Resumo: A deficiência de vitamina A é problema de saúde pública mundial e as principais populações acometidas são crianças e gestantes. Existem 250 milhões de pessoas no mundo com esta deficiência e sua principal causa é a redução da ingestão deste composto. O conceito de deficiência de vitamina A consta da depleção de estoques hepáticos associada à redução do retinol sérico. A deficiência de vitamina A é sabidamente prejudicial à fase embriogênica cardíaca. Após o nascimento, na idade adulta,~ vitamina A exerce papel na manutenção da estrutura e função do coração e su~ suplementação parece ser benéfica como atenuante da remodelação cardíaca. Pouco se sabe, no entanto, sobre a influência da deficiência de vitamina A sobre o coração após o nascimento, já que esta carência não é comum na população adulta, devido ao grande estoque hepático. Existe, entretanto, o transporte de vitamina A, para os tecidos, pela via dos quilomicrons. Esta via é dependente da ingestão vitamínica e não de seus estoques. Sendo assim, é possível que a ingestão inadequada deste composto, cause redução tecidual desta vitamina previamente à depleção dos estoques hepáticos e ao aparecimento da deficiência de vitamina A. Considerando que mais da metade da população brasileira, incluindo adultos, apresenta ingestão de vitamina A inferior a 50% das recomendações, a redução tecidual deste composto passa a ser uma possibilidade ainda não estudada nos tecidos, como o coração. Portanto, formulamos a hipótese que a ingestão inadequada de vitamina A, na ausência de deficiência deste composto, ou seja, com manutenção da retinolemia sé rica e estoques hepáticos, leva à redução vitamínica no tecido cardíaco causando remodelação. Assim, foram estudadas 91 ratas Wistars... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Pregnancy and childhood Vitamin A deficiency is an important public health concern. There are 250 million people around the world with this deficiency. The inadequate ingestion of this nutrient is the most important cause of it. Low serum retinol concentration and liver stores severely depleted are the biochemical findings in vitamin A deficiency. Cardiac embryonic development requires vitamin A. Postnatal heart are also a retinoid target organ, including the remodeling processo In spite of it, there are few studies about vitamin A deficiency at postnatal heélrt. Esterified retinol transported in chylomicron to tissues is reduced in low vitamin A ingestion and can cause target organ deficiency in spite of preserved serum and hepatic vitamin A. The hypothesis of this study is that inadequate vitamin A ingestion, without systemic deficiency of this nutrient, produces low heart levels of vitamin A, resulting in cardiac remodeling. Wistars female rats were studied: 45 at control group and 46 at diet reduced in vitamin A (RvitA) group. Control rats were born from dams fed with AIN-93 diet sufficient in vitamin A, during pregnancy and lactation. RvitA rats were born from dams fed with AIN-93 vitamin A-free diet, during pregnancy and lactation. Liver vitamin A was measured in sixteen newborns of each group. Twenty nine control rats were fed onto the same diet during weaning and post weaning period. Thirty RvitA rats were fed onto vitamin A-free diet during weaning and vitamin A containing 0,18 retinol equivalent (RE)(g of diet post weantng. When the animais were 200-250g, they were subjected to a transthoracic echocardiographic exam and to isolated rat heart study. Blood, liver and heart samples were collected to vitamin A dosage, to oxidative stress evaluation, to energetic metabolism evaluation, and to hypertrophy and fibrosis measurements. / Orientador: Sergio Alberto Rupp de Paiva / Coorientador: Leonardo Antonio Mamede Zornoff / Banca: Alceu Afonso Jordão / Banca: Thomas Prates Ong / Banca: Marina Politi Okoshi / Banca: Beatriz Bojikian Matsubara / Doutor

Introdução: Portadores de fibrose cística têm uma susceptibilidade à deficiência de vitamina D devido à má absorção de nutrientes. Os estudos da prevalência de hipovitaminose D em pacientes com fibrose cística apresentam resultados extremamente variáveis e não há dados a respeito da população não pediátrica no Brasil. Objetivos: Avaliar a prevalência de hipovitaminose D em pacientes não pediátricos portadores de fibrose cística e os fatores associados com as concentrações séricas de 25-hidroxivitamina D. Metodologia: Realizado estudo transversal. A população em estudo foi composta por pacientes maiores que 16 anos acompanhados no Ambulatório de Fibrose Cística do Hospital de Clínicas de Porto Alegre. Foi avaliada a prevalência de deficiência de vitamina D, definida como 25-hidroxivitamina D < 30ng/mL, de acordo com a Cystic Fibrosis Foundation, bem como os fatores clínicos e laboratoriais associados com o valor sérico desta. Foram avaliados o estado nutricional e internações hospitalares. Foi realizada coleta de dados em prontuário, entrevista com os pacientes e colheita de sangue. As análises laboratoriais foram realizadas no Laboratório de Patologia Clínica do Hospital. Foram dosados os valores séricos de proteína C-reativa, cálcio, fosfato, magnésio, albumina, 25-hidroxivitamina D (método: quimiluminescência) e