Objetivos: O objetivo deste estudo foi avaliar o efeito da suplementação de vitamina D nos parâmetros clínicos, laboratoriais, atividade da doença, e fadiga em pacientes com lúpus eritematoso de início juvenil (LESj). Métodos: Este trabalho foi um estudo randomizado, duplo-cego, controlado por placebo por um período de 24 semanas. Quarenta pacientes foram randomizadas (1:1) para receber colecalciferol via oral 50.000 UI / semana (LESj-VITD) ou placebo (LESj-PL). A terapêutica destes pacientes foi mantida estável durante este período. As concentrações séricas de 25- hidroxivitamina D (25OHD) foram medidas por radioimunoensaio. A atividade da doença foi avaliada por meio do Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) e pelo European Consensus Lupus Activity Measurement (ECLAM). Fadiga foi avaliada usando a Kids Fatigue Severity Scale (K-FSS). Resultados: No início do estudo, os grupos foram semelhantes em relação à idade, índice de massa corporal, envolvimento de órgãos, dose de glicocorticoide, uso de drogas imunossupressoras, SLEDAI, ECLAM, K-FSS e concentrações séricas de 25OHD. Após 24 semanas, as concentrações séricas de 25OHD foram maiores no grupo LESj-VITD que no LESj-PL [(31,3 (8,7) vs. 16,5 (5,8), p < 0,001)]. Ao fim da intervenção, uma melhoria significativa no SLEDAI [Delta= 0 (- 4 - 5)_ vs. 1 (-12 - 6) p =0,011] e no ECLAM [Delta = 0 (-2 -1) vs. 0 (-6 - 3) p=0,006], foi observado no grupo LESj- VITD em comparação com o LESj-PL. Em relação à avaliação de fadiga, uma redução da fadiga relacionada com a vida social foi encontrada no grupo LESj-VITD em comparação com o grupo LESj-PL (p = 0,008). A suplementação de colecalciferol foi bem tolerada sem eventos adversos graves. Conclusões: Este estudo sugere que a suplementação com colecalciferol por 24 semanas é eficaz em diminuir a atividade da doença e melhorar a fadiga em pacientes com LESj / Objective: The aim of this study was to evaluate the effect of vitamin D supplementation on disease activity and fatigue in Juvenile-onset Systemic Lupus Erythematosus (JoSLE). Methods: This study was a randomized double-blind placebo-controlled 24-week trial. Forty JoSLE patients were randomized (1:1) to receive oral cholecalciferol 50,000 IU/week (JoSLE-VitD) or placebo (JoSLE-PL). Medications remained stable throughout the study. Serum levels of 25OHD were measured using radioimmunoassay. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measurement (ECLAM). Fatigue was assessed using the Kids Fatigue Severity Scale (K-FSS). Results: At baseline, groups were similar regarding, age, body mass index, organ involvement, glucocorticoid dose, use of immunosuppressive drugs, SLEDAI, ECLAM, K-FSS and levels of 25OHD. After 24 weeks, the mean level of 25OHD was higher in the JoSLE-VitD group than in the JoSLE-PL [(31,3 (8,7) vs. 16,5 (5,8), p < 0,001)]. At the end of intervention, a significant improvement in SLEDAI [delta= 0 (- 4 - 5)_ vs. 1 (-12 - 6) p =0,011] and in ECLAM [delta = 0 (-2 -1) vs. 0 (-6 - 3) p=0,006] was observed in the JoSLE-VitD group compared to the JoSLE-PL. Regarding fatigue evaluation, a reduction of fatigue related to social life score was found in the JoSLE-VitD group compared to the JoSLE-PL group (p=0.008). Cholecalciferol was well tolerated with no serious adverse events. Conclusion: This study suggests that cholecalciferol supplementation for 24 weeks is effective in decreasing disease activity and improving fatigue in JoSLE patients

O remodelamento vascular é uma resposta adaptativa a estímulos específicos, participando da fisiopatologia de diversas doenças cardiovasculares. Devido à intersecção de fatores de risco cardiovasculares relacionados tanto ao remodelamento vascular como à calcificação vascular (CV), propomos a investigação de mecanismos que inter-relacionam tais condições. Postulamos que camundongos ob/ob com obesidade e resistência à insulina têm resposta exacerbada de remodelamento vascular associado à CV quando comparado aos camundongos controles C57BL/6 (C57) após estímulo com vitamina D3 (VD) in vivo. Camundongos C57 e ob/ob (OB) machos foram injetados com 8x103 UI/kg de vitamina D3 intraperitoneal (IP) ou solução fisiológica (CT) durante 14 dias (n=6). Houve aumento da circunferência da lâmina elástica externa da aorta, determinando aumento da área circunferencial do vaso em camundongos OBVD. A hipervitaminose D aumentou o comprimento da lâmina elástica interna da aorta, aumentando o lúmen vascular em camundongos OBVD. Ocorreu também diminuição da espessura da parede do vaso em camundongos OBVD, caracterizando remodelamento vascular positivo hipotrófico. Observamos ainda maior deposição de colágeno na parede do vaso e elastólise em camundongos OBVD. O remodelamento vascular positivo em camundongos OBVD se correlacionou diretamente com o aumento da calcificação na aorta (R2=0,8; p < 0,003). Aortas de camundongos