1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate

Stroke is now a well-recognised risk factor for hip fracture. The aim of this study was to elucidate the pathophysiological mechanisms by which hip bone loss occurs in hemiplegia and to test the efficacy of a novel pharmaceutical strategy for preserving bone in stroke patients. Patients who were admitted acutely with a first-ever stroke and who remained unable to walk one week later were studied prospectively for 12 months, with a series of bone mineral density measurements of the hips (dual energy X-ray absorptiometry) in the context of a randomised controlled trial. Untreated patients (n=13) experienced a decline in bone mineral density at the hemiplegic hip that was rapid, with the greatest losses in the trochanteric region of the affected side. This bone loss was prevented by the administration of a single 4 mg dose of the intravenous bisphosphonate, zoledronate (n=14) within 35 days of stroke onset. Computed tomography of the hips in 8 untreated patients more than a year after stroke confirmed that the greatest difference between sides was in the trochanteric region. Serum vitamin D measurements in 44 patients with acute stroke were substantially lower than healthy elderly controls, with 77% of patients in the insufficient range, suggesting that vitamin D insufficiency preceded stroke. Histomorphometric analysis of iliac bone biopsies from hemiplegic patients 10 weeks following stroke showed normal erosion parameters, but a striking decrease in the surface extent of osteoid when compared with healthy reference values. Unexpectedly, treatment with zoledronate was associated with a significantly higher osteoid surface compared with placebo treated subjects in cancellous, endocortical and cortical bone. Sclerostin, a newly discovered osteocyte-derived protein was studied using immunohistochemical staining of the bone biopsies. Sclerostin is known to be an inhibitor of active osteoblasts, which led to the hypothesis that in stroke, the proportion of osteocytes expressing sclerostin would be inversely associated with the surface extent of bone formation. Histological analysis revealed widespread expression of sclerostin in osteocytes and their canaliculi in all subjects. However, examining individual osteocytes in relation to bone forming surfaces revealed that newly embedded osteocytes did not express sclerostin until after primary mineralisation. It is proposed that this precise pattern and timing of sclerostin expression by osteocytes allows bone formation to continue locally (during remodelling), but prevents excessive new bone formation elsewhere, as seen in the single gene disorder sclerosteosis.

Menopause is an important period for bone health in women. Objective: To assess the determinants of bone mineral density (BMD) changes in women transitioning to menopause. Method: A secondary data analysis of the MONET (Montreal-Ottawa New Emerging Team) study. Outcome measures included yearly assessment of menopause status, body composition, BMD, physical activity energy expenditure (PAEE) and dietary calcium and vitamin D intakes. Results: 84 of the original 102 women had complete data for the purpose of the present study. Repeated measures analysis revealed significant decreases in lumbar spine and femoral neck BMD (P< 0.01). Regression analysis revealed that baseline femoral neck BMD, changes in PAEE and trunk fat explained 31% of the variation of BMD changes at the femoral neck, while changes in both PAEE and trunk fat account for 27% of BMD change at lumbar spine. Conclusion: Baseline femoral neck and changes in physical activity energy expenditure and trunk fat are determinants of the reduction of bone mineral density in women transitioning to menopause.

60 % of Canadians have suboptimal vitamin D (<75 nmol/L) and 25% are obese. Obesity has been reported to be a risk factor for low vitamin D, but there is uncertainty about the magnitude of the association. Linear regression was performed using data from the nationally representative cross-sectional Canadian Health Measures Survey (2007-2009). Height, weight, waist circumference (WC), and vitamin D levels were directly measured. There were 5298 participants aged 6 to 79 years. Using a conservative p value of 0.001, body mass index (BMI) category obese / obese I was positively associated and WC was inversely associated with vitamin D level in crude analysis. WC was inversely associated with vitamin D level in multivariate analysis. The pattern of relationship is not the same as other studies, yet this was a large study with direct measurements. There may be issues with linearity of relationships or subgroups disturbing the relationship.