paratormônio (método: imunoensaio para PTH intacto). A função pulmonar foi avaliada por espirometria e escores clínicos e radiológicos. O nível de significância estatística foi estabelecido como P<0,05. Resultados: A prevalência de hipovitaminose D foi de 61,0%, com valores séricos de 25-hidroxivitamina D de 28,42±10,94 ng/mL. Os pacientes com insuficiência pancreática apresentaram uma tendência a ter concentrações mais altas de vitamina D. Dezesseis pacientes apresentavam doença pulmonar grave, com FEV1% do predito inferior a 40%. Após análise multivariada, índice de massa corporal e hospitalizações no último mês permaneceram significativamente associados negativamente aos valores séricos de 25-hidroxivitamina D. Conclusões: A prevalência de hipovitaminose D no presente estudo foi inferior a previamente relatada. A insuficiência de vitamina D continua sendo um problema nos pacientes com fibrose cística, mesmo naqueles recebendo suplementação. / Introduction: Cystic fibrosis patients have a susceptibility to vitamin D deficiency due to nutrient malabsorption. Prevalence studies of hypovitaminosis D in patients with cystic fibrosis have highly variable results and there is no data about the non pediatric population in Brazil. Objectives: To evaluate the prevalence of hypovitaminosis D in non pediactric cystic fibrosis patients and the factors associated with serum 25-hydroxyvitamin D levels. Methods: Cross-sectional study. The study population was composed of patients older than 16 years accompanied in the Cystic Fibrosis Ambulatory of the Hospital de Clínicas de Porto Alegre. We evaluated the prevalence of vitamin D deficiency defined as 25-hydroxyvitamin D < 30 ng/mL, as suggested recently by the Cystic Fibrosis Foundation, and clinical and laboratory factors associated with its serum levels. Nutritional status and hospital admissions were evaluated. Data was collected from medical records and interviews with patient, blood was collected. Laboratory analisys were performed at Clinical Pathology Laboratory of the Hospital. Serum C-reactive protein, calcium, phosphate, magnesium, albumin, 25-hydroxyvitamin D (method: chemiluminescence), and parathyroid hormone levels (method: sandwich immunoassay to intact PTH) were measured. Lung function was evaluated by spirometry and clinical and chest radiographic scores were assessed. Statistical significance level was set at P<0.05. Results: Prevalence of hypovitaminosis D was 61.0 %, with serum 25-hydroxyvitamin D levels of 28,42±10,94 ng/mL. Patients with pancreatic insufficiency had a trend to have higher vitamin D levels. Sixteen patients had severe lung disease with FEV1% predicted below 40%. After multivariable analysis, body mass index and hospitalization in the last month remained significantly associated negatively with serum 25-hydroxivitamin D levels. Conclusions: The prevalence of hypovitaminosis D in the present study was inferior to previously related. Vitamin D insufficiency is still a problem in cystic fibrosis patients, even in those receiving supplementation.

A Deficiência de Vitamina A (DVA) é considerado um problema de saúde pública em diversos países. No Brasil, esse problema atinge todas as regiões em diferentes magnitudes. A Organização Mundial da Saúde recomenda a realização de estudos sobre base populacional com os objetivos de se estimar a prevalência da DVA, de definir intervenções, de monitorar as tendências da população e o impacto dos programas de intervenção ao longo do tempo. São considerados grupos vulneráveis à DVA: as gestantes e crianças jovens residentes em países em desenvolvimento. A pesquisa aqui realizada tem como objetivo contribuir para o esclarecimento dos fatores associados à Deficiência de Vitamina A no Brasil. Para isso, foram analisados os dados da Pesquisa Nacional de Demografia e Saúde da Criança e da Mulher. A população investigada foram crianças de 6 a 59 meses de idades (n=4.322) com dados sobre nível de retinol sérico. A associação entre deficiência de Vitamina A e as variáveis socioeconômicas, demográficas e de saúde foram analisadas no software SPSS através de análises complexas e da regressão logística. Na análise global não ajustada, incluindo todas as regiões, as variáveis associadas (p<0,05) à DVA foram a maior idade materna, macrorregião de residência (Sudeste e Nordeste) e situação de domicílio (urbano). Após o ajuste, se mantiveram associadas significativamente as variáveis maior idade materna e macrorregião de domicílio (Sudeste e Nordeste). Na análise ajustada, estratificada por regiões, houve modificação dos fatores associados. A região Centro-oeste não apresentou associação entre a deficiência de vitamina A e as variáveis investigadas. Na região Sudeste os fatores associados ao desfecho foram a maior idade materna, residir na zona urbana e crianças com risco para sobrepeso/sobrepeso/obesidade. Na região Nordeste a menor razão de chances foi associada ao menor tempo de aleitamento materno e mães com cor de pele não branca. Na região Sul somente as mães de cor de pele não branca apresentaram associação com a deficiência de vitamina A e, por fim, na região Norte a maior idade materna estava a associada a DVA. Na associação entre IA e DVA, tanto