Vitamin D deficiency at Middenbeemster and Hattem is the result of cultural variables that limit an individual’s exposure to sunlight. During growth spurts, such as the pubertal growth spurt, high demand for vitamin D puts individuals at an increased risk for developing conditions such as rickets. This thesis aims to determine whether adolescent rickets can be identified in archaeological skeletal remains, and how to quantify the observed changes. The current work also aims to use the prevalence of adolescent rickets to understand the underlying social changes affecting individuals in the Netherlands in the 17th to 19th centuries. Two collections of archaeological human remains from the 17th to 19th century Dutch sites of Middenbeemster (n=246) and Hattem (n=117) were evaluated using macroscopic, metric, radiographic, and micro-CT analysis of skeletal remains. Adolescent individuals were evaluated for signs of active adolescent rickets, and adults were evaluated for signs of residual adolescent rickets. Statistical analysis found that measurements quantifying shape changes at the distal ulna, medial clavicle, and sacral angle can be used to identify adolescent rickets in a skeletal sample. Adolescent rickets at Middenbeemster and Hattem was found to be distributed equally amongst males and females and was found to occur less frequently than rickets in infants and children from the same population. Rickets in adolescents was most likely caused by the onset of new jobs or roles resulting in individuals remaining indoors for long periods of time. Rickets may have also been caused by illness. By identifying rickets in adolescents, this thesis provides a window to view the changing roles of individuals as they begin to occupy new spaces in their transition from children into adults, thus providing a novel way to investigate the lives of adolescents. / Thesis / Master of Arts (MA)

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京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24551号 / 薬科博第168号 / 新制||薬科||18(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 金子 周司, 教授 竹島 浩, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Background: Osteoporosis is estimated to affect 200 million women in the world, affecting 10% of women aged 60, 20% of women aged 70, 40% of women aged 80 and 67% of women aged 90. Osteoporosis is characterized by low bone density and increases the risk for fractured bones; however, it may be prevented with modifiable factors such as supplements, diet, and physical activity. Vitamin D deficiency leads to bone mineral density loss, as Vitamin D3 is responsible for calcium absorption into the bones. Bone consolidation is believed to occur between 20 and 30 years old; thus, attaining peak bone mass is critical during pre-menopause. Methods: The relationship between vitamin D and bone mineral density has predominately been studied in postmenopausal populations. Therefore, we examined this association among 18-30 year old participants (n=271) in the cross-sectional UMass Vitamin D Status Study. The modified version of the Harvard Food Frequency Questionnaire was used to assess the average intake of vitamin D foods and supplements. Serum 25(OH)D3 concentrations were assayed from blood samples. Bone mineral content and bone area were measured by dual-energy X-ray absorptiometry scan. Bone mineral content (BMC), as measured in grams, provides a measure of bone mass. Bone area (BA), as measured in cm2, reflects a two-dimensional area, which is characterized by the periphery of a bone region. We used multivariable linear regression to model the relationship between bone mineral density and bone area with sources of vitamin D after adjusting for dietary and lifestyle factors. Results: In the present study, the mean and standard deviation of vitamin D is 372.7 IU and 285.8 IU, respectively. For vitamin D from supplements, the mean is 140.9 IU with a standard deviation of 232.3 IU. Finally, for vitamin D from food, the mean is 231.8 IU with a standard deviation of 182.0 IU. Compared to reference values of 600 IU, these data are below the recommended daily allowance. We did not observe an association between total vitamin D or vitamin D from foods sources with either BMC or BA. We also did not observe an association between serum 25-hydroxyvitamin D levels and BMC or BA. Conclusion: Future studies with larger sample sizes are warranted to validate this association among young premenopausal women.