L’obésité s’accompagne d’un état inflammatoire chronique qui joue un rôle délétère.Cet état associé à l’obésité été impliqué dans le développement de complications métaboliques:insulino-résistance et DT2.Chez les obèses,le TA est un site de production de médiateurs pro et/ou anti-inflammatoires, des adipokines.Les modifications et changements de style de vie et les approches thérapeutiques sont privilégiés pour lutter contre l’obésité.Toutefois,les approches préventives ne doivent pas être négligées,des études épidémiologiques ont mises en évidence une corrélation entre obésité et carence en micronutriments.Par ailleurs,il existe une corrélation inverse entre micronutriments lipophiles et caroténoïdes et la prévalence de l’obésité et du DT2.Le but de cette thèse est de comprendre le lien qui existe entre carence en micronutriments,obésité et complications associés.Une étude clinique transversale a été réalisée chez des obèses non diabétiques.Les résultats nous ont permis de montrer qu’il existe une association positive entre b-carotène et sensibilité à l'insuline chez l'obèse,effet pouvant être lié à une modulation de l'expression de certaines adipokines dont l'adiponectine qui est indépendamment associée à la concentration plasmatique en b-carotène.Une étude préclinique a été menée, dont l'objectif évaluer l'impact de la teneur en vitamines alimentaires sur la prise de poids et l'insulino-sensibilité.Des souris ont été soumises à un régime hypovitaminé.A 10 semaines,ce régime favorise la prise de masse grasse,modifie la sensibilité à l'insuline,en agissant au niveau du métabolisme lipidique hépatique,via une diminution des capacités oxydatives. / Obesity is associated with chronic inflammatory condition that plays a deleterious role.This inflammatory state associated with obesity was involved in the development of metabolic complications : insulin resistance and T2DM.Obese, AT is a site for the production of pro and/or anti-inflammatory adipokines, and plays a major role in the development of chronic inflammation associated with obesity.Modifications and changes in lifestyle and therapeutic approaches are preferred to deal with obesity. However,preventive approaches should not be ignored,several epidemiological studies have shown a correlation between obesity and micronutrient deficiency.In addition,there is an inverse correlation between lipophilic micronutrients and carotenoids and the prevalence of obesity and T2DM.The purpose of this thesis is to understand the possible link between LM and carotenoids deficiency, obesity and associated physiological disorders.A cross-sectional study was performed in non-diabetic obese patients.The results allowed us to conclude the existence of a favorable effect of b-carotene on insulin sensitivity in obese patients.This effect may be related to modulation of inflammation or the expression of some adipokines(such as adiponectin), either directly or through its pro-vitamin A activity.A preclinical study was performed; the objective is to assess the impact of the vitamins on weight gain and insulin sensitivity.Mice were subjected to a hypovitaminic diet.After 10 weeks of regimen, we observed an increased adiposity and an altered insulin sensibility.This diet probably acts on the hepatic lipid metabolism via a decrease in oxidative capacity.

Bakgrund: Sjukdomar i cirkulationsorganen är den vanligaste dödsorsaken i Sverige följt av tumörsjukdomar. År 2019 stod tumörsjukdomarna för hela 27% av dödsfallen. Epithelial-mesenchymal transition (EMT) är en process då epitelceller de-deffinerentierar till celler med en mesenkymal fenotyp. Vid denna process mister cellerna sin polaritet och cell-cell-kontakt. Cellerna får även en ändrad morfologi, från en rektangulär form till mer utsträckta och oregelbundna former. Processen möjliggör att cellerna får migrerande och invasiva egenskaper. EMT behövs för att cancercellerna ska kunna sprida sig från den primära tumören och bilda metastaser/dottertumörer på andra ställen i kroppen. Det är välkänt att Transforming Growth Factor beta (TGF-b) kan framkalla EMT. TGF-b kan stimulera tumörutvecklingen på många olika sätt, där ett av dessa sätt är genom att stimulera EMT. Andra studier har visat att kalcitrol, som är den aktiva formen av vitamin D, kan hämma TGF-b förmåga att driva tumörutveckling.   Syfte: Syftet är att undersöka om vitamin D kan motverka TGF-b orsakat EMT.    Metod: Data hämtades från databasen PubMed. För att finna relevanta studier användes sökorden Vitamin D, TGF-beta, EMT, Cancer tillsammans med sökkriterier. Inklusionskriterna var vetenskapliga orginalartiklar, artiklar i full text samt skrivna på språket engelska. Exklusionskriterierna vara artiklar äldre än 10 år.   Resultat: När humana cancerceller behandlades med vitamin D resulterade det i minskad EMT. Förändrat EMT kunde påvisas genom minskad migration och invasion samt ökning av epitela egenskaper. Vitamin D minskade cellmigrationen på ett tids- och dosberoende sätt. In vitro-testerna indikerade på att i cellkultur av cancerceller verkar vitamin D genom att motverka EMT, både i närvaro och i frånvaro av TGF-b. När EMT-programmet däremot redan initerats m.h.a. TGF-b kan inte längre vitamin D motverka att cellerna genomgår EMT.   Slutsats: Intag av vitamin D före och under TGF-b-signalering har ett positivt resultat på EMT-programmet.