OBVD apresentaram aumento na expressão de espécies reativas de oxigênio (ERO), que foi associado a aumento da atividade de metaloproteinases de matriz (MMP). Estes resultados fornecem evidências que camundongos obesos, insulino-resistentes, e com diabetes tipo 2 desenvolveram remodelamento vascular positivo hipotrófico correlacionado diretamente com calcificação vascular em camundongos OBVD após estímulo com vitamina D3. O desenvolvimento de remodelamento vascular positivo hipotrófico neste modelo murino é possivelmente mediado pela ativação de MMP na parede da aorta e a geração de ERO pode ter contribuído para a ativação de MMP no nosso modelo / Vascular remodeling is a vessel response to mechanical and hemodynamic stimuli, which is a major determinant of changes in vessel lumen caliber. The mechanisms that influence arterial remodeling include calcification. We hypothesized that ob/ob mice develop positive vascular remodeling associated with calcification. We quantify and assess mechanisms of vascular remodeling and vascular calcification in ob/ob mice (OB) after vitamin D3 stimulation (VD) or phosphate buffered saline (CT), compared with (C57BL/6) mice. Both ob/ob (OBVD) and C57BL/6 (C57VD) mice received 8x103 IU/day of (IP) vitamin D3 for 14 days. Control ob/ob (OBCT) and C57BL/6 (C57CT) mice received IP phosphate buffered saline (PBS) for 14 days (n=6). Hypervitaminosis D increased the external and internal elastic length in aortas from OB mice, resulting in increased total vascular area and lumen vascular area respectively, which characterizes positive vascular remodeling. OBVD mice decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increases in collagen deposition, elastolysis and calcification in the aortas of OBVD mice. These results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD mice (R2=0,8; p < 0,003). Furthermore, aorta from OBVD increased oxidative stress, coincidently with augmented metalloproteinase activity. Our data provide evidence that obese type 2 diabetes mellitus and insulin-resistant mice (ob/ob) developed positive hypotrophic vascular remodeling correlated directly with increased vascular calcification in OBVD mice after chronic vitamin D3 stimulation. The development of positive hypotrophic vascular remodeling in this mouse model is possibly mediated by the activation in the aortic wall of MMP and ROS may have contributed to the activation of MMP in our model

該前瞻性研究對香港中國裔孕婦的25羥基維生素D（25（OH）D）的水平及其影響因素進行調查，并對25（OH）D與甲狀旁腺激素（PTH）、孕期肌肉酸痛、不良妊娠結局、孕期及産後骨質流失，以及嬰兒的骨骼發育等關係進行探索，力求建立適用于香港的中國孕婦的25（OH）D正常值。 / 共有237名單胎妊娠婦女以及62名多胎妊娠的婦女在2010年8月至2011年11月間參加本研究中的隊列研究，分別在參加研究時（<20 孕周）、24-28孕周、31-36孕周以及産後6-11周進行抽血測量血清25（OH）D以及PTH水平，同時填寫一份包括對每月攝取含維生素D的食物以及營養補充劑頻度、接受日照情況及喜好、以及肌肉不適等情況的問卷，并在24-28孕周進行75克口服葡萄糖耐量試驗。參與隊列研究的單胎孕婦在20周前、31-36孕周以及産後隨訪時接受用定量超聲測量非優勢手的橈骨遠端以及中指近掌指骨的骨質超聲速率（SoS）。在産後複查時，對其嬰兒左側腓骨中部的骨質SoS進行測量。記錄婦女各次檢查時的體重、抽血月份紫外線輻射強度的歷史記錄、以及妊娠結局。另外募集一批孕婦參加病例對照研究，比較患早產（PTB）、子癇前期（PET）、妊娠糖尿病 （GDM）以及胎兒生長受限（FGR）併發癥的婦女與對照組 （體重指數以及抽血時紫外線強度配對）的血清25（OH）D水平。 / 孕婦在孕期的平均25（OH）D水平在44.7 ± 12.6 至48.9 ± 17.1 nmol/l範圍，25（OH）D水平與體重指數、維生素D營養補充劑、抽血時紫外線強度以及個人對陽光的喜好情況有關，而與胎兒數量、孕次、孕周以及終止妊娠無關。 / 單胎妊娠的孕婦三個孕期的血清25（OH）D與PTH水平均負相關，但在多胎妊娠中，二者無明顯相關性。PTH在孕期以及産後的變化相對不受25（OH）D影響。孕婦25（OH）D的水平與孕婦肌肉酸痛癥狀、産後恢復、孕期及產褥期骨質流失以及嬰兒骨質無關。患早期PTB（< 34孕周）、PET或FGR的孕婦的血清25（OH）D比對照組低，但GDM患者的25（OH）D水平與對照組無差別。血清25（OH）D低於34.3 nmol/l者的早期早產以及子癇前期的風險增高，低於50 nmol/l者發生胎兒生長受限的風險增高。服用維生素D補充劑情況可能影響25（OH）D與FGR的關係。 / 總而言之，血清25（OH）D水平不足以全面完全反映孕期維生素D的情況，對預測不良妊娠結局的作用有限。 / This prospective study explored the maternal serum level of 25(OH)D in Chinese pregnant women in Hong Kong and the factors affecting 25(OH)D level. It also explored the correlation between maternal 25(OH)D with PTH level, maternal musculoskeletal complaints, adverse pregnancy outcome, maternal bone turnover during pregnancy and postpartum, and the bone development of the offspring, aiming to explore and establish a normal range of 25(OH)D level in pregnancy for the Hong Kong Chinese women. / A total of 237 women with singleton pregnancy and 62 women with multiple pregnancies were recruited for the cohort study from August, 2010 to November, 2011. Maternal blood samplings for 25(OH)D and PTH measurements were performed at recruitment, 24-28 weeks, 31-36 weeks of gestation, and 6-11 weeks postpartum respectively. A questionnaire which included the monthly dietary and supplement intake of vitamin D, questions about sunlight exposure, and musculoskeletal complaints was administered on each visit. A 75g oral glucose tolerance test (OGTT) was performed on cohort cases at 24-28 weeks of gestation. Measurements of the speed of sound (SoS) at the distal one third of the maternal radius and the proximal phalanx of the third finger of the non-dominant side were performed with quantitative ultrasonography (QUS) measurement during the visits at the first and third trimesters, and postnatal period. The SoS