na análise bruta como na análise ajustada não foram observadas associações significativas. No entanto, a prevalência de DVA foi maior nas categorias de Insegurança Alimentar Grave e Leve quando comparado com a segurança alimentar. Os dados analisados mostram que no Brasil a DVA varia de leve a grave problema de saúde pública e os fatores associados são diferentes entre as macrorregiões, portanto estratégias preconizadas pela Organização Mundial da Saúde devem ser levadas em consideração na elaboração de políticas públicas adequadas a cada região. / The Vitamin A Deficiency (VAD) is considered a public health issue in many countries. In Brazil, this problem affects all theregions in different magnitudes. The World Health Organization recommends conducting studies on population basis with the objective of estimating the prevalence of VAD, to define interventions, to monitor population trends and the impact of intervention programs over time. Considered vulnerable groups to DVAare pregnant women and young children living in developing countries. The research performed here aims to contribute to understand the factors associated with Vitamin A Deficiency in Brazil. To do so, data from the National Survey of Demography and Health of Children and Women were analyzed. The investigated population were children 6-59 months of age (n = 4,322) with data on level of serum retinol. The association between vitamin A deficiency and socioeconomic, demographic and health variables were analyzed using SPSS software through complex analysis and logistic regression. In the overall unadjusted analysis, including all regions, the variables associated (p <0.05) to the DVA were higher maternal age, macro-region (Southeast and Northeast) and household situation (urban). After adjustment, remained significantly associated variables higher maternal age and address macro-region (Southeast and Northeast). In the adjusted analysis stratified by region, there was modification on the associated factors. The Midwest region showed no association between vitamin A deficiency and the investigated variables. In the Southeast, factors associated with outcome were higher maternal age; reside in urban areas and children at risk for overweight / overweight / obesity. In the Northeast the lowest odds ratio was associated with shorter duration of breastfeeding and mothers with nonwhite skin color. In the South, only non-white skin color mothers were associated with vitamin A deficiency, and finally, the northern region most maternal age was associated with VAD. The association between IA and DVA, both in the crude analysis as in the adjusted analysis significant associations were observed. However, the prevalence of VAD was higher in the categories of Food Insecurity Record and Take compared to food security. The data analyzed show that in Brazil the DVA varies from mild to severe public health problem and associated factors differ among regions, so strategies recommended by the World Health Organization should be taken into account in the design of appropriate policies to each region.

A Deficiência de Vitamina A (DVA) é considerado um problema de saúde pública em diversos países. No Brasil, esse problema atinge todas as regiões em diferentes magnitudes. A Organização Mundial da Saúde recomenda a realização de estudos sobre base populacional com os objetivos de se estimar a prevalência da DVA, de definir intervenções, de monitorar as tendências da população e o impacto dos programas de intervenção ao longo do tempo. São considerados grupos vulneráveis à DVA: as gestantes e crianças jovens residentes em países em desenvolvimento. A pesquisa aqui realizada tem como objetivo contribuir para o esclarecimento dos fatores associados à Deficiência de Vitamina A no Brasil. Para isso, foram analisados os dados da Pesquisa Nacional de Demografia e Saúde da Criança e da Mulher. A população investigada foram crianças de 6 a 59 meses de idades (n=4.322) com dados sobre nível de retinol sérico. A associação entre deficiência de Vitamina A e as variáveis socioeconômicas, demográficas e de saúde foram analisadas no software SPSS através de análises complexas e da regressão logística. Na análise global não ajustada, incluindo todas as regiões, as variáveis associadas (p<0,05) à DVA foram a maior idade materna, macrorregião de residência (Sudeste e Nordeste) e situação de domicílio (urbano). Após o ajuste, se mantiveram associadas significativamente as variáveis maior idade materna e macrorregião de domicílio (Sudeste e Nordeste). Na análise ajustada, estratificada por regiões, houve modificação dos fatores associados. A região Centro-oeste não apresentou associação entre a deficiência de vitamina A e as variáveis investigadas. Na região Sudeste os fatores associados ao desfecho foram a maior idade materna, residir na zona urbana e crianças com risco para sobrepeso/sobrepeso/obesidade. Na região Nordeste a menor razão de chances foi associada ao menor tempo de aleitamento materno e mães com cor de pele não branca. Na região Sul somente as mães de cor de pele não branca apresentaram associação com a deficiência de vitamina A e, por fim, na região Norte a maior idade materna estava a associada a