta = -0.219, se = 0.045, P = 1.14*10-6), "urinary calculus" (beta = -0.129, se = 0.027, P = 1.31*10-6), "alveolar and parietoalveolar pneumonopathy" (beta = 0.418, se = 0.101, P = 3.53*10-5) survived Bonferroni correction. Nine outcomes, including systolic blood pressure, diastolic blood pressure, body mass index, risk of hypertension, type 2 diabetes, ischemic heart disease, depression, non-vertebral fracture and all-cause mortality were explored in MR analyses. The MR analysis had more than 80% power for detecting a true odds ratio of 1.2 or larger for binary outcomes. None of explored outcomes were statistically significant. Results from multiple MR methods and sensitivity analyses were consistent. Discussion Vitamin D and its association with multiple outcomes has been widely studied. More than 230 outcomes have been linked with vitamin D by meta-analyses of observational studies and RCTs. On the contrary, evidence from Mendelian Randomization studies is lacking. In particular I identified only 20 existing MR studies and only 13 outcomes were suggested to be causally related to vitamin D. In the systematic literature review of previous PheWAS studies, I summarized the applied methods, predictors and results. Although phenotyping based on ICD codes provided good performance and was widely applied by previous PheWAS studies, phenotyping can be improved if lab data, imaging data and medical notes can be incorporated. Alternative algorithms, which takes advantage of deep learning and thus enable high precision phenotyping, needs to be developed. From the PheWAS analysis, the score of vitamin D related genetic variants was not statistically significantly associated with any of the 920 phenotypes tested. In the single variant analysis, only rs17216707 (CYP24A1) was shown to be associated with calculus outcomes statistically significantly. Previous studies reported associations between vitamin D and hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, may be due to the role of vitamin D in calcium homeostasis. In the MR analysis, I found no evidence of large to moderate (OR > 1.2) causal associations of vitamin D on a very wide range of health outcomes. These included SBP, DBP, hypertension, T2D, IHD, BMI, depression, non-vertebral fracture and allcause mortality which have previously been proposed to be influenced by low vitamin D levels. Further, even larger studies, probably involving the joint analysis of data from several large biobanks with future IVs that explain a higher proportion of the trait variance, will be required to exclude smaller causal effects which could have public health importance because of the high population prevalence of low vitamin D levels in some populations.

Introdução: Uma elevada prevalência de deficiência de vitamina D (DVD) em crianças tem sido observada em todo o mundo, mas poucos são os estudos com relação ao estado nutricional da vitamina D (VD) em lactentes saudáveis. A principal causa da deficiência em crianças saudáveis é o aleitamento materno sem suplementação e a falta ou insuficiência de exposição solar. Objetivos: Determinar as concentrações séricas de VD e verificar sua associação com concentrações de paratormônio (PTH), fosfatase alcalina (FA), cálcio (Ca), fósforo (P) e albumina e uso da suplementação de VD em lactentes saudáveis com idades entre >= 6 e <= 24 meses atendidos em duas Unidades Básicas de Saúde do município de Ribeirão Preto, SP, Brasil. Métodos: Estudo transversal, observacional e analítico em que foram determinadas as concentrações séricas de 25 (OH)D, PTH, FA, Ca, P e albumina de 155 lactentes saudáveis. Informações sobre exposição solar, aspectos sociodemográficos das mães e características clínico-nutricionais dos lactentes foram obtidas por entrevistas com os responsáveis dos lactentes. Concentrações séricas de 25(OH)D maiores que 20ng/ml foram consideradas adequadas, entre 12 a 20ng/ml insuficientes e < 12ng/ml deficientes. Resultados: Dez lactentes (6,5%, Intervalo de Confiança 95% 3,5-11,4) apresentaram insuficiência de VD e nenhum apresentou DVD. Nenhuma alteração nas concentrações séricas de P, Ca e albumina foram detectadas. Apenas um lactente apresentou aumento nas concentrações séricas de PTH e 35,5% dos lactentes apresentaram FA elevada, porém nenhum apresentou DVD ou insuficiência de VD. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e as de FA, Ca e albumina. Houve associação entre concentrações séricas de 25(OH)D e PTH mesmo após ajuste para sexo, idade e Índice de Massa Corporal; também foi observada associação entre concentrações séricas de 25(OH)D e P apenas após o ajuste pelas covariáveis. Não foram verificadas associações entre insuficiência de VD, exposição solar e suplementação de VD. Conclusões: Uma baixa prevalência de concentrações insuficientes de 25(OH)D foi observada. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e PTH, FA, Ca, P e albumina. Da mesma forma, não foram encontradas associações entre de concentrações séricas de 25(OH)D, exposição solar e suplementação de VD. / Introduction: A high prevalence of vitamin D deficiency (VDD) in children has been observed worldwide, but there are few studies on the nutritional status of vitamin D (VD) in healthy infants. The main cause of deficiency in healthy children is breastfeeding without supplementation and lack or insufficiency of sun exposure. Objective: To determine serum concentrations of VD and verify its association with parathyroid hormone (PTH) levels and use of VD supplementation in healthy infants aged >= 6 to <= 24 months attended at two Basic Health Units in Ribeirão Preto city, São Paulo, Brazil. Methods: A cross-sectional, observational and analytical study was performed in which were determined serum concentrations of 25 (OH) D, PTH, alkaline phosphatase (AP), calcium (Ca), phosphorus (P) and albumin of 155 healthy infants. Information of sun exposure, sociodemographic aspects of mothers and clinical and nutritional characteristics of infants were obtained through interviews with responsible for infants. Serum concentrations of 25(OH)D greater than 20ng / ml were considered adequate, between 12 to 20ng / ml insufficient and <12ng/ml, deficient. Results: Ten infants (6.5%, 95% Confidence Interval 3.5-11.4) presented VD insufficiency and none presented DVD. Only one infant had an increase in PTH serum concentrations and 35.5% of infants had high AP but none presented DVD or VD insufficiency. No changes in serum P, Ca and albumin concentrations were detected. No associations were found between serum concentrations of 25 (OH) D and AP, Ca and albumin. There was an association between serum concentrations of 25(OH)D and PTH even after adjusting for sex, age and body mass index; an association between serum concentrations of 25(OH)D and P was observed only after adjustment for covariates. There were no associations between VD insufficiency, sun exposure and VD supplementation. Conclusions: A low prevalence of insufficient concentrations of 25 (OH)D was observed. No associations were found between serum concentrations of 25 (OH)D and PTH, FA, Ca, P and albumin. Likewise, no associations were found between serum concentrations of 25 (OH)D, sun exposure and VD supplementation.

Thesis (M.S.)--University of Missouri-Columbia, 2009. / Thesis advisor: Dr. Catherine Peterson. The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. "May 2009" Includes bibliographical references.

<p>Zastupljenost deficita vitamina D3 je mnogo veći kod bolesnika sa dijabetesnom bolesti tipa 2 nego u populaciji zdravih osoba. Bolesnici sa DM tipa 2 i deficitom vitamina D3 imaju veći rizik za razvoj dijabetesne nefropatije. Eksperimenti na životinjama i neka klinička istraživanja ukazuju da bi primena nižih doza vitamina D3 mogla imati renoproktektivno delovanje. Cilj istraživanja je bio da se utvrdi zastupljenost deficita vitamina D3 u populaciji bolesnika sa dijabetesnom nefropatijom koja je definisana proteinurijom ˃0,150 g/du. Drugi cilj je bio da se utvrdi da li primena holekaciferola u dozi koja predstavlja razliku između utvrđenog i optimalnog nivoa vitamina D3 dovodi do statistički značajnog smanjenja proteinurije. Bolesnici sa dijabetesom tipa 2 i proteinurijom ˃0,150 g/du su uključivani u skrining na nivo vitamina D3 (25(OH)D) nakon čega su svrstavani u grupe sa deficitom i normalnim nivoom vitamina D3. Granična vrednost za utvrđivanje deficita vitamina D3 je odreĎivana na osnovu tabele koja defini&scaron;e ove vrednosti za svaki mesec tokom godine, posebno za mu&scaron;karce i žene. Bolesnici sa deficitom vitamina D3 su podeljeni u 2 grupe od po 45 ispitanika. Studijska grupa je primala holekaciferol u dozi koja je izračunata na osnovu razlike između izmerene vrednosti i određenog optimalnog nivoa vitamina D3 od 90-100 nmol/L. Kontrolna grupa bolesnika je uzimala svoju uobičajenu terapiju. Istraživanje je trajalo 24 nedelje tokom koje su na drugi mesec praćeni parametri bubrežne funkcije, parametri inflamacije i ko&scaron;tanog metabolizma. Na početku i kraju istraživanja su odreĎeni nivo vitamina D3 u studijskoj grupi, dok su u obe grupe određivani vrednost HbA1c i lipidni profil. Analizom dobijenih podataka je utvrđeno da je zastupljenost deficita vitamina D3 kod bolesnika sa dijabetesnom nefropatijom, uzimajući u obzir sezonske varijacije u nivou ovog vitamina, bila veća od vrednosti od 30-50% koje su postavljene u radnoj hipotezi. Učestalost bolesnika sa nedostakom vitamina D3 je u ispitivanom uzorku je bila 82,56% , dok je normalne vrednosti vitamina D3 imalo 17,43% ispitanika, od toga je bilo 10 (52,63%) mu&scaron;karaca i 9 (47,36%) žena. Sniženje