at the left mid-shaft tibia of the offspring was determined during the postnatal visit. Maternal characteristics, ultraviolet radiation (UVR) intensity at blood sampling, and pregnancy outcome, were also recorded. Cases with pregnancy complications were recruited for case-control studies, and maternal 25(OH)D level was examined with respect to preterm birth (PTB), preeclampsia (PET), gestational diabetes (GDM), and fetal growth restriction (FGR, birthweight below the 10th percentile of the customized estimated birthweight). The controls were matched for booking body mass index (BMI) and UVR intensity at blood sampling. / The mean 25(OH)D level in ranged from 44.7 ± 12.6 to 48.9 ± 17.1 nmol/l in the three trimesters, and was related to BMI, vitamin D supplementation, UVR intensity at blood sampling, and the acceptance of sunlight exposure, but not the number of fetus, parity, gestational age, or the completion of pregnancy. / Inverse correlation between PTH and 25(OH)D were observed in singleton, but not in multiple, pregnancy. The change in maternal PTH level is found to be relatively independent from that of 25(OH)D. There was no correlation between maternal 25(OH)D level with musculoskeletal complaints, postnatal recovery, bone turnover during and after pregnancy, or the bone density of the offspring. Maternal 25(OH)D level was lower in women with early PTB ( < 34 weeks), PET, and FGR, but not for GDM. A maternal 25(OH)D level of lower than 34.3nmol/l and 50 nmol/l was associated with increased risk of early PTB, PET, and FGR respectively. But the correlation between maternal 25(OH)D level with FGR might be affected by supplementation. / In conclusion, serum level of 25(OH)D is insufficient in reflecting maternal vitamin D status and metabolism in pregnancy, and is of limited use in predicting adverse pregnancy outcome. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Hu, Zhiyang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 201-223). / Abstracts and appendixes also in Chinese. / Thesis dedication --- p.i / Acknowledgments --- p.ii / Abstract --- p.v / Abstract (Chinese) --- p.viii / List of Abbreviation --- p.x / Table of contents --- p.xiii / List of Figures --- p.xxii / List of Tables --- p.xxiv / Chapter Chapter 1: --- Literature Review --- p.1 / Chapter 1.1 --- The synthesis and metabolism of vitamin D --- p.3 / Chapter 1.1.1 --- The synthesis of vitamin D --- p.3 / Chapter 1.1.2 --- The metabolism of vitamin D --- p.4 / Chapter 1.1.3 --- Vitamin D binding protein --- p.10 / Chapter 1.1.4 --- Factors related to 25(OH)D level --- p.11 / Chapter 1.2 --- Function of vitamin D --- p.13 / Chapter 1.2.1 --- Mechanism of vitamin D function --- p.13 / Chapter 1.2.2 --- Classic function --- p.14 / Chapter 1.2.3 --- Non-classic function --- p.16 / Chapter 1.2.3.1 --- Immune system --- p.17 / Chapter 1.2.3.2 --- Cardiovascular system --- p.18 / Chapter 1.2.3.3 --- Cell proliferation and differentiation --- p.18 / Chapter 1.2.3.4 --- Neurological system --- p.19 / Chapter 1.2.3.5 --- Reproductive system --- p.20 / Chapter 1.2.3.6 --- Fetal development --- p.21 / Chapter 1.3 --- The definition of vitamin D deficiency --- p.21 / Chapter 1.4 --- Vitamin D status and pregnancy --- p.24 / Chapter 1.4.1 --- Alteration in vitamin D metabolism during pregnancy --- p.24 / Chapter 1.4.2 --- Factors affecting maternal serum level of 25(OH)D --- p.25 / Chapter 1.4.3 --- Vitamin D and bone resorption during pregnancy and lactation --- p.27 / Chapter 1.4.3.1 --- Alteration of calcium metabolism, bone absorption and the role of vitamin D --- p.27 / Chapter 1.4.3.2 --- Measurement of bone density in pregnant women and babies --- p.33 / Chapter 1.4.4 --- Current studies on maternal vitamin D status and pregnancy outcome --- p.35 / Chapter 1.4.4.1 --- Birthweight --- p.35 / Chapter 1.4.4.2 --- Infection --- p.37 / Chapter 1.4.4.3 --- Preterm delivery --- p.39 / Chapter 1.4.4.4 --- Diabetes (DM) and gestational diabetes (GDM) --- p.39 / Chapter 1.4.4.5 --- Hypertension and preeclampsia --- p.41 / Chapter 1.4.4.6 --- Multiple pregnancy, muscular symptoms --- p.42 / Chapter 1.4.4.7 --- Vitamin D supplementation and pregnancy outcome --- p.44 / Chapter 1.5 --- Defining vitamin D deficiency in pregnancy --- p.45 / Chapter 1.6 --- Objective of the study --- p.46 / Chapter Chapter 2: --- Study design and methods --- p.48 / Chapter 2.1 --- Case recruitment and study design --- p.48 / Chapter 2.1.1 --- Longitudinal singleton study --- p.49 / Chapter 2.1.2 --- Cross-sectional study --- p.50 / Chapter 2.1.2.1 --- Preterm birth (PTB) --- p.51 / Chapter 2.1.2.2 --- Preeclampsia (PET) --- p.51 / Chapter 2.1.2.3 --- Gestational diabetes (GDM) --- p.52 / Chapter 2.1.3 --- Multiple pregnancy study --- p.52 / Chapter 2.2 --- Measurements --- p.53 / Chapter 2.2.1 --- Hormonal analysis of serum levels of 25(OH)D and PTH --- p.53 / Chapter 