DVA. Na associação entre IA e DVA, tanto na análise bruta como na análise ajustada não foram observadas associações significativas. No entanto, a prevalência de DVA foi maior nas categorias de Insegurança Alimentar Grave e Leve quando comparado com a segurança alimentar. Os dados analisados mostram que no Brasil a DVA varia de leve a grave problema de saúde pública e os fatores associados são diferentes entre as macrorregiões, portanto estratégias preconizadas pela Organização Mundial da Saúde devem ser levadas em consideração na elaboração de políticas públicas adequadas a cada região. / The Vitamin A Deficiency (VAD) is considered a public health issue in many countries. In Brazil, this problem affects all theregions in different magnitudes. The World Health Organization recommends conducting studies on population basis with the objective of estimating the prevalence of VAD, to define interventions, to monitor population trends and the impact of intervention programs over time. Considered vulnerable groups to DVAare pregnant women and young children living in developing countries. The research performed here aims to contribute to understand the factors associated with Vitamin A Deficiency in Brazil. To do so, data from the National Survey of Demography and Health of Children and Women were analyzed. The investigated population were children 6-59 months of age (n = 4,322) with data on level of serum retinol. The association between vitamin A deficiency and socioeconomic, demographic and health variables were analyzed using SPSS software through complex analysis and logistic regression. In the overall unadjusted analysis, including all regions, the variables associated (p <0.05) to the DVA were higher maternal age, macro-region (Southeast and Northeast) and household situation (urban). After adjustment, remained significantly associated variables higher maternal age and address macro-region (Southeast and Northeast). In the adjusted analysis stratified by region, there was modification on the associated factors. The Midwest region showed no association between vitamin A deficiency and the investigated variables. In the Southeast, factors associated with outcome were higher maternal age; reside in urban areas and children at risk for overweight / overweight / obesity. In the Northeast the lowest odds ratio was associated with shorter duration of breastfeeding and mothers with nonwhite skin color. In the South, only non-white skin color mothers were associated with vitamin A deficiency, and finally, the northern region most maternal age was associated with VAD. The association between IA and DVA, both in the crude analysis as in the adjusted analysis significant associations were observed. However, the prevalence of VAD was higher in the categories of Food Insecurity Record and Take compared to food security. The data analyzed show that in Brazil the DVA varies from mild to severe public health problem and associated factors differ among regions, so strategies recommended by the World Health Organization should be taken into account in the design of appropriate policies to each region.

Introdução: Portadores de fibrose cística têm uma susceptibilidade à deficiência de vitamina D devido à má absorção de nutrientes. Os estudos da prevalência de hipovitaminose D em pacientes com fibrose cística apresentam resultados extremamente variáveis e não há dados a respeito da população não pediátrica no Brasil. Objetivos: Avaliar a prevalência de hipovitaminose D em pacientes não pediátricos portadores de fibrose cística e os fatores associados com as concentrações séricas de 25-hidroxivitamina D. Metodologia: Realizado estudo transversal. A população em estudo foi composta por pacientes maiores que 16 anos acompanhados no Ambulatório de Fibrose Cística do Hospital de Clínicas de Porto Alegre. Foi avaliada a prevalência de deficiência de vitamina D, definida como 25-hidroxivitamina D < 30ng/mL, de acordo com a Cystic Fibrosis Foundation, bem como os fatores clínicos e laboratoriais associados com o valor sérico desta. Foram avaliados o estado nutricional e internações hospitalares. Foi realizada coleta de dados em prontuário, entrevista com os pacientes e colheita de sangue. As análises laboratoriais foram realizadas no Laboratório de Patologia Clínica do Hospital. Foram dosados os valores séricos de proteína C-reativa, cálcio, fosfato, magnésio, albumina, 25-hidroxivitamina D (método: quimiluminescência) e paratormônio (método: imunoensaio para PTH intacto). A função pulmonar foi avaliada por espirometria e escores clínicos e radiológicos. O nível de significância estatística foi estabelecido como P<0,05. Resultados: A prevalência de hipovitaminose D foi de 61,0%, com valores séricos de 25-hidroxivitamina D de 28,42±10,94 ng/mL. Os pacientes com insuficiência pancreática apresentaram uma tendência a ter concentrações mais altas de vitamina D. Dezesseis pacientes apresentavam doença pulmonar grave, com FEV1% do predito inferior a 40%. Após análise multivariada, índice de massa corporal e hospitalizações no último mês permaneceram significativamente associados negativamente aos valores séricos de 25-hidroxivitamina D. Conclusões: A prevalência de hipovitaminose