Receptor interacting protein kinase 1 (RIPK1) is an enzyme acting downstream of tumor necrosis factor alpha to control cell survival and death. RIPK1 expression has been reported to cause drug resistance in cancer cells; but so far, no published studies have investigated the role of RIPK1 in vitamin D action. In the present study, we investigated whether RIPK1 played any role in 1,25-dihydroxyvitamin D3 (1,25D3)-induced growth suppression. In our studies, RIPK1 decreased the transcriptional activity of vitamin D receptor (VDR) in luciferase reporter assays independently of its kinase activity, suggesting a negative role of RIPK1 in 1,25D3 action. RIPK1 also formed a complex with VDR and deletion analyses mapped the RIPK1 binding region to the C-terminal ligand-binding domain of VDR. Subcellular fractionation analyses indicated that RIPK1 increased VDR retention in the cytoplasm, which may account for the inhibition of VDR transcriptional activity. Consistent with the reporter analyses, 1,25D3-induced growth suppression was more pronounced in RIPK1-null mouse embryonic fibroblasts (MEF) and RIPK1 knockdown ovarian cancer cells than control cells. We have also shown that VDR was involved in RIPK1-mediated cell death pathway in a cell line specific manner. In vivo study showed that VDR deletion delayed the necroptotic response to tumor necrosis factor alpha in mice. Western blot analyses of platinum sensitive and resistant cell lines showed a correlation between RIPK1 expression and drug resistance, suggesting a possible role of RIPK1 in drug resistance. In conclusion, this study is the first to define RIPK1 as a VDR repressor, projecting RIPK1 depletion as a potential strategy to increase the potency of 1,25D3 and its analogs for cancer intervention.

Background: With usual supplementation practices, most children are Vitamin D Deficient (VDD) following Congenital Heart Disease (CHD) surgery and alternative regimens need consideration. Methods/Results: i) A systematic review identified 88 pediatric trials of high dose vitamin D. Studies evaluating the Institute of Medicine (IOM) Tolerable Upper Intake Level (UL) did not rapidly normalize levels, while loading therapy (≥ 40000 IU) did so within 3 days. Hypercalcemia occurred more often with doses above 400000 IU. ii) A double blind RCT was designed to determine whether pre-operative administration of the IOM UL can prevent post-operative VDD. Results after the first 30 participants completed study procedures demonstrated it was possible to recruit (1.8 patients per month) and complete study procedures (i.e. blood collection). Unfortunately few participants (45%) received more than 30 doses of study drug. Conclusion: Prevention of post-operative VDD in the majority of CHD patients will require alternatives to the IOM recommendations.

The accurate assessment of human diabetic somatic polyneuropathy (DSPN) is important to define at risk patients, predict deterioration, and assess the efficacy of pathogenetic treatments. Corneal confocal microscopy (CCM) has been proposed as a surrogate endpoint for DSPN. Approximately 50% of patients with DSPN experience neuropathic pain or symptoms and the underlying reasons are not clearly elucidated. Vitamin D deficiency has been associated with diabetic complications including DSPN and diabetic retinopathy (DR). However there is a paucity of data regarding the interaction of vitamin D status with diabetic complications. This thesis shows that CCM can readily detect small fibre neuropathy prior to large fibre involvement and assess rapidly progressive nerve fibre loss prior to conventional thermal threshold testing. CCM has a superior diagnostic capabilities compared to intra-epidermal nerve fibres and correlates better with nerve conduction studies. Patients with LADA have a greater prevalence of small fibre neuropathy compared to matched patients with type 2 diabetes. Vitamin D deficiency is highly prevalent in patients with diabetes and despite relatively aggressive replacement regimens are inadequate in raising vitamin D levels in a significant proportion of patients. Vitamin D deficiency is not associated with DR but there is a strong association between painful DSPN and vitamin D insufficiency and more so with overt deficiency.