2.2.2 --- Calculation of monthly intake of vitamin D from diet --- p.55 / Chapter 2.2.3 --- SoS measurements --- p.56 / Chapter 2.2.4 --- Ultraviolet radiation strength assessment --- p.59 / Chapter 2.3 --- Statistical analysis --- p.60 / Chapter Chapter 3 --- Longitudinal Study on the Level of and Factors Affecting Vitamin D in Singleton Pregnancy --- p.62 / Chapter 3.1 --- Introduction --- p.62 / Chapter 3.2 --- Material and method --- p.63 / Chapter 3.3 --- Statistics --- p.64 / Chapter 3.4 --- Results --- p.65 / Chapter 3.4.1 --- Demographic data of the subjects --- p.65 / Chapter 3.4.2 --- Maternal levels of 25(OH)D and PTH, and the factors affecting their levels --- p.66 / Chapter 3.4.2.1 --- Distribution of 25(OH)D level and PTH level in the four visits --- p.66 / Chapter 3.4.2.2 --- Dietary intake of vitamin D and supplementation --- p.69 / Chapter 3.4.2.3 --- Seasonality and sunlight exposure --- p.73 / Chapter 3.4.2.4 --- Parity --- p.76 / Chapter 3.4.3 --- Changes of maternal levels of 25(OH)D and PTH in pregnancy --- p.78 / Chapter 3.4.4 --- Independent factors related to maternal 25(OH)D level in pregnancy --- p.79 / Chapter 3.4.5 --- Maternal and fetal 25(OH)D level at delivery --- p.80 / Chapter 3.4.6 --- Muscular symptoms and other complaints in pregnancy, pregnancy outcome, and their relationships with maternal 25(OH)D level --- p.81 / Chapter 3.4.7 --- Postnatal recovery and factors related to postnatal level of 25(OH)D and PTH --- p.86 / Chapter 3.4.7.1 --- Postnatal symptoms and relationship with 25(OH)D and PTH --- p.86 / Chapter 3.4.7.2 --- The postnatal level of 25(OH)D and PTH in women with different feeding mode --- p.88 / Chapter 3.4.7.3 --- Independent factors related to postnatal 25(OH)D and PTH level --- p.89 / Chapter 3.4.7.4 --- Factors related to the change of 25(OH)D and PTH after delivery --- p.90 / Chapter 3.4.8 --- Correlation between 25(OH)D with PTH in pregnancy and postnatal period --- p.91 / Chapter 3.5 --- Discussion --- p.92 / Chapter 3.5.1 --- 25(OH)D level in Chinese pregnant women --- p.92 / Chapter 3.5.2 --- Factors related to maternal 25(OH)D level --- p.93 / Chapter 3.5.2.1 --- Dietary and supplementation --- p.93 / Chapter 3.5.2.2 --- Seasonality and outdoor activity --- p.96 / Chapter 3.5.2.3 --- Gestational age --- p.98 / Chapter 3.5.2.4 --- Age and parity --- p.98 / Chapter 3.5.3 --- Relationship of 25(OH)D level in the cord blood with maternal 25(OH)D level --- p.99 / Chapter 3.5.4 --- 25(OH)D level and muscular complains in pregnancy --- p.100 / Chapter 3.5.5. --- Postnatal recovery and 25(OH)D level --- p.101 / Chapter 3.5.6 --- PTH level in pregnancy and postnatal period --- p.101 / Chapter 3.6 --- Conclusion --- p.102 / Chapter Chapter 4 --- Longitudinal Study on the Relationship between Maternal 25(OH)D level with Changes of Maternal Bone Density in Pregnancy and Lactation, and Factors Affecting Bone Density of newborn Infants --- p.105 / Chapter 4.1 --- Introduction --- p.105 / Chapter 4.2 --- Material and method --- p.106 / Chapter 4.3 --- Statistics --- p.108 / Chapter 4.4 --- Results --- p.108 / Chapter 4.4.1 --- Demographic data --- p.108 / Chapter 4.4.2 --- Maternal bone density and the changes in pregnancy and postnatal recovery --- p.109 / Chapter 4.4.2.1 --- Maternal bone density in the first trimester and related factors --- p.109 / Chapter 4.4.2.2 --- Maternal bone density in the three visits --- p.109 / Chapter 4.4.2.3 --- The change in maternal bone density in the three visits --- p.110 / Chapter 4.4.2.4 --- Diversity in the change of bone density in pregnant women --- p.112 / Chapter 4.4.3 --- Factors related to the changes in bone density --- p.114 / Chapter 4.4.3.1 --- Changes between the first and the third trimesters --- p.114 / Chapter 4.4.3.2 --- Change between the third trimester and postnatal visits --- p.116 / Chapter 4.4.4 --- The bone density in infants and related factors --- p.120 / Chapter 4.5 --- Discussion --- p.122 / Chapter 4.5.1 --- Maternal bone density changes in pregnancy and postnatal period --- p.122 / Chapter 4.5.2 --- Factors related to the maternal bone density changes in pregnancy and postnatal period --- p.124 / Chapter 4.5.2.1 --- Initial bone density, parity, and BMI --- p.125 / Chapter 4.5.2.2 --- 25(OH)D and PTH level --- p.126 / Chapter 4.5.2.3 --- Supplement --- p.127 / Chapter 4.5.2.4 --- Lactation --- p.128 / Chapter 4.5.2.5 --- Height --- p.129 / Chapter 4.5.3 --- Factors related to bone density of the infant. --- p.130 / Chapter 4.5.3.1 --- Maternal 25(OH)D level --- p.130 / Chapter 4.5.3.2 --- Gestational age and birthweight --- p.131 / Chapter 4.5.3.3 --- Maternal bone density change --- p.131 / Chapter 4.5.3.4 --- The gender of the offspring and feeding method --- p.132 / Chapter 4.6 --- Conclusion --- p.133 / Chapter Chapter 5 --- Maternal 25(OH)D Level in Multiple Pregnancy --- p.134 / Chapter 