Abstract available in The Journal of Nutrition, Health, and Aging.

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Introduction: Obesity is a major health problem that affects an individual's overall health. Bariatric metabolic surgery is most important and has permanent impact on weight loss in comparison with conservative therapy. The downside is that it often leads to a row nutritional deficiencies requiring long-term supplementation. Object: The aim of the thesis is to map the intake of nutrients in the diet of bariatric patients six months and one year after the procedure. The research is primarily focused on the intake of vitamin D and calcium in diet, vitamin D, parathyroid hormone and calcium levels are also evaluated. Marginally, laboratory values are assessed prior to surgery as deficiencies are known to occur before surgery. Methodology: The research sample consists of 30 respondents who are six months (M6) and one year (Y1) from the procedure. Micronutrients are evaluated from three-day dining records recorded by respondents for at least one week. The research laboratory data was used from the medical information system of the hospital information system. The evaluation parameters for vitamin D-25 (OH)D (limit level was established to > 30 ng/ml). To assess the parathyroid hormone concentration, a minimum limit is set to 1.58 pmol/l, calcium 2.00-2.75 (mmol/l). We were wondering if the profile of...

Age-related macular degeneration (AMD) is the leading cause of vision loss in individuals aged 50 years and older and is estimated to affect as many as 11 million individuals in the United States. The purpose of this study was to examine the association between vitamin D and AMD disease progression. The life course epidemiology framework model was used to explore how vitamin D level as a risk factor may have an association to AMD disease through time. Data in the 2005-2008 National Health and Nutrition Examination Survey (NHANES) database were collected on vitamin D levels and identified stages of AMD level based on graded fundus eye exams from an available sample size of 5,604 participants. A quantitative cross-sectional study approach was used to address this gap in knowledge. A bivariate analysis was used to examine each independent variable (age, race/ethnicity, smoking status, and diabetes) to the dependent variable AMD from the 2005-2008 NHANES dataset. A multivariate logistic regression analysis was performed with AMD including each independent variable found to be significant. The findings from this study failed to suggest an association between vitamin D levels to AMD, with or without the covariates included in the model. There was not an association found between vitamin D level and presence of AMD. An association was found between age, smoking, and race to presence of AMD in each of the bivariate models. The findings from this study could be used for positive social change by encouraging medical and public health agencies to target screening programs at high-risk age, smoking, and race groups. There remains to be conflicting data in the literature. This study adds to the body of literature suggesting that higher levels of vitamin D are not necessarily beneficial as they pertains to AMD.

Die Mortalität bei Dialysepatienten ist bedeutend höher als in der Allgemeinbevölkerung. Hauptgrund ist eine deutlich erhöhte kardiovaskuläre Morbidität und Mortalität. Als wichtige Ursachen hierfür gelten bei Dialysepatienten unter anderem das vermehrte Auftreten systemischer Inflammation und die Störung des Kalzium-Phosphathaushaltes, welche mit vermehrter vaskulärer Kalzifikation einhergeht. Da große Beobachtungsstudien darauf hinweisen, dass aktive Vitamin D-Therapie mit einem Überlebensvorteil für Dialysepatienten assoziiert ist, besteht die Hypothese, dass Paricalcitol antiinflammatorische und verkalkungsinhibitorische Effekte haben könnte. In dieser vorliegenden multizentrischen, doppelverblindeten, prospektiven und Placebo-kontrollierten Crossover-Studie wurden 43 Hämodialysepatienten eingeschlossen, randomisiert und zwei