Orientadores: Denise Engelbrecht Zantut Wittmann, Sarah Monte Alegre / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-28T02:28:01Z (GMT). No. of bitstreams: 1 Botelho_IlkaMaraBorges_M.pdf: 1340793 bytes, checksum: 6ef5a41b67a7eddca52fc55dea2f96d4 (MD5) Previous issue date: 2014 / Resumo: Introdução: Vitamina D tem sido apontada como importante regulador da resposta imune. Estudos tem demonstrado haver relação entre insuficiência de vitamina D e presença de doenças autoimunes como Tireoidite de Hashimoto (TH). É possível que o processo autoimune na TH seja inibido em diferentes estágios pela vitamina D em sua forma ativa. Nossos objetivos foram estudar a prevalência de insuficiência de vitamina D e a relação de suas concentrações séricas com marcadores de função e autoimunidade tireoideana. Material e Métodos: Amostras de sangue foram coletadas de 54 pacientes com TH e 54 indivíduos saudáveis sem diagnóstico de TH com idade entre 18 e 75 anos. Foram realizadas dosagens séricas de vitamina D (25OHD), TSH, T4 livre, cálcio, fósforo, paratormônio (PTH), anticorpos anti-tireoperoxidase (AcTPO), anti-tireoglobulina (AcTG) e anti-receptor de TSH (TRAb). Volume tireoideano foi estimado por ultrassonografia. Foram coletados dados demográficos, de peso, altura, índice de massa corporal (IMC) e tempo de diagnóstico. Pacientes e indivíduos do grupo de controle foram pareados por idade e sexo. O nível de significância estatística adotado foi 5%. Resultados: Prevalência de insuficiência de vitamina D foi encontrada em 68.5% dos pacientes e em 38.9% dos indivíduos do grupo de controle (p =0,002). Houve uma correlação positiva entre níveis de AcTPO e maior volumetireoideano nos pacientes (r = 0,319; p= 0.019). Não houve correlação entre concentração de vitamina D, TSH, T4livre,TRAb, AcTGe volume tireoideano. Conclusões: Demonstramosmaior prevalência deinsuficiência de vitamina Dem pacientescom tireoidite de Hashimotoem relaçãoa indivíduos de um grupo controlesaudável, não havendo correlaçãocom o estado hormnal tireoideanooumarcadores séricos deautoimunidadeda tireóide.Por sua vez, maior volume da tireóidese associou a maior grau de infiltração inflamatóriaautoimune,refletido pelacorrelaçãocom maiores concentrações AcTPO / Abstract: Introduction: Vitamin D has been pointed out as an important immune response regulator. Studies have shown a relationship between vitamin D insufficiency and the presence of autoimmune diseases such as Hashimoto's Thyroiditis (HT). It's possible that the autoimmune process in HT is inhibited in its different stages by vitamin D on its active form .Our aims were to study the prevalence of vitamin D insufficiency and relationship of the serum concentrations with thyroid function and autoimmunity markers. Material and Methods: Blood samples were collected from 54 patients with HT and 54 healthy individuals without a diagnosis of HT, aged 18 to 75 years. We conducted serum 25OH vitamin D, TSH, free T4, calcium, phosphorus, PTH, TPOAb, TgAb and TRAb. Thyroid volume was estimated by ultrasound. Data on demographic, weight, height, body mass index and time since diagnosis were collected. Patients and control subjects were matched by sexand age. The significance level for statistical analysis was 5%. Results: Prevalence of vitamin D insufficiency was found in 68.5% of patients and in 38.9% of subjects in the control group (p= 0.002). There was a positive correlation between TPOAb and volume in patients (p= 0.019). There was no correlation between vitamin D concentration and thyroid volume, TRAb, TgAb, TSH or free T4. Conclusions: We demonstrated a higher prevalence of vitamin D insufficiency in patients with Hashimoto's thyroiditis compared to individuals of a healthy control group, no correlation with thyroid state hormonal or serum markers of thyroid autoimmunity. In turn, greater thyroid volume was associated with a higher degree of autoimmune inflammatory infiltration, reflected by the correlation with higher concentrations AcTPO / Mestrado / Clinica Medica / Mestra em Ciências

Green sea turtles (Chelonia mydas) are an endangered species prone to a debilitating disease called fibropapillomatosis (FP). The aim of this study was to determine the influence of UV light on vitamin D levels and immune function in juvenile green sea turtles with FP. Phagocytosis, plasma vitamin D levels and viral load of ChHV5 were measured for FP- and FP+ turtles kept at the Gumbo Limbo Nature Center (GLNC) and for turtles caught at the St. Lucie power plant. Turtles kept at GLNC were housed in tanks exposed to varying amounts of UV light. Turtles brought into GLNC had lower phagocytosis compared to turtles at the St. Lucie power plant. Individuals exposed to greater UV light had higher plasma vitamin D levels and a more successful recovery. The results of this project will provide rehabilitation facilities with a mechanism to improve the recovery of animals with this disease. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Multiple sclerosis (MS) is a progressive, autoimmune neurodegenerative disorder affecting nearly 350,000 people in the United States and resulting in significant disability. As an immunomodulator, vitamin D may play a role in the development of MS. Previous studies have observed an inverse association of 25-hydroxyvitamin D (25(OH)D) levels and MS risk in younger populations; however, whether this relationship persists in older adults remains unclear. We prospectively investigated the association between predicted 25(OH)D level and incident MS in the Nurses’ Health Study (NHS) (n=121,701) and NHS II (n=116,430). 25(OH)D levels were predicted using validated regression models that include important determinants of vitamin D status, including race, UV-B flux (based on state of residence), physical activity, body mass index, dietary vitamin D intake, alcohol consumption and post-menopausal hormone use. Data on these factors were self-reported on NHS and NHS II questionnaires starting in 1986 and 1991, respectively, and updated every 2-4 years. MS diagnoses were ascertained by self-report and confirmed by medical records. Cox proportional hazards models adjusted for age, ethnicity, latitude of residence at age 15, and BMI at age 18 were used to estimate hazard ratios (HR)s and 95% confidence intervals (CI)s in each cohort. During up to 18 years of follow-up, we documented 179 definite/probable cases of MS with first symptoms after baseline. Multivariable HRs comparing highest and lowest quintiles of predicted 25(OH)D were 1.09 (95% CI: 0.40-2.96) in the NHS and 0.52 (95% CI: 0.28-0.95) in the NHS II. Higher predicted plasma 25(OH)D may be modestly associated with lower risk of MS, primarily in younger women.

