Brain calcification is a common occurrence in the aging process, with over 20% of individuals over the age of 65 showing hardened plaques in the basal ganglia. Loss of the vitamin D receptor (VDR) in transgenic mice leads to formation of calcified plaques in the basal ganglia and thalamus within the mice. Vitamin D signals through two known vitamin D responsive proteins, protein disulfide isomerase A3 (PDIA3) and VDR. In vitro, vitamin D has been demonstrated to suppress calcification in osteoblast-like cells. Here, we aim to elucidate which of PDIA3 or VDR transduce vitamin D mediated suppression of calcification in vitro. PDIA3 or VDR were selectively knocked out in human osteosarcoma (SaOs) cells using CRISPR/CAS9 technology to generate PDIA3 -/- or VDR -/- cells. Knockout for PDIA3 or VDR was confirmed by RT-qPCR assay or western blot analysis. The calcification of SaOs-2 cells was induced with treatment of β-glycerophosphate along with ascorbic acid allowing for determination of whether loss of PDIA3 or VDR would lead to altered calcium deposition. Cells null for PDIA3 but not VDR grew at a significantly slower rate than wild-type (WT) cells. Intriguingly, PDIA3 and VDR -/- cells displayed significantly more calcification relative to WT control cells. Calcitriol or the synthetic analogue EB-1089 suppressed calcification in vitro in WT and PDIA3 -/- but not VDR -/- cells as measured by alizarin red staining. These data suggest VDR is critical for mediating vitamin D’s inhibition of calcification in vitro, and that PDIA3 has a role in suppressing calcification. This study provides novel insights into vitamin D signaling and provides a foundation for further study and understanding of vitamin D related pathologies.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第20287号 / 医科博第78号 / 新制||医科||5(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 岩井 一宏, 教授 萩原 正敏, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Environmental chemicals may interrupt physiological adaptations necessary in pregnancy, contributing to pregnancy complications with health implications for the mother and child. Nutrients may modify the impact of chemical exposures by blocking their absorption or facilitating their excretion. However, the nature, directionality, and implications of these relationships remain unclear. Objectives: We sought to understand: 1) the potential bidirectional nature of the relationship between vitamin D (25-hydroxyvitamin D, 25OHD) and the toxic metals cadmium (Cd) and lead (Pb) in pregnancy; 2) the association between metals (Cd, Pb, arsenic (As), mercury) and preterm birth and the potential modification of that association by 25OHD; and 3) the long-term association of pregnancy complications with maternal cardiometabolic health. Methods: We used data from the Maternal-Infant Research on Environmental Chemicals Study (n=1983) pregnancy cohort, including long-term follow-up approximately 9 years post-pregnancy. We used cross-lagged panel models to determine the direction of the relationship of 25OHD with Cd and Pb in pregnancy, discrete-time survival analysis to examine the association between metals in pregnancy and preterm birth, and multivariable linear regression to investigate the association of pregnancy complications with long-term maternal outcomes. Results: Each doubling in first trimester 25OHD concentrations was associated with 9% (95% CI: -15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. One-unit increases in Pb (μg/dL) and arsenic (μg/L) concentrations in pregnancy were associated with an increased relative risk (RR) of preterm birth (RR_Pb: 1.48, 95% CI: 1.00, 2.20; RR_As: 1.10, 95% CI 1.02, 1.19); the association with Pb was stronger among those with lower 25OHD. Finally, relative to uncomplicated pregnancy, experiencing a pregnancy complication was positively associated with body fat percentage (β=2.6, 95% CI: 0.3, 4.8) and systolic (average increase of 9.0 mm Hg, 95% CI 5.1, 12.8) and diastolic (average increase of 5.5 mm Hg, 95% CI: 2.6, 8.4) blood pressure 9 years later. Conclusions: Nutrient status during pregnancy may affect and interact with environmental chemicals to impact pregnancy outcomes. Future studies should continue to use methods that elucidate the causal direction of associations and evaluate interactions. Chemicals associated with pregnancy complications could have lasting impacts on maternal health.