Behandlungssequenzen zugeordnet. In der einen Behandlungssequenz erfolgte zunächst eine 12-wöchige Behandlung mit Paricalcitol (Startdosis 2 μg/Tag) und nach einer 4-wöchigen Washout- Phase eine 12-wöchige Behandlung mit Placebo. In der anderen Behandlungssequenz erfolgte nach gleichem Modus zunächst eine Behandlung mit Placebo und dann eine Behandlung mit Paricalcitol. Die Adjustierung der Dosis der Studienmedikation erfolgte entsprechend der Werte für Kalzium, Phosphat und PTH intakt. Zur Untersuchung der Hypothese wurden Zielparameter für Inflammation (hsCRP, Hepcidin) und Kalzifikation (Fetuin A , t-ucMGP, FGF-23) in regelmäßigen Intervallen gemessen. Als primärer Endpunkt wurden die 30%-ige Senkung des hsCRP-Levels und 20%-ige Steigerung der Fetuin A-Serumwerte definiert. Sekundäre Endpunkte waren Veränderungen der Serumkonzentrationen von Hepcidin, FGF-23 und t- ucMGP. Insgesamt wurde die Studie von 25 Patienten protokollgemäß beendet. Bezüglich der primären Zielparameter zeigten sich keine signifikanten Unterschiede zwischen der Behandlung mit Paricalcitol und Placebo. Es konnte lediglich bei hsCRP ein leichter Trend zu niedrigeren Werten unter Paricalcitolbehandlung registriert werden. Bei den sekundären Zielparametern zeigte sich eine Borderline-Signifikanz (p = 0,051) hinsichtlich höherer FGF-23- Werte unter Paricalcitol. Bei Hepcidin und t-ucMGP konnten keine signifikanten Unterschiede zwischen der Behandlung mit Paricalcitol und Placebo verzeichnet werden. In der vorliegenden Studie konnten die primären Endpunkte unter Paricalcitoltherapie somit nicht erreicht werden. Die Expression von Fetuin A wird von Paricalcitol wahrscheinlich nicht beeinflusst. Möglicherweise existiert aber ein leichter antiinflammatorischer Effekt, der eine Senkung der hsCRP- Serumwerte bedingen könnte. Des Weiteren steigert Paricalcitol die Expression von FGF-23, während die von Hepcidin und t-ucMGP unbeeinflusst zu sein scheint. / Background. Mortality in dialysis patients is much more higher than in general population. A main reason for this fact is the increased cardiovascular morbidity and mortality. Important causes for cardiovascular diseases in dialysis patients are the increased incidences of systemic inflammation and disorders of mineral metabolism, which lead to vascular calcification. Recent studies showed an improved survival in dialysis patients undergoing a therapy with vitamin D receptor activators. Therefore, it could be hypothesized that paricalcitol inhibits inflammation and calcification. Methods. In this multicentre, double-blinded, prospective and placebo-controlled crossover trial 43 patients on hemodialysis were randomised within one of two sequence groups. In the first period the patients received a 12-week treatment with either paricalcitol (2 µg per day) or placebo. After a 4-week washout period the therapy was exchanged respectively for a second 12-week treatment period. During the periods parameters of inflammation (hsCRP, hepcidin) and calcification (fetuin-A, t-ucMGP, FGF-23) were measured regularly. The primary endpoint was defined as 30 percent decrease in hsCRP level and as a 20 percent increase in fetuin-A level. Secondary endpoints were changes of hepcidin, t-ucMGP and FGF-23. Results. 25 participants finished the study per-protocol and could be included in statistical analyses. Regarding hsCRP and fetuin-A no significant differences could be detected between the treatment with either paricalcitol or placebo. There was only a discrete trend towards lower hsCRP levels under treatment with paricalcitol. Furthermore there was a borderline significant increase in FGF-23 levels (p = 0,051) in treatment phases with paricalcitol. Regarding hepcidin and t-ucMGP no changes could be perceived. Conclusion. In this study primary endpoints were not achieved. Paricalcitol has likely no influence on expression of fetuin-A. Potentially paricalcitol has a slight anti-inflammatory effect, which leads to a decrease in hsCRP levels. Furthermore paricalcitol increases the expression of FGF-23 whereas there is no influence on hepcidin and t-ucMGP.