D no presente estudo foi inferior a previamente relatada. A insuficiência de vitamina D continua sendo um problema nos pacientes com fibrose cística, mesmo naqueles recebendo suplementação. / Introduction: Cystic fibrosis patients have a susceptibility to vitamin D deficiency due to nutrient malabsorption. Prevalence studies of hypovitaminosis D in patients with cystic fibrosis have highly variable results and there is no data about the non pediatric population in Brazil. Objectives: To evaluate the prevalence of hypovitaminosis D in non pediactric cystic fibrosis patients and the factors associated with serum 25-hydroxyvitamin D levels. Methods: Cross-sectional study. The study population was composed of patients older than 16 years accompanied in the Cystic Fibrosis Ambulatory of the Hospital de Clínicas de Porto Alegre. We evaluated the prevalence of vitamin D deficiency defined as 25-hydroxyvitamin D < 30 ng/mL, as suggested recently by the Cystic Fibrosis Foundation, and clinical and laboratory factors associated with its serum levels. Nutritional status and hospital admissions were evaluated. Data was collected from medical records and interviews with patient, blood was collected. Laboratory analisys were performed at Clinical Pathology Laboratory of the Hospital. Serum C-reactive protein, calcium, phosphate, magnesium, albumin, 25-hydroxyvitamin D (method: chemiluminescence), and parathyroid hormone levels (method: sandwich immunoassay to intact PTH) were measured. Lung function was evaluated by spirometry and clinical and chest radiographic scores were assessed. Statistical significance level was set at P<0.05. Results: Prevalence of hypovitaminosis D was 61.0 %, with serum 25-hydroxyvitamin D levels of 28,42±10,94 ng/mL. Patients with pancreatic insufficiency had a trend to have higher vitamin D levels. Sixteen patients had severe lung disease with FEV1% predicted below 40%. After multivariable analysis, body mass index and hospitalization in the last month remained significantly associated negatively with serum 25-hydroxivitamin D levels. Conclusions: The prevalence of hypovitaminosis D in the present study was inferior to previously related. Vitamin D insufficiency is still a problem in cystic fibrosis patients, even in those receiving supplementation.

Introdução - A concentração sérica de vitamina D pode variar em indivíduos de diferentes grupos etários e de diversas regiões geográficas e pode ser influenciada pela exposição solar, estação do ano, bem como pelos valores de IMC e paratormônio (PTH). A classificação utilizada para definir concentração sérica adequada de vitamina D refere valores de 25(OH)D acima de 30 ng/mL. Porém, essa classificação pode estar inapropriada para a população brasileira, devido às particularidades climáticas e alimentares. Objetivo - Verificar as concentrações séricas médias de 25(OH)D e PTH e sua relação com IMC, exposição solar e estação do ano e identificar os valores de corte da 25(OH)D associados à elevação do paratormônio (PTH) em adultos e idosos de amostra representativa da população do município de São Paulo. Métodos - Para esta dissertação foi desenvolvido um artigo original. O artigo original descreve o estudo transversal realizado com indivíduos do estudo ISA-Capital, estudo multicêntrico e de base populacional, onde foram investigados 589 indivíduos, de ambos os sexos, dos grupos etários: 20 a 59 (adultos) e 60 e mais (idosos). Foram coletadas amostras de sangue, para dosagens de 25(OH)D e PTH. Os indivíduos que aceitaram participar da coleta de sangue, também responderam um questionário sobre exposição solar. A análise estatística incluiu a curva ROC, testes t de Student, correlação e ANOVA. Os cálculos foram realizados pelo software SPSS versão 17.0. e p 0,05 foi considerado significante. Resultados - No artigo original observou-se idade média de 54,83 (19,21) anos, sendo 61,3 por cento do sexo feminino e 38,7 por cento do sexo masculino. A concentração sérica média de 25(OH)D foi 50,02 (22,69) ng/mL, já entre os grupos foi de 47,48 (23,03) (adultos) e 52,68 (22,06) ng/mL (idosos) havendo diferença significativa entre eles (p=0,005). Observou-se variação sazonal da concentração sérica de 25(OH)D e correlação positiva entre 25(OH)D e IMC (r = 0,114, p = 0,006). O novo valor de corte 55.8 ng/mL, determinado pela análise da curva ROC, encontrou 67,6 por cento dos indivíduos insuficientes de 25(OH)D e entre os grupos 72,1 por cento (adultos) e 62,8 por cento (idosos). Conclusão - Os resultados demonstram a presença de variação sazonal nas concentrações séricas de 25(OH)D no municipio de São Paulo. O ponto de corte proposto para nossa população indicou elevada prevalência de insuficiência de vitamina D. Portanto, se faz necessário políticas públicas de prevenção de insuficiência de vitamina D visando os efeitos benéficos na saúde e qualidade de vida desta população. / Introduction - The serum concentration of vitamin D may vary in individuals of different age groups and geographic regions and may be influenced by sun exposure, season and by BMI and parathyroid hormone (PTH). The classification widely used as a cut-off for appropriate vitamin D status refers serum 25 (OH) D above 30 