faustino.perez@unizar.es / Objective: To assess the effects of vitamin D supplementation during pregnancy on obstetric outcomes and birth variables. Design: Systematic review and meta-analysis of randomized controlled trials (RCTs). Setting: Not applicable. Patient(s): Pregnant women and neonates. Intervention(s): PubMed and 5 other research databases were searched through March 2014 for RCTs evaluating vitamin D supplementation calcium/vitamins/ferrous sulfate vs. a control (placebo or active) during pregnancy. Main Outcome Measure(s): Measures were: circulating 25-hydroxyvitamin D [25(OH)D] levels, preeclampsia, gestational diabetes mellitus (GDM), small for gestational age (SGA), low birth weight, preterm birth, birth weight, birth length, cesarean section. Mantel-Haenszel fixed-effects models were used, owing to expected scarcity of outcomes. Effects were reported as relative risks and their 95% confidence intervals (CIs). Result(s): Thirteen RCTs (n ¼ 2,299) were selected. Circulating 25(OH)D levels were significantly higher at term, compared with the control group (mean difference: 66.5 nmol/L, 95% CI 66.2–66.7). Birth weight and birth length were significantly greater for neonates in the vitamin D group; mean difference: 107.6 g (95% CI 59.9–155.3 g) and 0.3 cm (95% CI 0.10–0.41 cm), respectively. Incidence of preeclampsia, GDM, SGA, low birth weight, preterm birth, and cesarean section were not influenced by vitamin D supplementation. Across RCTs, the doses and types of vitamin D supplements, gestational age at first administration, and outcomes were heterogeneous. Conclusion(s): Vitamin D supplementation during pregnancy was associated with increased circulating 25(OH)D levels, birth weight, and birth length, and was not associated with other maternal and neonatal outcomes. Larger, better-designed RCTs evaluating clinically relevant outcomes are necessary to reach a definitive conclusion. (Fertil Steril 2015;-:-–-. 2015 by American Society for Reproductive Medicine.) / Revisión por pares

Vitamin D is a fat-soluble hormone essential for humans as it is a key player in calcium and phosphorus homeostasis for bone mineralization, and is linked to many nonskeletal health outcomes such as autoimmune diseases and cardiovascular disease as well. The primary source of vitamin D is the conversion of 7-dehydrocholestrol (7-DHC), which naturally exists in the plasma membranes of skin cells, to previtamin D3 by the exposure to the ultraviolet-B (UV-B) portion of sunlight. Despite humans’ ability to cutaneously synthesize vitamin D, many factors limit this process, and consequently vitamin D deficiency has become a common medical issue worldwide. Deficient individuals may not respond well to traditional vitamin D replacement through dietary supplementation if suffering from fat malabsorption syndromes while unable to get sufficient vitamin D from sun exposure due to location, sunscreen use, or cultural practices, among other reasons. It has been previously reported that exposure to artificial sources of UV-B radiation (UV lamps, tanning beds, among others) produces cutaneous vitamin D, but heat generation, poor portability, and other inconveniences to the deficient patient limit therapeutic use of these devices. In addition, broad-spectrum sources of UV radiation reduce the production of vitamin D compared to narrow-band sources because of the photoequilibrium that is established. The advent of the light-emitting diode (LED) provided a compact, energy-efficient, high-intensity, low-heat alternative radiation source, and the recent development of the UV LED offers a viable alternative for developing a personalized vitamin D-producing device. This thesis presents evidence that UV LEDs have the capacity to efficiently synthesize vitamin D3 in vitro and in human skin. Ampoules of 7-DHC were irradiated in triplicate with LEDs at 280, 285, 290, 295, 298, 300, and 310 nm. The 298 nm LED was found to have the most efficient previtamin D3 production of 7.0% in vitro at the equivalent of 0.75 minimal erythemal dose (MED, rated at 1 MED = 32 milliJoules per centimeter squared for type II skin), compared to all other assessed LEDs. Irradiation of human skin samples (IRB-exempt) with the 298 nm diode (~39 seconds of radiation) indicated that 1.5% of the original 7-DHC in type II (Caucasian) skin could be converted to vitamin D3 in situ after exposure to 0.75 MED. These results imply that manufacturing a cuff containing 298 nm LEDs that covers 3.8% of the total surface area of skin could provide 600 IUs of vitamin D3 if operated for just 39.0 seconds. The data provide a promising new approach to treat vitamin D-deficient patients suffering from fat malabsorption syndromes.