Adequate vitamin D status plays an important role in bone health and may also protect against Type 1 Diabetes (T1D), multiple sclerosis and certain cancers. Vitamin D is obtained from two sources; diet and through skin synthesis through the action of ultraviolet (UV) light. Dietary intakes of vitamin D are low in New Zealand (NZ) and the majority of our vitamin D comes from UV exposure. The NZ population may be at risk of low vitamin D status because of low dietary intakes, the country�s latitude (35-46 �S), and high proportion of darker skinned Maori and Pacific People. While case reports have described the occurrence of rickets, predominantly in immigrant groups, there are currently no national data on the vitamin D status of the NZ population. Reports of low vitamin D status in countries of similar latitude to NZ justify an examination of New Zealanders� vitamin D status. The best method to assess of vitamin D status is to measure circulating 25-hydroxyvitamin D concentrations. This thesis comprises three main studies. The first two had the following aims: to measure 25-hydroxyvitamin D concentrations and their determinants in a national sample (n=1585) of NZ children aged 5-14 y and to measure serum 25-hydroxyvitamin D concentrations and their determinants in a national sample (n=2948) of New Zealanders aged 15 y and over. The 2002 Children�s Nutrition Survey CNS02 was a year long (December, March-November) cross-sectional survey of a nationally representative sample of NZ school children 5-14 y. Over-sampling of Maori and Pacific children allowed ethnic specific analyses. The 1997 National Nutrition Survey (NNS97) participants were recruited over one year according to an area-based sampling frame with a 3 stage stratified design consisting of primary sampling units, households within each unit, and one randomly selected respondent from each household. Mean (99% CI) serum 25-hydroxyvitamin D concentrations were similar in children and adults (both 50 nmol/L). Among Maori, Pacific and NZEO children respectively, prevalence (%, 99% CI) of serum 25-hydroxyvitamin D deficiency (< 17.5 nmol/L) was 5% (2, 12), 8% (5, 14), and 3% (1,7). Based on a cutoff of < 37.5 nmol/L, prevalence of insufficiency was 41% (29, 53), 59% (42, 75) and 25% (15, 35), respectively. Based on a cutoff of 50 nmol/L, 56% of children were insufficient. Three percent of adult New Zealanders had serum 25-hydroxyvitamin D concentrations indicative of deficiency ([less than or equal to] 17.5 nmol/L); 48% and 84% were insufficient based on cutoffs of [less than or equal to] 50 and [less than or equal to] 80 nmol/L The main determinants of vitamin D status in NZ children were season, ethnicity and sex. After adjustment for other factors and covariates, boys had an adjusted mean (99% CI) 25-hydroxyvitamin D concentration 5 (1, 9) nmol/L higher than girls, Maori children were 7 (2, 11) and Pacific children 15 (11, 20) nmol/L lower than NZ European and Other (NZEO) children. Obese children were 7 (2, 11) nmol/L lower than overweight or �normal� weight. Children�s mean 25-hydroxyvitamin D concentrations (adjusted for other variables) peaked in March (69 nmol/L) and was at its lowest in August (36 nmol/L). In adults, there were effects of a similar magnitude of ethnicity and season on serum 25-hydroxyvitamin D concentrations. Obesity, latitude and age were determinants of vitamin D status in women but not men. Obese (BMI > 30) women had an adjusted mean vitamin concentration 6 (3, 10) nmol/L lower than women with BMI < 25. Women living in the South Island were 6 (3, 9) nmol/L lower than women living in the North Island. Additionally, adjusted mean serum 25-hydroxyvitamin D was 13 (8, 18) higher in women 15 -18 y than women 65 y or older. The third and final study aimed to determine whether the higher rates of vitamin D inadequacy reported in the winter than summer months in NZ also result in higher PTH concentrations, which would provide evidence for functional effect of inadequate vitamin D status. We also aimed to objectively explore the effect of natural skin colour on vitamin D status, given the higher prevalence of vitamin D insufficiency in dark-skinned groups living far from the equator. Skin colour measurements were taken with a hand-held light reflectometer (Datacolor Mercury[TM] 1000 colorimeter, Lawrenceville, NJ). In the 342 residents of Invercargill and Dunedin, mean serum 25-hydroxyvitamin D concentrations were lower in the late summer versus early spring (79 vs 51 nmol/L; P< 0.001). The lower serum 25-hydroxyvitamin D in early spring versus summer was associatedwith a 2 pg/mL (P< 0.001) higher parathyroid hormone (PTH) concentration. Interestingly, no significant effect of natural skin colour, based on light reflectance at the inside of the upper arm, was discovered, though there was a positive effect of tanning, based on light reflectance at the upper forearm, on serum 25-hydroxyvitamin D concentrations. Ethnicity and season are major determinants of serum 25-hydroxyvitamin D in New Zealanders. There is a high prevalence of vitamin D insufficiency in NZ children and adults, which may contribute to increased risk of osteoporosis and other chronic disease. While there is a pressing need for more convincing evidence with regards to the health risks associated with the low vitamin D status in children, evidence from the study of adults, where higher PTH concentrations were found during spring versus summer, suggests that the low 25-hydroxyvitamin D concentrations are having an adverse effect on bone health of adults. The high prevalence of vitamin D insufficiency in New Zealanders, warrants serious consideration of strategies such as fortification, to improve the vitamin D status of the population.