Approximately 15 million Americans are diagnosed with a major depressive disorder each year, with higher rates among women and college-aged adults. Recent research suggests a vitamin D insufficiency may be associated with an increased risk of depression among the elderly. However, studies have not been conducted among young women. A recent study of young adults in Massachusetts suggests that two-thirds of this population is vitamin D deficient. We evaluated the association between dietary vitamin D intake and serum levels of 25-hydroxyvitamin D (25(OH)D3) and history of depression using data from the UMass Vitamin D Status Study, a cross-sectional study of 237 college-aged women. Information on depression and health-related factors was collected by questionnaire at a single clinic visit. Dietary vitamin D intake was assessed by a Food Frequency Questionnaire, and serum 25(OH)D3 levels were assessed in fasting blood samples by radioimmunoassay. In multivariable analyses, we observed the suggestion of an association between vitamin D from food sources and history of depression. For each 100 IU/day increase of dietary vitamin D there is a 13% decreased risk of depression (95% CI: 0.6, 1.2). However, total vitamin D intake (foods and supplements combined) was not associated with history of depression. Compared to women in the lowest tertile (median=51 nmol/L) of serum 25(OH)D3, women in the second tertile (median=72 nmol/L) had an 82% decreased risk of depression (95% CI: 0.04, 0.90; ptrend=0.008). The results of this study are consistent with vitamin D as a modifiable risk factor for depression and may inform intervention studies among college-aged women.

In einer Vielzahl von epidemiologischen Studien zeigten Patienten, die an einem idiopathischen Parkinson-Syndrom (IPS) erkrankt waren, erniedrigte Vitamin D-Serumspiegel (25-(OH)-Vit D). Die Rolle von Vitamin D im Knochenstoffwechsel ist weitgehend bekannt, allerdings konnten Assoziationen zwischen Vitamin D und chronischen Erkrankungen, die das Nervensystem sowie das kardiovaskuläre und immunologische System betreffen, nachgewiesen werden. In Tiermodellen konnten anti-oxidative Effekte von Vitamin D im Nervensystem gezeigt werden. In den letzten Jahren häuften sich allerdings Studien, die gegen einen direkten Zusammenhang zwischen IPS und Vitamin D sprechen. Demnach stellt sich die Frage, ob dem gehäuften Auftreten eines Vitamin D-Mangels bei IPS-Patienten eine krankheitsspezifische Ursache zugrunde liegt oder ob diese lediglich ein unspezifisches krankheitsbegleitendes Phänomen darstellt. In der vorliegenden Arbeit wurden in einer retrospektiven Analyse Parkinson-Patienten aus der neurogerontopsychiatrischen Tagesklinik sowie der neurogeriatrischen Frührehastation der Neurologischen Klinik der Universitätsklinik Würzburg hinsichtlich ihres 25-(OH)-Vit D-Serumspiegel mit zwei Kontrollgruppen bestehend aus Patienten mit psychiatrischer bzw. anderweitig neurologischer Erkrankung, die keiner Parkinson-Erkrankung entsprach, verglichen. Im Anschluss wurde auf mögliche Konfounder sowie der Zusammenhang zwischen IPS-Risiko bzw. Krankheitsschwere und 25-(OH)-Vit D-Serumspiegel untersucht. Der mittlere 25-(OH)-Vit D-Serumspiegel der Neurologie-Gruppe war im Vergleich zur Psychiatrie-Gruppe signifikant niedriger. Der Unterschied zwischen IPS-Gruppe und Psychiatrie- bzw. Neurologie-Gruppe war nicht signifikant. Bei Hinzunahme von weiteren rekrutierten Parametern (Body-Mass-Index, Frailty, Sturzanamnese, Gehhilfe, CHA2DS2-VASc-Score, C-reaktives Protein, Hämoglobin) konnte kein signifikanter Unterschied zwischen der Neurologie- und Psychiatrie-Gruppe mehr gefunden werden. Das Risiko sowie die Krankheitsschwere einer Parkinson-Erkrankung, gemessen am Hoehn-Yahr-Stadium und den erreichten Werten im MDS UPDRS III, korrelierten mit dem Vitamin D-Serumspiegel. Allerdings war auch hier nach Hinzunahme von Kovariaten wie Alter, Geschlecht und Krankheitsdauer der Effekt nicht mehr signifikant. Die Ergebnisse unterstützen die Annahme, dass die vorgefundenen niedrigen 25-(OH)-Vit D-Serumspiegel bei Parkinson-Patienten ein krankheitsbegleitendes Phänomen ist, das womöglich durch die eingeschränkten motorischen Fähigkeiten mit resultierend niedriger Sonnenexposition bedingt ist und durch zunehmende Kranheitsdauer und damit Krankheitsschwere verstärkt wird. Da es sich jedoch beim IPS um eine Krankheit handelt, die zum Einen mit motorischen Einschränkungen und resultierend erhöhtem Sturzrisiko einhergeht und zum Anderen vorwiegend Menschen höheren Alters betrifft, besteht ein erhöhtes Osteoporose- und sturzbedingtes Frakturrisiko, sodass ein Monitoring des Vitamin D-Serumspiegels sowie eine gegebenenfalls notwendige Vitamin D-Supplementierung weiterhin eine Rolle in der Behandlung von Parkinson-Patienten spielen. / A large number of primarily epidemiologic studies revealed low serum vitamin D in patients with idiopathic Parkinson’s disease (PD). The role of vitamin D in bone health is well-known, but there is also increasing evidence suggesting an association between vitamin D and chronic diseases affecting nervous, cardiovascular and immune system. Animal studies demonstrated antioxidative effects of pretreatment with vitamin D in central nervous system after exposure to neurotoxic substances. However, results of recent studies are inconsistent with prior findings as they could not show low vitamin D levels in PD. The objective of this study was to further evaluate the