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Vitamin D plays a vital role in modulating both innate and adaptive immune systems. Therefore, vitamin D deficiency has been associated with higher levels of autoimmune response and increased susceptibility to infections. CYP27B1 encodes a member of the cytochrome P450 superfamily of enzymes. It is instrumental in the conversion of circulating vitamin D (calcifediol) to active vitamin D (calcitriol). This is a crucial step for macrophages to express Cathelicidin Anti-microbial Peptide (CAMP), an anti-bacterial factor released during the immune response. Our recent study indicated that Crohn's disease (CD)-associated pathogen known as Mycobacterium avium paratuberculosis (MAP) decreases vitamin D activation in macrophages, thereby impeding cathelicidin production and MAP infection clearance. The mechanism by which MAP infection exerts these effects on the vitamin D metabolic axis remains elusive. In this study, we found that MAP infection interferes with vitamin D activation inside THP-1 macrophages by reducing levels of CYP27B1 and vitamin D receptor (VDR) gene expression via interaction with the TLR2-dependent p38/MAPK pathway. MAP infection exerts its effects in a time-dependent manner, with the maximal inhibition observed at 24 hours post-infection. We also demonstrated the necessity to have toll-like receptor 2 (TLR2) for MAP infection to influence CYP27B1 and CAMP expression, as TLR2 gene knockdown resulted in an average increase of 7.78±0.88 and 13.90±3.5 folds in their expression, respectively. MAP infection also clearly decreased the levels of p38 phosphorylation and showed dependency on the p38/MAPK pathway to influence the expression of CYP27B1, VDR, and CAMP which was evident by the average fold increase of 1.93±0.28, 1.86±0.27, and 6.34±0.51 in their expression, respectively, following p38 antagonism. Finally, we showed that calcitriol treatment, and p38/MAPK blockade reduce cellular oxidative stress and inflammatory markers in Caco-2 monolayers following macrophage-mediated MAP infection. In conclusion, this study characterized the primary mechanism by which MAP infection leads to diminished levels of active vitamin D and cathelicidin in CD patients, which may explain the exacerbated vitamin D deficiency state in these cases.

As productive performance is improved by breed selection, amino acid requirements may change to support this higher performance in poultry. The first objective of this dissertation was to update the valine and tryptophan requirement of small-framed laying hens and the lysine requirement of young broilers using empirical dose-response methods. The tryptophan requirement was estimated as 155.8 mg/d for egg mass, 153.2 mg/d for egg production and 140.4 mg/d for feed conversion ratio using a linear broken line model. For valine, the requirement was highest for egg mass, 597.3 mg/d, followed by egg production, 591.9 mg/d and feed conversion ratio (FCR), 500.5 mg/d. The lysine requirement of young chicks was estimated by conducting four short term experiments from 1 to 3, 3 to 5, 5 to 8 and 8 to 11 days of age, respectively. The lysine requirement from 1 to 3, 3 to 5 and 5 to 8 days of age were not able to be estimated as no dose response was observed on growth performance most likely due to an overestimation of the lysine requirement. Digestible lysine requirement from 8 to 11 days of age was 1.057%, 1.050% and 1.016% based on body weight gain, FCR and pectoralis major weight using a linear broken line model, respectively. In addition to determining amino acid requirements, research was conducted to develop a new bacterial protein meal for use in laying hens diets. The data suggested that diets containing 7.5% of the bacterial protein meal was able to at least maintain egg production in laying hens, but 15% bacterial protein meal resulted in reduced performance. The second objective of this dissertation was to investigate the effects of various concentrations of dietary vitamin D3 on pullet and laying hen performance, eggshell quality and bone health in laying hens. Pullets/hens were randomly assigned to five dietary treatments containing vitamin D3 from 1,681 to 68,348 IU/kg diet from day of hatch until 68 weeks of age. These data suggested that dietary vitamin D3 fed at 68,348 IU/kg resulted in reduced egg production, but vitamin D from 8,348 to 35,014 IU/kg diet maintained egg production, increased egg vitamin D content in a dose dependent manner, and generally increased both eggshell quality and pullet and hen bone mineral status. / Ph. D. / The goal of the poultry industry is to increase the efficiency of meat and egg production. To achieve this goal, laying hens with higher egg production and broilers with faster growth rates are genetically selected over time. By