vrednosti vitamina D3 u odnosu na donje granične vrednosti je bilo izraženije u letnjem periodu i bilo je statistički značajno kod svih ispitanika zajedno, potom u studijskoj grupi, dok je utvrđeno i u kontrolnoj grupi ali je u njoj bilo bez statisičke značajnosti. Utvrđen je porast HbA1c koji je bio veći u kontrolnoj grupi ispitanika. Suplementacija vitaminom D3 je imala povoljan efekat na lipidni profil. Registrovan je porast vrednosti ukupnog holesterola koji je bio izraženiji u kontrolnoj grupi, pad vrednosti triglicerida u grupi bolesnika koji su uzimali vitamin D3 i njihov porast u kontrolnoj grupi ispitanika. U studijskoj grupi je registrovan porast vrednosti HDL-holesterola koji je bio na granici statističke značajnosti dok je istovremeno nađeno njegovo smanjenje u kontrolnoj grupi. Vrednost LDL-holesterola je ostala bez promene pod delovanjem vitamina D3, dok je u kontrolnoj grupi do&scaron;lo do njegovog porasta. Utvrđeno je snižavanje vrednosti sedimentije, CRP-a i fibrinogena koje je bilo bez statističke značajnosti. Bezbednosni profil vrednosti kalcijuma u serumu i urinu tokom dugotrajnije primene je dobar. Primenom vitamina D3 je do&scaron;lo do signifikatnog smanjenja proteinurije u grupi bolesnika koji su primali holekaciferol čime je ujedno i potvrđena radna hipoteza.</p> / <p>The prevalence of vitamin D3 deficiency is much higher in patients with type 2 diabetes than in the healthy population. Patients with type 2 DM and vitamin D3 deficiency are at increased risk for developing diabetic nephropathy. Animal experiments and some clinical studies suggest that administration of lower doses of vitamin D3 could have renoprotective effect. The aim of the study was to determine the prevalence of vitamin D3 deficiency in the population of patients with diabetic nephropathy defined by proteinuria ˃0.150 g / du. The second goal was to determine whether the use of cholecaciferol in a dose that represents the difference between the established and optimal levels of vitamin D3 leads to a statistically significant reduction in proteinuria. Patients with type 2 diabetes and proteinuria ˃0.150 g / du were screened for vitamin D3 (25 (OH) D) levels and then classified as deficient and normal vitamin D3. The limit value for determining vitamin D3 deficiency was set on the basis of a table defining these values for each month during the year, separately for men and women. Patients with vitamin D3 deficiency were divided into 2 groups of 45 subjects each. The study group received cholecaciferol at a dose calculated on the basis of the difference between the measured value and the set optimal vitamin D 3 level of 90-100 nmol/L. The control group of patients was taking their usual therapy. The study lasted 24 weeks during which the parameters of renal function, parameters of inflammation and bone metabolism were monitored every second month. At the beginning and end of the study, the levels of vitamin D3 in the study group were determined, while in both groups HbA1c and lipid profile were determined. The analysis of the obtained data showed that the prevalence of vitamin D3 deficiency in patients with diabetic nephropathy, taking into account seasonal variations in the level of this vitamin, was higher than the values of 30-50%, which were set in the working hypothesis. The frequency of patients with vitamin D3 deficiency in the study sample was 82.56%, while the normal values of vitamin D3 were in 17.43% of the subjects, of which 10 (52.63%) were men and 9 (47.36%) woman. The decrease in vitamin D3 compared to the lower limit values was more pronounced in the summer and was statistically significant in all subjects together, as well in the study group, while it was also found in the control group but was not statistically significant. An increase in HbA1c was found to be higher in the control group. Vitamin D3 supplementation had a beneficial effect on the lipid profile. An increase in the total cholesterol level that was more pronounced in the control group, a decrease in triglyceride values in the group of patients taking vitamin D3 and its increase in the control group of subjects were registered. An increase in HDL-cholesterol was reported in the study group, which was at the limit of statistical significance, while at the same time a decrease was found in the control group. LDL-cholesterol levels remained unchanged under the influence of vitamin D3, while in the control group it increased. The decrease in sedimentation, CRP and fibrinogen values was found to be of no statistical significance. The safety profile of serum and urine calcium during long-term administration is good. The use of vitamin D3 resulted in a significant decrease in proteinuria in the group of patients receiving cholecaciferol, which also confirmed the working hypothesis.</p>