correlation between vitamin D and PD as there is the possibility of reverse causality: Either low vitamin D level as an independent factor is involved in the pathogenesis of PD or impaired physical mobility caused by the disease itself results in less sun exposure and therefore low vitamin D levels. This retrospective study examined serum vitamin D level of three patient cohorts affected by either PD, a psychiatric or neurologic disease other than PD. All groups were recruited from either the neurogerontopsychiatric day hospital or the early neurorehabilitation unit of the University Hospital Würzburg. Potential confounding variables were identified and vitamin D levels and risk as well as severity of PD using Part III of the Unified Parkinson’s Disease Rating Scale and Hoehn & Yahr Stage were examined. The prevalence of vitamin D insufficiency was higher in the neurologic cohort than in the PD and psychiatric cohort. After adjusting for potential confounding variables (Body mass index, frailty, history of falls, mobility devices, CHA2DS2-VASc-Score, C-reactive protein, hemoglobin) no statistically significant difference could be seen. In regard to PD risk and disease severity a correlation with vitamin D levels was also demonstrated but not significant after adjusting for confounders. The results of this study support the hypothesis that vitamin D level in patients with Parkinson’s disease is low because of disease- and frailty-mediated impaired mobility and consecutive reduced sun exposure. Therefore a disease progression with worsened motor symptoms can lower serum levels. In addition to the motor symptoms Parkinson’s disease occurs mostly in people of older age; thus, risk for fractures are higher in patients with PD compared to healthy controls. In summary, monitoring serum vitamin D levels and if required supplementation of vitamin D is still a necessary part in the treatment of Parkinson’s disease.

The main objective of this study was to measure the nutritional status of iron and vitamin D in varsity female athletes from the University of Ottawa and the possible relationship with their dietary patterns (mixed diet or plant-based diet). Among 63 athletes interested in participating, 17 completed the study. Nutritional intakes were assessed during sports season using two 24-hour recalls with the self-administered dietary assessment tool (ASA24). A blood sample was taken to measure indicators of iron and vitamin D status. The results revealed that 5% of the athletes suffered from vitamin D deficiency and as much as 47% had suboptimal vitamin D levels. No athletes suffered from iron deficiency anemia (IDA), but 26% had iron deficiency (ID). The vitamin D intake for 94% of athletes was below the estimated average requirements (EAR) and the use of supplements helped athletes attain the EAR. In contrast, 94% of athletes were able to meet the EAR for iron and the use of supplements caused athletes to exceed upper limits (UL). Lastly, due to the small number of plant-based athletes recruited, it was not possible to establish any relationships with this dietary pattern.

Vitamin D is important to the health of college students. The objective of our study was to measure sun exposure, skin pigmentation, vitamin D intake, and serum 25-hydroxyvitamin D (25[OH]D) in a subset of participants from The Following the Longitudinal Aspects of Student Health (FLASH) Study to determine the best predictors of 25(OH)D status. Participants were college-aged freshman who had their blood drawn in spring (Visit 1) and fall 2010 (Visit 2) at California Polytechnic State University (Cal Poly), San Luis Obispo, CA. (35.3°N). Vitamin D intake was measured using a 28-day food frequency recall questionnaire (specific to vitamin D foods and supplements) while questions specific to the frequency of milk and fish intake were accessed from the FLASH questionnaire. Sun exposure was measured using a 28-day recall questionnaire (time in sun and sun exposure index [SEI]) and questions (frequency of weekday/ weekend exposure) from the FLASH questionnaire. Skin pigmentation was measured using a reflectance spectrophotometer. Serum 25(OH)D was measured at a local pathology lab as measured by an IDS-iSYS. Means (SD) were as follows (n= 40): reflectance of the forehead was 61 (3.5) L* (Lightness) for Visit 1 and 61 (4.3) L* for Visit 2. Vitamin D intake was 308 (234) IU for Visit 1 and 316 (257) IU for Visit 2. Time outside was 81 (44) mins for Visit 1 and 76 (39) mins for Visit 2. Serum 25(OH)D was 85 (24) nmol/L for Visit 1 and 113 (28) nmol/L in Visit 2 which was significantly higher (p < 0.0001). The SEI was 53 (38) body surface area (BSA) exposed (m2) x mins for Visit 1 and 55 (34) m2 x mins Visit 2. Although 90% of participants in Visit 1 and 88% in Visit 2 were below the RDA guidelines for vitamin D intake (600 IU/day), 5% of participants in Visit 1 and none in Visit 2 had serum 25(OH)D serum levels < 50 nmol/L (the recommended level of sufficiency for bone health), demonstrating the importance of sun exposure to vitamin D status in these college students. To determine the strongest predictors of status we used regression analysis to predict serum 25(OH)D with skin reflectance, vitamin D intake, and sun exposure. We found that weekend sun exposure, fish intake, and forehead skin reflectance were the strongest predictors of serum 25(OH)D (R2= 0.50, p= 0.0010) demonstrating that simple questionnaires can help to predict serum 25(OH)D status.