The research presented in this thesis relates to the gastrointestinal control of appetite and some of the consequences of nutritional frailty, namely postprandial hypotension and vitamin D insufficiency. Undernutrition and its consequences are increasingly common problems in an ageing population, and improved management is dependent on an understanding of the factors which are involved in the control of appetite, and the physiological decline of appetite with increasing age termed ‘the anorexia of ageing’. The role of the gastrointestinal hormone ghrelin was specifically evaluated, in relation to the effects of age and nutrient digestion on circulating ghrelin concentrations (Chapters 6 and 7). The effect of fat digestion on the postprandial blood pressure response in healthy older subjects was evaluated in the study reported in Chapter 8. In addition, the results of some intervention studies are described in Chapters 9 and 10, the former study relating to nutritional supplementation as a strategy to increase energy intake, and the latter study to the effects of vitamin D replacement therapy on glucose and insulin metabolism. Whilst plasma ghrelin concentrations are less in older than young rodents, the consequences of healthy ageing on circulating plasma ghrelin concentrations in humans are unclear. The variations in fasting ghrelin concentrations over a sixty year age range were evaluated in healthy young and older subjects (Chapter 6). Plasma ghrelin concentrations were higher in females than males, but did not correlate with age, and were inversely related to body mass index. Ghrelin was independently, and inversely, related to total body skeletal muscle mass, but not to any other body composition variable. Strategies for increasing muscle mass, through resistance exercises, may, accordingly, aid in abolishing the compensatory rise in ghrelin concentrations seen with undernutrition and weight loss. Plasma ghrelin concentrations increase before, and decrease to trough levels within one hour of ingestion of a meal. Macronutrients differ in their ability to suppress ghrelin, being earlier and more pronounced after carbohydrate, and relatively delayed after fat or protein, ingestion. The role of carbohydrate and fat digestion in the suppression of plasma ghrelin concentrations was investigated in healthy young adults (Chapter 7). The suppression of ghrelin concentrations following a sucrose drink was attenuated by acarbose, which slows small intestinal carbohydrate absorption. Ghrelin concentrations were also suppressed after consumption of a fat-enriched drink, however addition of orlistat, which reduces fat digestion and absorption, attenuated the fall in plasma ghrelin. Thus, nutrient digestion is required, in addition to exposure of the small intestine to nutrients, for suppression of ghrelin. Postprandial hypotension describes a significant fall in blood pressure occurring up to two hours after a meal. The magnitude of the fall in postprandial blood pressure depends, in part, on the macronutrient composition of a meal, and the effects are particularly discernable in older adults. Although carbohydrates are particularly potent in reducing postprandial blood pressure in older adults, fat ingestion appears to have comparable, but delayed effects. The role of fat digestion in modifying the blood pressure responses was evaluated in healthy older adults (Chapter 8). There was a fall in blood pressure after ingestion of a high-fat drink. Orlistat, a lipase inhibitor which reduces intestinal fat absorption, potentiated the fall in postprandial blood pressure after a fat-enriched drink. Gastrointestinal function and appetite can be modulated by dietary manipulation of the macronutrient composition of an individual’s diet. The intervention study described in Chapter 9 evaluated the effects of two weeks of