INTRODUCTION: The inflammation observed in patients with IBD can negatively impact the intake or absorption of vitamin D. This can increase the risk of disease relapse, impact patients’ quality of life, and increase the risk of IBD related surgeries. In addition to the traditional observation that vitamin D deficiency may be a comorbid manifestation of IBD, there is now growing evidence pointing to serum vitamin D levels as a pathogenic factor contributing to the initiation and propagation of mucosal inflammation in patients with IBD. It is well-established that variation in clinical practice leads to less optimal outcomes in any clinical setting. The relative scarcity of clinical and translational studies is even more pronounced in the pediatric population. OBJECTIVES: The primary objective of this study is to quantify the prevalence of clinician assessment of vitamin D levels in pediatric patients with IBD. We will also look at this behavior in subpopulations and compare their vitamin D status. It is secondary for this study to also describe variations in physician practices with respect to the testing and treatment of vitamin D deficiency at a single tertiary care IBD Center. METHODS: We conducted a retrospective cohort study on consecutive patients with UC, CD, and ID, that were followed in the ambulatory program in the Center for Inflammatory Bowel Disease at Boston Children’s Hospital from 1/1/2014 to 12/31/2014. We identified 498 patients and collected their demographic information, serologic testing, and physician prescribing behavior. RESULTS: Out of the entire population, 64% of the patients were vitamin D deficient (vitamin D level below 32 ng/ml). 24% of the patients received vitamin D supplementation. Vitamin D deficiency was less prevalent in patients with UC than those with CD, with an OR of 0.64 (95% CI 0.43-0.94). Out of the ones receiving supplementation, 37% of them were deficient. In terms of physician practice trends, 62% of the patients were not formally prescribed supplementation. 14.5% of those who were prescribed supplementation were receiving 50,000 IU weekly, and the rest receiving 400 – 2,000 IU daily. Patients with vitamin D levels below 20 ng/ml were more likely to receive the high dose vitamin D prescription (OR 11.5) than those with levels between 20 and 30 ng/ml (OR 5.7). CONCLUSIONS: Our study suggests that despite high prevalence of vitamin D deficiency in pediatric patients with IBD, there is a lack of consensus with respect to the assessment of vitamin D levels and consistency in prescribing vitamin D supplementation. With the potential role that vitamin D plays in IBD pathology and suggestions of the therapeutic effects of vitamin D supplementation, further studies are needed to explore this area.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22000号 / 医博第4514号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 竹内 理, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with outcomes that include hepatobiliary malignancy and liver transplantation. The pathogenesis of PSC is incompletely understood and, as a result, few markers of disease progression have been identified. Vitamin D is associated with the development and treatment of multiple cancers as well as the progression of inflammatory bowel disease, making it a possible candidate as a biomarker associated with PSC outcomes. In this study, we retrospectively and prospectively collected complete laboratory results and outcome datapoints on 179 patients with PSC to determine the association between total 25(OH)-vitamin D levels, vitamin D supplementation, and both hepatobiliary malignancy and liver transplantation. Through survival analysis, we found that history of vitamin D supplementation was significantly associated with increased hepatobiliary malignancy-free and liver transplantation-free survival (p=0.025 and p=0.042, respectively). These results indicate that vitamin D is a promising factor associated with the progression of PSC to transplantation and malignancy. Future studies on this registry cohort as it increases in size and age may provide more conclusive data on the relationship between vitamin D and PSC.

Introduction: Osteoporosis is one of the most frequent bone metabolic disease. It is a systemic metabolic skeleton disease, where the architecture of bone tissue is damaged due to the loss of bone mass, and therefore the bone quality is reduced. Thus, it comes to increased bones fragility and reduction in mechanical resistance, which leads to a higher risk of fractures. The principle of pathogenesis is an imbalance between resorption and bone formation. Due to increasing lifetime and lifestyle changes, the prevalence of the disease increases. Aim: The aim of the practical part of the diploma thesis is to evaluate the eating habits of postmenopausal women treated for osteoporosis and to evaluate their nutritional condition in relation to bone mineral density (BMD). Methods: Nutritional habits were obtained and evaluated through a questionnaire survey. Three-day meal records were collected and analysed using the Nutriservis Profesional nutritional software, to determine the energy intake and selected nutrients. Osteodensitometric data were measured using dual emission X-ray absorptiometry (DXA). Results: The analysis of the diet showed that the observed group of women consumes an excessive amount of energy on average, especially in form of fats. Higher intake of protein was also observed....