<p> Background: Vitamin D activity is important for the functioning of a broad range of body systems. Some of these, including the skeletal, immune, and cardiovascular systems, are particularly relevant in the management of HIV-infection; thus, and in consideration of evidence that factors associated with the scenario of HIV-infection can disrupt vitamin D metabolism, the assessment of vitamin D status in people living with HIV-infection may be particularly important. In this thesis, I address cardiovascular implications of vitamin D status in HIV-infection. More specifically, and based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), I hypothesized that in HIV-positive adults low 25-hydroxyvitamin D (25(0H)D) concentration would be associated with increased subclinical vascular disease as measured by carotid intima-medial thickness (IMT).</p> <p> Methods: Using regression analyses I cross-sectionally studied the relationship between 25(0H)D and carotid IMT in 283 participants of the Canadian HIV Vascular Study, a prospective study of CVD risk among HIV-positive Canadians.</p> <p> Results: The prevalence of vitamin D deficiency in the Canadian HIV Vascular study was surprisingly low. Plasma 25(0H)D by quartile was not associated with carotid IMT. However, in restricted cubic spline regression analyses designed to accommodate non-linearity there was evidence of an inverted U-shaped 25(0H)D-carotid IMT relationship. In exploratory regression models restricted to participants comprising the suboptimal range of vitamin D status, lower 25(0H)D concentration was statistically significantly associated with lower carotid IMT after adjustment for known CVD risk factors and other variables hypothesized to potentially confound a 25(0H)D-carotid IMT association.</p> <p> Main implication: While inference from these exploratory findings requires cautious interpretation, future investigations into the relationship between vitamin D status and vascular disease should consider the problem of non-linearity as a feature of primary analyses; otherwise, such studies might fail to detect a true association.</p> / Thesis / Master of Science (MSc)

Exercise and diet may preserve muscle mass and bone health, thereby preventing age-related functional decline among older community-dwelling subjects. We used data from two studies to examine effects of exercise administered through a home-based program for hip fracture patients and the effects of dietary protein, vitamin D, and calcium on physical functioning in older adults. In the Health and Independence Post-Rehabilitation (HIP) study, the effects of a home-based exercise program (vs. attention-based control) (n=232) on functional recovery following hip fracture was assessed using two standardized physical performance batteries. In a sub-analysis (n=56), we evaluated the effects of food frequency questionnaire-derived protein, calcium, and vitamin D intakes on these outcomes. In the Framingham Offspring Study (FOS), dietary protein, calcium, and vitamin D intakes were measured using two sets of 3-day diet records. Physical functioning over 12 years was measured using the Rosow-Breslau and Nagi scales. In the HIP study, the exercise intervention led to significant improvement in physical performance at 6 months for all primary endpoints [(SPPB (P<0.001), AMPAC Mobility Function (P=0.01) and Daily Activity (P=0.01). However, we found no beneficial effects of dietary protein, calcium, or vitamin D on physical functioning. In the FOS, Cox proportional hazard’s models were used to estimate risk of functional decline over 12 years, adjusting for potential confounding by age, sex, education, physical activity, cigarettes per day, height, and energy intake. Subjects consuming ≥ 1.2 gm/kg protein intake (vs <0.8 gm/kg) had a lower risk of becoming dependent the following tasks: heavy work at home; walking one-half mile; climbing stairs; stooping, kneeling, crouching; lifting >10 lbs, lifting <10 lbs. Subjects consuming ≥ 1.2 (vs <0.8) gm/kg/day of protein had a 41% lower risk of becoming dependent in ≥1 functional task over 12 years. The beneficial effect of higher protein intake was strengthened among subjects who were more active and had higher SMM. There was also evidence of a beneficial interaction of both vitamin D and calcium with physical activity and SMM. These results suggest that participation in home-based functional exercise in older post-hip fracture adults and higher intakes of dietary protein help to preserve functional capacity among community-dwelling older adults.