breed selection, laying hens are able to produce 2-3 additional eggs every year. The body weight of a broiler chicken raised today is approximately four times greater than one raised to the same age in 1958. This Increased egg production and body growth requires a higher nutrient intake, especially amino acids, to support protein production. One objective of this dissertation was to update the requirement of three amino acids (valine, tryptophan and lysine) in poultry production to provide current and accurate information to poultry producers. Valine, tryptophan and lysine are essential amino acids that cannot be synthesized by poultry in sufficient quanities and needs to be ingested from the diet. Three experiments were conducted to determine the valine and tryptophan requirement in laying hens and lysine requirement in broilers. The results of the current experiment show that a laying hen require at least 156 mg tryptophan and 597 mg valine per day to maximize egg production from 41 to 60 weeks of age. The broiler chicks need to ingest rations containing at least 1.06% lysine to support growth from 8 to 11 days of age. Bacterial protein meal is a feed ingredient that has been proposed for use in poultry diets. It is usually produced via the fermentation process by converting various substrates such as methane, methanol, or agriculture by-products into protein-rich biomass. The advantage of using bacterial protein meal in the poultry industry is to decrease feed cost and alleviate the demand on croplands. A novel bacterial protein meal, generated from waste water purification, was evaluated as a feedstuff for laying hens. Two levels of bacterial protein meal, 7.5 or 15%, were added to a regular laying hen diet to replace soybean. The results indicated that replacing soybean meal with 7.5% bacterial protein meal was a feasible solution for egg production but a 15% inclusion rate may result in a decreased egg production. During egg production, bone structural health can be reduced as laying hens age. This loss of bone structural health is due to the loss of bone mineral content, especially calcium and phosphorus, as laying hens produce the calcium rich eggshell. With age, decreased bone mineral mass will induce a higher probability of bone structural failure. Vitamin D plays an important role on calcium absorption and bone mineral deposition. In addition to benefits to skeletal health, the addition of vitamin D₃ in the diet will result in increased vitamin D₃ content in eggs used for human consumption. An experiment was conducted to evaluate the use of high concentrations of vitamin D to increase egg vitamin D content, improve eggshell quatility and increase hen skeletal health. The data suggest that adding vitamin D₃ from 8,300 to 35,000 IU/kg diet will increase egg viatimn D content, and generally improve eggshell and bone quality; however, adding vitamin D₃ at 68,000 IU/kg diet resulted in negative effects on pullet growth and subsequent egg production of adult hens.

Polycystic ovary syndrome (PCOS) is a complex disorder commonly affecting women of reproductive age. Diagnostic criteria include abnormal menstrual cycles, elevated androgens, and cystic ovaries, although insulin resistance is also common. PCOS puts patients at an elevated risk for complications such as type 2 diabetes and cardiovascular disease, so proper management of this condition is essential. It has been found that vitamin D deficiency is prevalent among the PCOS patient population, therefore, this study aims to evaluate the efficacy of vitamin D supplementation as a treatment for PCOS. A meta-analysis was performed using six randomized, placebo-controlled trials that each examined the effects of vitamin D administration in PCOS women compared to a control group. Subgroups of low doses (50,000 IU of vitamin D every 14 – 21 days) and high doses (50,000 IU of vitamin D every 7 days) were employed when possible. Analysis revealed that vitamin D significantly improved fasting plasma glucose and insulin resistance (HOMA-IR) when given in a low dose. Vitamin D also significantly improved insulin levels overall, although the low dose proved more effective. Insignificant yet marginal improvements were observed in total testosterone and insulin sensitivity (QUICKI). These results indicate that vitamin D can benefit some of the metabolic and endocrine parameters that are typically abnormal in PCOS. On this basis, health care providers are urged to test the vitamin D levels of their patients and encourage supplementation when deficiencies are present, as vitamin D may provide a low cost, low risk treatment to patients.