ng/mL. However, this classification may be inappropriate for the Brazilian population, due to the particular food and the climate of our population. Objective - To determine the mean serum concentrations of 25(OH)D and PTH and correlate them with BMI, sunlight exposure and season and to identify the cutoff values of 25 (OH) D associated with elevation in PTH. Methods For this dissertation, one original article were developed. Original article describe cross-sectional study performed with subjects from the ISA Capital, multicenter population-based. We investigated 589 individuals were of both sexes, age groups: 20-59 (adults) and 60 (elderly). Blood samples for laboratory measurements of 25(OH)D and PTH were collected. Individuals, who agreed to participate in blood collection, also answered a questionnaire on sunlight exposure. Statistical analysis included ROC curve, Student t test, correlation tests, ANOVA. The calculations were performed by the software SPSS version 17.0. and p 0.05 was considered significant. Results - In the original article, the mean age of participants was 54.83 (19.21) years, 61.3 per cent female and 38.7 per cent were male. The mean serum 25 (OH) D was 50.02 (22.69) ng/mL, between the groups was 47.48 (23.03) (adults) and 52.68 (22.06) ng/ mL (elderly) and significant difference between them (p = 0.005). A seasonal variation in serum 25 (OH) D was observed and positive correlation between 25(OH)D and BMI (r = 0.114, p = 0.006). The new cutoff value 55.8 ng / mL, determined by ROC curve analysis found 67.6 per cent of subjects insufficient 25 (OH) D and between groups 72.1 per cent (adults) and 62.8 per cent (elderly). Conclusion - The results demonstrate the presence of seasonal variation in serum 25 (OH) D in the municipality of Sao Paulo. The cutoff point proposed for our population showed a high prevalence of insufficient vitamin D. Therefore, public policy is needed to prevent vitamin D insufficiency in order to beneficial effects on health and quality of life in this population.

Vitamin D is an important immunomodulator. Epidemiological studies have shown that vitamin D deficiency impairs the immune functions and participates in the pathogenesis of infectious and autoimmune diseases. Vitamin D supplementation has shown significant changes on circulating concentrations of inflammatory markers in different clinical conditions. However, the effect of single large-dose of vitamin D3 in immune system in elderly people remains unclear. We carried out a randomized, double-blind, placebo-controlled clinical trial to evaluate the possible benefic effect of single oral dose of 300.000 IU of vitamin D3 on inflammatory markers in elderly post-menopausal women. A total of 40 women aged over 60 years were selected to receive 300.000 IU of cholecalciferol (n = 20) or placebo (n = 20) at baseline. Serum 25-hydroxyvitamin D [25(OH)D] were similar in both group at baseline [16.4 ng/ml (± 3.8) in vitamin D group and 15 ng/ml (± 3.7) in placebo groups, p = 0.23]. Serum levels of IL-6, TNF-α and IL-10 were measured by ELISA at baseline, and 30, 60 and 90 days after intervention. In the vitamin D group, we found a significant median percent decline in levels of IL-6 (30.8%, p = 0.006) and TNF-α (48.6%, p < 0.0001), associated with a significant median percent increase in levels of IL-10 (68.4%, p < 0.0001) after 90 days. We concluded that a single oral dose of 300.000 IU of cholecalciferol, in the short time, is able to improve the cytokines profile in elderly women with vitamin D deficiency. / A vitamina D é um importante imunomodulador. Estudos epidemiológicos têm demonstrado que a deficiência de vitamina D prejudica as funções imunológicas e participa na patogênese de doenças infecciosas e autoimunes. A suplementação de vitamina D tem demonstrado significativas alterações nas concentrações circulantes de marcadores inflamatórios em diferentes condições clínicas. No entanto, o efeito de dose única e elevada de vitamina D3 no sistema imune de pessoas idosas, permanece obscuro. Nós realizamos um ensaio clínico, randomizado, duplo-cego, controlado por placebo para avaliar o possível efeito benéfico de uma dose oral única de 300.000 UI de vitamina D3 em marcadores inflamatórios em mulheres idosas na pós-menopausa. Um total de 40 mulheres com idade superior a 60 anos foram selecionados para receber 300.000 UI de colecalciferol (n = 20) ou placebo (n = 20) no início do estudo. As dosagens de 25-hidroxivitamina D séricas [25(OH)D] foram semelhantes em ambos os grupos no início do estudo [16,4 ng/ml (± 3,8) no grupo vitamina D e 15 ng/ml (± 3,7) no grupo placebo, p = 0,23]. Os níveis séricos de IL-6, TNF-α e IL-10 foram medidos por ELISA no início do estudo e 30, 60 e 90 dias após a intervenção. No grupo da vitamina D, verificou-se uma diminuição significativa na percentagem média dos níveis de IL-6 (30.8 %, p = 0.006) e TNF-α (48.6 %, p < 0.0001), associada com um aumento percentual médio significativo nos níveis de IL-10 (68.4 %, p < 0.0001) após 90 dias. Concluímos que uma dose oral única de 300.000 UI de colecalciferol, em um curto espaço de tempo, é capaz de melhorar o perfil das citocinas em mulheres idosas com deficiência de vitamina D.