5.1 --- Introduction --- p.134 / Chapter 5.2 --- Material and method --- p.135 / Chapter 5.3 --- Statistics --- p.136 / Chapter 5.4 --- Results --- p.137 / Chapter 5.4.1 --- Demographic data of the subjects --- p.137 / Chapter 5.4.2 --- The level of 25(OH)D in multiple pregnancy and singleton pregnancy --- p.137 / Chapter 5.4.3 --- Supplementation in multiple pregnancy --- p.140 / Chapter 5.4.4 --- The change of maternal 25(OH)D and PTH levels in the three trimesters --- p.141 / Chapter 5.4.5 --- 25(OH)D level in cord blood and its correlation with 25(OH)D level of the sibling --- p.143 / Chapter 5.4.6 --- Correlation between 25(OH) with PTH in pregnancy --- p.143 / Chapter 5.5 --- Discussion --- p.144 / Chapter 5.5.1 --- 25(OH)D level in multiple pregnancy and singleton pregnancy --- p.144 / Chapter 5.5.2 --- Supplementation in multiple pregnancy --- p.146 / Chapter 5.5.3 --- Changes of maternal levels of 25(OH)D and PTH in the three trimesters in multiple pregnancy --- p.146 / Chapter 5.5.4 --- The PTH/25(OH) correlation --- p.147 / Chapter 5.6 --- Conclusion --- p.148 / Chapter Chapter 6 --- Maternal level of 25(OH)D in complicated pregnancy --- p.150 / Chapter 6.1 --- Introduction --- p.150 / Chapter 6.2 --- Method --- p.153 / Chapter 6.2.1 --- Preterm birth --- p.155 / Chapter 6.2.2 --- Preeclampsia --- p.155 / Chapter 6.2.3 --- Gestational diabetes --- p.156 / Chapter 6.2.4 --- Fetal growth restriction --- p.157 / Chapter 6.2.5 --- The association between 25(OH)D level with pregnancy complication --- p.158 / Chapter 6.3 --- Statistics --- p.159 / Chapter 6.4 --- Results --- p.160 / Chapter 6.4.1 --- Setting of the cutoff values of hypovitaminosis D --- p.160 / Chapter 6.4.2 --- Preterm birth --- p.160 / Chapter 6.4.3 --- Preeclampsia --- p.164 / Chapter 6.4.4 --- Gestational diabetes --- p.168 / Chapter 6.4.4.1 --- Case-control study --- p.168 / Chapter 6.4.4.2 --- Factors affecting OGTT results --- p.170 / Chapter 6.4.5 --- Fetal growth restriction --- p.173 / Chapter 6.5 --- Discussion --- p.179 / Chapter 6.5.1 --- Adjustment for confounders for case-control study --- p.179 / Chapter 6.5.2 --- PTB and 25(OH)D level --- p.181 / Chapter 6.5.3 --- PET and 25(OH)D level --- p.182 / Chapter 6.5.4 --- GDM and 25(OH)D level --- p.186 / Chapter 6.5.5 --- FGR and 25(OH)D level --- p.189 / Chapter 6.5.6 --- Defining vitamin D deficiency in pregnancy --- p.192 / Chapter 6.6 --- Conclusion --- p.195 / Chapter Chapter 7 --- Summary --- p.196 / References --- p.201 / Chapter Appendix 1 --- Antenatal questionnaire (English/Chinese) --- p.224 / Chapter Appendix 2 --- Postnatal questionnaire (English/Chinese) --- p.238

Objetivos: O objetivo deste estudo foi avaliar o efeito da suplementação de vitamina D nos parâmetros clínicos, laboratoriais, atividade da doença, e fadiga em pacientes com lúpus eritematoso de início juvenil (LESj). Métodos: Este trabalho foi um estudo randomizado, duplo-cego, controlado por placebo por um período de 24 semanas. Quarenta pacientes foram randomizadas (1:1) para receber colecalciferol via oral 50.000 UI / semana (LESj-VITD) ou placebo (LESj-PL). A terapêutica destes pacientes foi mantida estável durante este período. As concentrações séricas de 25- hidroxivitamina D (25OHD) foram medidas por radioimunoensaio. A atividade da doença foi avaliada por meio do Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) e pelo European Consensus Lupus Activity Measurement (ECLAM). Fadiga foi avaliada usando a Kids Fatigue Severity Scale (K-FSS). Resultados: No início do estudo, os grupos foram semelhantes em relação à idade, índice de massa corporal, envolvimento de órgãos, dose de glicocorticoide, uso de drogas imunossupressoras, SLEDAI, ECLAM, K-FSS e concentrações séricas de 25OHD. Após 24 semanas, as concentrações séricas de 25OHD foram maiores no grupo LESj-VITD que no LESj-PL [(31,3 (8,7) vs. 16,5 (5,8), p < 0,001)]. Ao fim da intervenção, uma melhoria significativa no SLEDAI [Delta= 0 (- 4 - 5)_ vs. 1 (-12 - 6) p =0,011] e no ECLAM [Delta = 0 (-2 -1) vs. 0 (-6 - 3) p=0,006], foi observado no grupo LESj- VITD em comparação com o LESj-PL. Em relação à avaliação de fadiga, uma redução da fadiga relacionada com a vida social foi encontrada no grupo LESj-VITD em comparação com o grupo LESj-PL (p = 0,008). A suplementação de colecalciferol foi bem tolerada sem eventos adversos graves. Conclusões: Este estudo sugere que a suplementação com colecalciferol por 24 semanas é eficaz em diminuir a atividade da doença e melhorar a fadiga em pacientes com LESj / Objective: The aim of this study was to evaluate the effect of vitamin D supplementation on disease activity and fatigue in Juvenile-onset Systemic Lupus Erythematosus (JoSLE). Methods: This study was a randomized double-blind placebo-controlled 24-week trial. Forty JoSLE patients were randomized (1:1) to receive oral cholecalciferol 50,000 IU/week (JoSLE-VitD) or placebo (JoSLE-PL). Medications remained stable throughout the study. Serum levels of 25OHD were measured using radioimmunoassay. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measurement (ECLAM). Fatigue was assessed using the Kids Fatigue Severity Scale (K-FSS). Results: At baseline, groups were similar regarding, age, body mass index, organ involvement, glucocorticoid dose, use of immunosuppressive drugs, SLEDAI, ECLAM, K-FSS and levels of 25OHD. After 24 weeks, the mean level of 25OHD was higher in the JoSLE-VitD group than in the JoSLE-PL [(31,3 (8,7) vs. 16,5 (5,8), p < 0,001)]. At the end of intervention, a significant improvement in SLEDAI [delta= 0 (- 4 - 5)_ vs. 1 (-12 - 6) p =0,011] and in ECLAM [delta = 0 (-2 -1) vs. 0 (-6 - 3) p=0,006] was observed in the JoSLE-VitD group compared to the JoSLE-PL. Regarding fatigue evaluation, a reduction of fatigue related to social life score was found in the JoSLE-VitD group compared to the JoSLE-PL group (p=0.008). Cholecalciferol was well tolerated with no serious adverse events. Conclusion: This study suggests that cholecalciferol supplementation for 24 weeks is effective in decreasing disease activity and improving fatigue in JoSLE patients

Poison operations are a widely used technique for rodent control in the indigenous forests of New Zealand. This study examined the bait-take and rat monitoring data obtained for continuous poison operations at Boundary Stream Mainland Island (BSMI), Hawke’s Bay, between 1996 and 2007. Since the beginning of the Mainland Island project at BSMI in 1996, 800 ha of indigenous forest have been treated with an ‘Integrated Pest Management’ approach, in which rodents (primarily ship rats) have been targeted by consecutive ground poison operations. The aim of the intensive pest control was to allow the ecosystem to recover and provide a safe environment for threatened native bird species to recover or be re-introduced. Another important aim of this pest control is to provide experience and expert knowledge in management techniques especially applicable to the protection of indigenous habitat on the New Zealand mainland. This research study had two main aims: to identify spatial patterns of the rodent population at BSMI and to determine the efficacy of the different rodenticides applied for their control. The distribution of the rodent population was investigated by spatial analysis of bait-take across the reserve and through time. Visualisation of high and low bait-take areas revealed that there was a noticeable reinvasion from adjacent unmanaged native forests, but not markedly from exotic forest or pasture. Reinvasion from small and isolated adjacent forests ceased to be noticeable consistently after approximately four years of the poison operation, while a large scenic native reserve, as well as a narrow part of the treatment area surrounded by many native bush patches, were continuously affected by reinvasion through the entire project time. Bait-take was visibly higher after the bait had either been removed, or left in the field unserviced, over winter. No consistent areas of no bait-take were identified. Further statistical analysis of bait-take data revealed that bait-take was higher in bait stations within 150 m of the treatment edge than interior bait stations. Bait-take in broadleaf/tawa/podocarp forest was significantly higher than in kamahi/kanuka/rewarewa, beech and cloud-cap forest. The second aim of the study was to determine the efficacy of the various bait types with different active ingredients used during the operation. Rat monitoring data, namely rat tracking indices (RTI) obtained from tracking tunnels, were statistically modelled using Generalised Linear Models. Diphacinone cereal pellets (Pestoff® 50D, 0.05g/kg diphacinone) obtained the lowest RTI, followed by pindone cereal pellets (Pindone Pellets®, 0.5g/kg pindone), brodifacoum cereal pellets (Pestoff® 20p and Talon®, 0.02 g/kg brodifacoum), coumatetralyl paste (Racumin®, 0.375 g/kg) and diphacinone bait blocks (Ditrac®, 0.05 g/kg). Cereal pellet baits worked better than any other bait type used at this location. Season had no statistically significant effect on either RTI or bait-take estimates. The overall goal of the poison operation to decrease rat numbers, and to maintain low levels, has been met. However, the results of this study suggest that baiting needs to be done continuously and over the entire treatment area. Edge bait stations – particularly next to adjacent native forests – should be prioritised to target reinvading rodents. Poisons presented in cereal pellet baits should be preferred to other bait types. Both pindone and brodifacoum showed very good results, as well as diphacinone in cereal pellet baits.