Bakgrund: Hjärtsjukdom är den vanligaste dödsorsaken i västvärlden. De senaste åren har forskare upptäckt kopplingar mellan D-vitaminbrist och en ökad risk att insjukna i hjärt-och kärlsjukdom. Ny forskning tyder på att D-vitamin är oerhört viktigt del i immunförsvaret och för vår hälsa på många olika områden. Idag pågår ett stort antal studier som undersöker om D-vitaminbrist kan vara en riskfaktor för att drabbas av olika sjukdomar såsom ökad infektionskänslighet, cancer, depression, diabetes samt hjärt- och kärlsjukomar etc. Den rekommenderade dosen D-vitamin har varit omdiskuterad de senaste åren och myndigheter höjer rekommendationerna i takt med nya upptäcker inom forskningen. Syfte: Att undersöka om D-vitamintillskott kan användas som en kortsiktig behandling mot hjärtsvikt orsakad av hypertoni eller kardiohypertrofi. Metod: Detta examensarbete är en litteraturstudie där vetenskapliga artiklar har sökts via databasen PubMed med sökorden: “Vitamin D”,“heart failure”,”heart disease”. Av de artiklar som kunde erhållas så inkluderades sökresultaten till observationsstudier och kliniska studier. I de kliniska studierna varierade doserna mellan 100-400 g/dag. Slutligen valdes 6st studier ut och granskades noggrant. Dessa studier är sammanfattade i Tabell VI & Tabell VII. Resultat: Det kliniska randomiserade studierna visade att D-vitamin hade en statistisk signifikant reducerande effekt på det systoliska blodtrycket, parathormon (PTH), aldosteron koncentrationen, Brain natriuretic peptide (BNP) och C-reaktivt protein (CRP). Observationsstudierna visade att D-vitaminbrist kan leda till hypertoni, hjärt -och kärlrelaterade sjukdomar och kardiohypertrofi. Enligt observationsstudierna är D-vitaminbrist en oberoende markör för ökad mortalitet. D-vitaminbrist visade sig även kunna leda till en längre sjukhusvistelse hos både HF patienter och övrig population. De upptäckte även att HF patienter i regel har lägre D-vitamin koncentration än övrig population.   Diskussion: De kliniska randomiserade studierna har många brister i sin studiedesign. Det är inte tillräckligt stora med enbart 23-100st deltagare. Alla deltagare hade ej en uttalad D-vitaminbrist från studiens början, effekt av behandling blir därför svår att utreda. Observationsstudierna har sina redan kända brister och det är svårt att utreda ett orsakssamband. Det har gjorts för få studier för att säkert kunna besvara frågan om D-vitamins koppling till uppkomst av hjärt- och kärlsjukdom. Ännu fler, större, längre och noggrannare studier behövs. D-vitamins verkningsmekanism i kroppen behöver också utredas vidare. Studierna visade på en viss koppling mellan D-vitaminbrist och risken att drabbas av hjärt-och kärlsjukdom. Även om vissa samband kan observeras så har denna eventuella effekt idag ännu inte kunnat bekräftas i kliniska studier. Då vetenskapliga bevis fortfarande saknas kan D-vitamintillskott ännu inte rekommenderas som behandling mot hjärt-och kärlsjukdom. / Background: Heart disease is the leading cause of death among people in the northern countries. It is also very common with vitamin D deficiency. The geographical position affects the availability of UVB radiation and people avoid sunlight because of the risk of getting malign melanoma and other types of skin cancer. New research have shown that vitamin D is very important for us and vitamin D deficiency may play a role in many diseases such as depression, infection, autoimmune and cardiovascular diseases. This particular subject is still unexplored and more research have to be done to investigate vitamin D role in these diseases. The Vitamin D recommended dose have been questioned for many years and the agencies have been raising the recommended dose and is still investigating the subject. Objective: The aim of this study is to investigate if vitamin D supplements may decrease the risk of heart failure (HF). Methods: This bachelor thesis is a literature review. Article search is made in the database PubMed in February 2017 by using the keywords “vitamin D/heart disease/heart failure”. Inclusion criteria were clinical, controlled, randomized trials on human and observation studies, written in English.  Results: Six studies were chosen for this bachelor thesis, three of the studies are clinical randomized and three of the studies are observation studies. The doses given in the clinical studies varies between 100-400 g/daily. The clinical studies did find some statistic significant reduced effect comparing baseline with after treatment with vitamin D in the systolic blood pressure, aldosterone, PTH, EF%, CRP and BNP. The observation studies did find a correlation between vitamin D deficiency and a decreased risk getting hypertension and cardio hypertrophy. They also observed that vitamin D deficiency was common in HF patients. The observation studies also found that vitamin D deficiency is an independent predictor of increased mortality in patients with HF.     Conclusion: In the clinical studies the population was small and the time for the treatment was highly limited only 4 or 6 months. The treatment dose of Vitamin D was not a standard dose because it varied between the studies which made it hard to compare the results. The observation studies have its known limitations. It is hard to tell if patients with HF have vitamin D deficiency because they spend more time inside than healthy people. May the sickness cause some reaction in the body that leading to vitamin D deficiency or does vitamin D deficiency cause HF. Because lack of good quality in these six studies they have failed to show convincing results and correlation between vitamin D deficiency and HF. It is necessary with larger controlled, study over long time, randomized trials to investigate whether vitamin D deficiency can cause heart failure. More research has to be done.

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