M.Sc. (Environmental Management) / The Kruger National Park (KNP) is a world renowned wildlife reserve and a source of South African ecotourism benefiting the economy. The Olifants River is the largest river running through the KNP and it is known to be one of South Africa’s most polluted rivers. In the winters of 2008 and 2009 Nile crocodile carcasses were found in the Olifants River gorge in the KNP. In a very short period nearly the entire population of Nile crocodile was lost, the cause of which was later identified as pansteatitis. Pansteatitis is caused by lipid peroxidation known to be nutritionally mediated, as it is associated with diets high in polyunsaturated fats, often of fish origin and insufficient antioxidants specifically vitamin E, which is solely synthesized by plants and must therefore be obtained through diet. The hypothesis of this study is therefore that the fish inhabiting the Olifants River are antioxidant deficient, more specifically, vitamin E deficient, causing the wildlife e.g. crocodiles and predatory fish species, that feed on the fish, to become vitamin E deficient as well, and subsequently develop pansteatitis. If the hypothesis is true, the top fish predator in this aquatic system, the tigerfish Hydrocynus vittatus, should therefore also exhibit signs of dietary vitamin E deficiency. The aim of this study was to determine if tigerfish from the Olifants River in the KNP are exhibiting any signs of antioxidant deficiency, specifically vitamin E deficiency. The objectives to accomplish this aim were firstly to analyse the total plasma antioxidant activity using an ELISA assay, and secondly, to perform a histology-based fish health assessment on the target organs of the tigerfish to identify any histological alterations, specifically those known to be associated with vitamin E deficiency. The results were compared to the results from fish of the same species from two reference sites where there have been no signs of vitamin E deficiency, such as pansteatitis-related wildlife deaths. The results of the plasma analysis as well as the histological assessment showed no conclusive signs of vitamin E deficiency in tigerfish from the Olifants River. It is therefore unlikely that the pansteatitis in the affected wildlife is caused by dietary vitamin E deficiency in the aquatic system, but rather by vitamin E depleting mechanisms such as the presence of high amounts of toxicants with pro-oxidant properties, which may be causing an imbalance of pro-oxidants and antioxidants within the body. Hence the rate of vitamin E regeneration cannot keep up with the rate of oxidation. This is occurring only in certain species due to their specific behaviour or eating habits.

Vitamin A is an essential nutrient; it is not synthesized by mammals and therefore must be obtained through the diet. During times of fasting or dietary vitamin A insufficiency, retinol, the alcohol form of the vitamin is released from the liver, its main storage tissue, for circulation in complex with retinol-binding protein 4 (RBP) to provide an adequate supply to peripheral tissues. Stimulated by Retinoic Acid 6 (STRA6), the transmembrane RBP receptor, mediates retinol uptake across blood-tissue barriers such as the retinal pigment epithelium of the eye, the placenta and the choroid plexus of the brain. Our understanding as to how this protein functions has been greatly enhanced by the high-resolution 3D structure of zebrafish STRA6 in complex with calmodulin (CaM) solved by single-particle cryogenic-electron microscopy. However, the nature of the interaction of STRA6 with retinol remains unclear. Here, I present the high-resolution structures of zebrafish and sheep STRA6 reconstituted in nanodisc lipid bilayers in the presence and absence of retinol. The nanodisc reconstitution system has allowed us to study this protein in a close to physiological environment and examine its interaction with the cell membrane and relationship with its ligand, retinol. We also present the structure of sheep STRA6 in complex with human RBP. The structure of the STRA6-RBP complex confirms predictions in the literature as to the nature of the protein-protein interaction needed for retinol transport. Calcium-bound CaM is bound to STRA6 in the RBP-STRA6 structure, consistent with a regulatory role of this calcium binding protein in STRA6-RBP interaction. The analysis of the three states of STRA6 – pre, post and during interaction with retinol – provide unique insights into the mechanism of STRA6-mediated cellular retinol uptake.