O remodelamento vascular é uma resposta adaptativa a estímulos específicos, participando da fisiopatologia de diversas doenças cardiovasculares. Devido à intersecção de fatores de risco cardiovasculares relacionados tanto ao remodelamento vascular como à calcificação vascular (CV), propomos a investigação de mecanismos que inter-relacionam tais condições. Postulamos que camundongos ob/ob com obesidade e resistência à insulina têm resposta exacerbada de remodelamento vascular associado à CV quando comparado aos camundongos controles C57BL/6 (C57) após estímulo com vitamina D3 (VD) in vivo. Camundongos C57 e ob/ob (OB) machos foram injetados com 8x103 UI/kg de vitamina D3 intraperitoneal (IP) ou solução fisiológica (CT) durante 14 dias (n=6). Houve aumento da circunferência da lâmina elástica externa da aorta, determinando aumento da área circunferencial do vaso em camundongos OBVD. A hipervitaminose D aumentou o comprimento da lâmina elástica interna da aorta, aumentando o lúmen vascular em camundongos OBVD. Ocorreu também diminuição da espessura da parede do vaso em camundongos OBVD, caracterizando remodelamento vascular positivo hipotrófico. Observamos ainda maior deposição de colágeno na parede do vaso e elastólise em camundongos OBVD. O remodelamento vascular positivo em camundongos OBVD se correlacionou diretamente com o aumento da calcificação na aorta (R2=0,8; p < 0,003). Aortas de camundongos OBVD apresentaram aumento na expressão de espécies reativas de oxigênio (ERO), que foi associado a aumento da atividade de metaloproteinases de matriz (MMP). Estes resultados fornecem evidências que camundongos obesos, insulino-resistentes, e com diabetes tipo 2 desenvolveram remodelamento vascular positivo hipotrófico correlacionado diretamente com calcificação vascular em camundongos OBVD após estímulo com vitamina D3. O desenvolvimento de remodelamento vascular positivo hipotrófico neste modelo murino é possivelmente mediado pela ativação de MMP na parede da aorta e a geração de ERO pode ter contribuído para a ativação de MMP no nosso modelo / Vascular remodeling is a vessel response to mechanical and hemodynamic stimuli, which is a major determinant of changes in vessel lumen caliber. The mechanisms that influence arterial remodeling include calcification. We hypothesized that ob/ob mice develop positive vascular remodeling associated with calcification. We quantify and assess mechanisms of vascular remodeling and vascular calcification in ob/ob mice (OB) after vitamin D3 stimulation (VD) or phosphate buffered saline (CT), compared with (C57BL/6) mice. Both ob/ob (OBVD) and C57BL/6 (C57VD) mice received 8x103 IU/day of (IP) vitamin D3 for 14 days. Control ob/ob (OBCT) and C57BL/6 (C57CT) mice received IP phosphate buffered saline (PBS) for 14 days (n=6). Hypervitaminosis D increased the external and internal elastic length in aortas from OB mice, resulting in increased total vascular area and lumen vascular area respectively, which characterizes positive vascular remodeling. OBVD mice decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increases in collagen deposition, elastolysis and calcification in the aortas of OBVD mice. These results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD mice (R2=0,8; p < 0,003). Furthermore, aorta from OBVD increased oxidative stress, coincidently with augmented metalloproteinase activity. Our data provide evidence that obese type 2 diabetes mellitus and insulin-resistant mice (ob/ob) developed positive hypotrophic vascular remodeling correlated directly with increased vascular calcification in OBVD mice after chronic vitamin D3 stimulation. The development of positive hypotrophic vascular remodeling in this mouse model is possibly mediated by the activation in the aortic wall of MMP and ROS may have contributed to the activation of MMP in our model

<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>

Aerial control using 1080 (sodium monofluoroacetate) baits is widely used in New Zealand for the control of introduced brushtail possums (Trichosurus vulpecula), with the aim of protecting national conservation and agricultural values from these damaging pests. This thesis integrates research, completed over 25 years, that was motivated by growing recognition in the 1970s of the extent of possum impacts and the need to improve the effectiveness and efficiency of the control operation. Field research assessed the palatability of three types of cereal-based pellet baits and carrot baits in different regions, habitat types and seasons. Palatability was assessed by the consumption of the different bait types presented independently of each other on 15-30 plots, with rotation of bait types at plots on successive nights to provide equal exposure to each bait type. There was regional variation in possums' bait preferences, possibly reflecting genotypic differences, whereas seasonal variation was less evident. Carrot bait was preferred or equally preferred to cereal bait in 