BACKGROUND: Patients who have been diagnosed with Inflammatory Bowel Disease (IBD) present with increased risk of deficient vitamin D levels. Previous studies have demonstrated that these IBD patients who live in areas with lack of sun exposure are especially susceptible to becoming vitamin D deficient. Studies have also shown that the standard vitamin D dosing protocols have not proven effective in consistently improving vitamin D status. This failure is likely related to a combination of under-dosing and patient noncompliance. Vitamin D sufficiency is essential in the maintenance of both skeletal health and the immune system in children and adolescents. OBJECTIVES: The primary aim of this study is to investigate the safety and efficacy of administering an interval, high dose oral vitamin D supplementation in pediatric patients with IBD treated with Remicade. A secondary aim is to study the association between changes in serum 25OHD (25-hydroxyvitamin D3) levels and clinical and biochemical markers of IBD. The findings from this study will provide preliminary data for future studies using serial measurements of serum 25OHD levels to better articulate the optimal dosage for interval vitamin D supplementation in pediatric patients with IBD. METHODS: We identified and screened pediatric patients with IBD at Boston Children’s Hospital (BCH) with vitamin D deficiency (serum 25OHD level < 30 ng/mL). Vitamin D dosing was determined by a patient’s Remicade interval. Patients received either 50,000 international units (IU) of vitamin D3 (every 4-5 weeks) or 100,000 IU of vitamin D3 (every 6-8 weeks), concurrent with their Remicade infusion interval. Longitudinal data, including anthropomorphic measurements, serum chemistry labs, spot urine calcium to creatinine ratios, quality of life metrics, and surveys gauging dietary vitamin D intake and sunlight exposure, were collected throughout the study. RESULTS: Baseline vitamin D status in the 60 enrolled patients did not differ by gender, dosing group, diet, or diagnosis (Crohn disease, ulcerative colitis, or indeterminate colitis). Of the 57 patients for whom baseline and final serum 25OHD levels were available, there was a significant increase in total serum 25OHD levels from 22.53 ± 4.65 ng/mL to 29.91 ± 6.60 ng/mL, respectively. Similarly, increases in mean serum 25OHD levels were noted in both dosing formats and disease groups. Interestingly, there was no significant parallel impact of increased 25OHD levels on either disease activity or quality of life. There were no significant changes in serum calcium, phosphorous, and creatinine levels in response to changes in 25OHD levels. There were no reports of significant adverse events related to vitamin D supplementation. CONCLUSION: High dose, interval vitamin D supplementation improved vitamin D status from baseline in a majority of studied pediatric patients with IBD. The data suggest that this type of interval, high dose format is likely more effective than more traditionally once-daily dosing. Further studies are necessary to determine the optimal dosage regimens optimal in further increasing vitamin D status and to assess for its impact on clinical management.

Vitamin D and calcium are essential for the health of the elderly population. Due to the changes that occur in the body during aging, it is necessary to monitor the intake of these micronutrients and, if necessary, to supplement or substitute them appropriately. This thesis focuses on prevention of vitamin D and calcium deficiency in old age. The theoretical part explains the function of vitamin D and calcium in the human body, their metabolism, sources and problems of deficiency or excess. There is information about diseases related to the deficiency, especially osteoporosis and sarcopenia. The practical part has two sections. The first analyses the data from the SPRINTT trial. Data related to vitamin D, calcium, their supplementation and sarcopenia, as a disease associated with vitamin D deficiency, were used. The second section analyzes the data from a questionnaire survey in nursing homes, which obtained information about the health of seniors, the frequency of consumption of selected foods and vitamin D and calcium supplementation. Using data from the SPRINTT, it was found that 55 % of men and 40 % of women had the values of sarcopenia. 11 % of the participants had vitamin D deficiency. The data from the questionnaire found that only 51 % of respondents over the age of 70 supplemented with...