Multiple sclerosis (MS) is among the most common neuroinflammatory diseases across the globe and is autoimmune mediated in nature. This progressive, highly debilitating disease often leaves individuals wheelchair bound within 15-25 years of onset. MS is characterized by inflammatory lesions that appear in unpredictable locations around the central nervous system. Lesions can be visualized using magnetic resonance imaging (MRI) technology. As neuroinflammation continues and lesions accumulate, patients can experience a wide array of progressively worsening symptoms including but not limited to motor impairments, sensory disturbances, loss of control of bodily functions, and/or neuropathic pain, depending on the location of lesion formations. There are different types of MS, the most common being relapsing-remitting MS (RRMS) seen in about 85% of cases and characterized by periods of symptom remission followed by flare-ups. A large majority of these patients go on to develop secondary progressive MS (SPMS) where neurological damage and patient decline is progressive and continuous. Primary progressive MS (PPMS) is seen in about 10% of cases and is characterized by progressive and continuous patient decline from the outset of disease. Other rarer forms of MS do exist but will not be discussed further. Research aimed at MS is at an all-time high and the timing could not be better: its global incidence and prevalence is climbing. For decades MS has been thought of as a disease caused by dysfunctional CD4+ T-helper 1 (Th1) cells. It is now known that many different cell types contribute to MS pathophysiology. These other cell types include macrophages and dendritic cells of the innate immune system due to their expression of MHC class II molecules that function to activate CD4+ Th1 cells. More recent research has implicated CD8+ T-cells and B-cells in contributing to disease through direct destruction of neural cells that express MHC class I molecules and through the generation of autoantibodies, respectively. While these discoveries are important and provide hope for future breakthrough treatments, there are still enormous gaps in the medical community’s knowledge of what causes MS. The epidemiologic pattern of MS prevalence has for many decades interested scientists and hinted at a potential cause of this disease. MS tends to affect white individuals with genetic ties to northern Europe, but this relationship may not still hold true, as MS incidence and prevalence may be rising faster in black populations compared to other races/ethnicities, at least in the United States. MS occurs nearly 3 times as often in females than in males, and is strongly associated with Epstein-Barr virus (EBV) infection—especially in those that go on to develop infectious mononucleosis (IM). MS prevalence increases markedly in regions north of 40 degrees North latitude or south of 40 degrees South latitude. MS risk also changes depending on body mass index (BMI) considerations, migration history, and in families with a genetic history of the disease. It is well-accepted that MS has a genetic component, the most important of which is the presence of the HLA-DRB1*1501 allele that codes for certain proteins in MHC class II molecules. However, genetics alone are unable to sufficiently account for MS risk as the concordance rate for identical twins with MS is only 25-30%. These well-established findings imply that some unknown environmental factor(s) must be contributing to MS initiation and progression. All of the environmental factors listed above have a common connecting thread that is logically and empirically verifiable: vitamin D. This fat-soluble vitamin can either be endogenously synthesized in the skin after exposure to ultraviolet B (UVB) light or consumed through the diet, the former being of more importance to humans. Epidemiologic patterns suggest a protective role for vitamin D in MS, where low or deficient levels of vitamin D may be a contributor to increased risk for MS. Populations living at greater latitudes, north or south, have significantly greater prevalence of MS which coincides with the reduction of endogenously produced vitamin D in these regions due to a lesser amount of UVB light (and of lower intensity) experienced year-round. Increases in BMI, especially increased adiposity, correlate with increased risk for MS and with prevalence of vitamin D deficiency. Women tend to naturally have greater adiposity than men, thus increasing their risk for MS. Estrogens and vitamin D have been shown to act synergistically to protect against MS, therefore vitamin D deficiency may increase risk for MS in women. Vitamin D is a known immunomodulatory agent that promotes tolerogenic immune states. Vitamin D also offsets many of the harmful effects caused by EBV, among these including repression of B-cell differentiation into plasma cells, reduced MHC II expression, and promotion of B cell apoptosis. This serves to repress deleterious immunoglobulin secretion by B-cells. Vitamin D is also immunologically beneficial as it promotes regulatory T cell function and their expression of protective cytokines, and through its inhibition of inflammatory Th1 and Th17 cell functions. In total, the immunomodulatory mechanisms of vitamin D are important as the immunological states produced by vitamin D are exactly the opposite of those observed in MS patients and MS animal models. Research in vitamin D is gaining attention as the scientific community is quickly discovering that its true physiologic role extends far beyond its classical function as a calcium regulator. Indeed, rapidly evolving research is revealing roles for vitamin D in cardiovascular function and blood pressure regulation, brain development and neurological function, and even in the prevention of certain cancers. However, this thesis will focus on its most well-known function secondary to calcium regulation: immunomodulation and its anti-inflammatory capabilities. The last portion of this thesis will present information advocating for the increase in minimum dietary intake of vitamin D from its current value of 800 IU/day to 5,000 IU/day. While a more than 5-fold increase may seem drastic, the tolerable upper limit is at least 10,000 IU/day even by the most conservative of estimates—the true upper limit is probably around 20,000 IU/day and may even be 50,000 IU/day. The global prevalence of vitamin D deficiency is so extensive that some authors have even considered it a global pandemic: upwards of 50% of the entire world population may be deficient in this crucial vitamin. Increasing vitamin D supplementation is an extremely low risk way to reduce risk for MS and other diseases.