14 out of 20 field trials. The proportion of possums eating baits was then investigated by, firstly, developing a technique for tracing bait acceptance using rhodamine B, a UV-fluorescent dye. In four field trials, more than 95% of possums accepted three types of dye-marked bait, eliminating bait refusal as a major reason for low kills in winter control operations. In a fifth trial, conducted in summer, only 68% of possums accepted bait suggesting that seasonal availability of favoured foods may influence bait acceptance. Since possums must encounter baits before deciding whether to eat them, field studies were undertaken to assess the coverage achieved in normal aerial baiting operations. Large gaps, up to 400 m in width, were often found between baiting swaths; these could allow some possums to survive. A controlled field experiment, using acceptance of rhodamine-dyed bait as a measure of effectiveness, showed that bait distribution was least accurate where flight paths were not marked. Where gaps of 100 m between flight paths were deliberately created, bait acceptance was slower and less than where coverage was complete. Sowing baits at 3 kg/ha was as effective as at 10 kg/ha, indicating the potential for substantially reducing operational costs by using machinery capable of faultlessly distributing baits at low rates. Navigational guidance systems were evaluated and found to improve the accuracy of bait distribution. During 1993-1997, when a lower sowing rate of 5 kg/ha was adopted operationally by regional managers, control effectiveness was unchanged but annual savings of around $9 million accrued. Because of the lack of suitable sowing machinery, a bucket was developed to permit faultless distribution of baits at lower rates, demonstrating the possibility of yet further cost-savings. The possibility of seasonal food availability affecting bait acceptance was investigated in three different forest habitats. Dyed baits were aerially distributed on 100 ha at each site in each season over two years. In each trial, fat-based condition indices of possums were calculated and the abundance of possum-preferred plant foods described. Bait acceptance was consistently high (85-100%) in the 24 trials, and was not influenced by either condition or availability of preferred foods. It seems likely that seasonal variation in operational effectiveness is caused by either the availability of sharply seasonal, scarce foods that possums may feed on intensively for brief periods, or by warmer temperatures that render 1080 less effective. The influence of 1080 on acceptance of (rhodamine-dyed) baits was investigated in a field trial. Examination of possums for dye-marking showed that 25% of possums refused to eat either a lethal quantity of bait or any bait at all, compared with 98% of possums eating non-toxic bait. This indicated that 1080 is aversive to possums, which is a potential major reason for their surviving control operations. Pen trials were therefore conducted to further examine the problem and to seek solutions. Toxic carrot baits were rejected by 27.5% of possums, equally by smell and taste aversion, whereas toxic cereal pellets were rejected by 34%, mainly by taste aversion. Orange and cinnamon were shown to be among the most preferred of 42 flavours tested and, when applied to toxic baits, 1080 was effectively masked. Bait refusal was reduced to ≤7%, the same as that recorded for possums presented with flavoured non-toxic baits. For long-term control of possum populations, aerial 1080 baiting can be used sequentially with other poisoning methods. However, the compatibility of these methods is dependent on the likelihood of possums developing bait shyness if sublethally dosed. Studies were therefore conducted to characterise and compare the four main toxicants used (1080, cyanide, cholecalciferol and brodifacoum) for induction and mitigation of bait shyness. Shyness was induced in approximately 80% of possums sublethally dosed with cyanide, 60% with 1080, 20% with cholecalciferol, and 0% with brodifacoum. Cyanide and 1080 shyness were found to persist in many possums for at least 12 and 24 months, respectively. Use of alternative bait types, and of baits containing an alternative slow-acting toxin (brodifacoum) were shown to be effective ways of overcoming shyness. This, and other related research, is reviewed to provide operational specifications that maximise the likelihood that all targeted possums will (i) encounter bait, (ii) eat it, and (iii) die. The likely future use of aerial 1080 baiting is described and the technological, economic, environmental and social constraints on its sustainability are discussed. Finally, the uptake of the research by possum managers is considered, and areas identified in the thesis where information is incomplete are summarised as prioritised topics for further research.