dietary fat supplementation on the sensitivity to the satiating effects of intravenous cholecystokinin-8 in healthy older subjects. No differences were observed in fasting, or postprandial plasma cholecystokinin concentrations after the dietary supplementation period compared to regular diet. There were also no differences in spontaneous energy intake at a buffet meal in response to exogenously administered cholecystokinin between the two diet periods. Vitamin D deficiency is common, as is type 2 diabetes, and the two conditions may be linked. There is mounting evidence linking vitamin D deficiency with abnormalities of glucose and insulin metabolism. The effects of vitamin D therapy in healthy young and older adults with low vitamin D concentrations in the setting of normal or impaired glucose tolerance were evaluated (Chapter 10). Vitamin D therapy, which normalised serum 25-hydroxyvitamin D concentrations in these individuals, did not alter glucose or insulin concentrations or insulin sensitivity during an oral glucose tolerance test. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1339020 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

1,25-(OH)2 vitamin D3 inhibits cell proliferation of a variety of cancers including prostate. In the human prostate cancer cell line LNCaP, 1,25-(OH)2 vitamin D3-mediated growth inhibition is attributed to cell cycle G1 accumulation which correlates with a robust decrease of cyclin-dependent kinase 2 (CDK2) activity and pronounced relocalization of CDK2 into the cytoplasm. Nuclear targeting CDK2 blocks the 1,25-(OH)2 vitamin D3-mediated growth inhibition and cell cycle G1 accumulation. Further, the nuclear targeted CDK2 blocks 1,25-(OH)2 vitamin D3-mediated inhibition of CDK2 activity and nuclear exclusion in LNCaP cells. Therefore, CDK2 cytoplasmic relocalization is the key mechanism for 1,25-(OH)2 vitamin D3 effects. Since cyclin E is important for CDK2 nuclear localization and activation, 1,25-(OH)2 vitamin D3 may exert its effects through regulation of cyclin E. Cyclin E but not a cyclin E mutant deficient in CDK2 binding reverses 1,25-(OH)2 vitamin D3-mediated antiproliferation which suggests the involvement of cyclin E as a mechanism. However, the studies showed no effects of 1,25-(OH)2 vitamin D3 on cyclin E levels, intracellular localization or binding to CDK2. In order to develop a model for studying 1,25-(OH)2 vitamin D3-mediated antiproliferative effects, LNCaP vitD.R cell line, a vitamin D resistant LNCaP derivative, was generated by continuously culturing of LNCaP cells in medium supplemented with 10 nM 1,25-(OH)2 vitamin D3 for over 9 months. The initial characterization of this cell line showed complete resistance to 1,25-(OH)2 vitamin D3-mediated effects. Analysis of vitamin D regulation of VDR target gene expression revealed that vitamin D resistance in LNCaP vitD.R cells was not due to deregulation of VDR signaling. HDAC inhibitor Trichostatin A (TSA) did not confer sensitivity of LNCaP vitD.R cells to vitamin D treatment suggested the resistance to 1,25(OH)2 vitamin D3 effect of LNCaP vitD.R cells is not due to histone deacetylase remodeling of the chromatin structure which leads to inhibition of gene transcription. While the partial sensitization of LNCaP vitD.R cells to 1,25(OH)2 vitamin D3 effect by demethylation reagent 5-Aza-2¡¯-deoxycytidine treatment suggested a set of genes involved in 1,25(OH)2 vitamin D3-mediated antiproliferative effects is silenced via hypermethylation in LNCaP vitD.R cells. These results suggested LNCaP vitD. R cell line is a useful tool and further studies to elucidate the genes involved in this effect will help uncover the mechanisms of 1,25(OH)2 vitamin D3-mediated antiproliferative effects.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the most active metabolite of vitamin D, inhibits the proliferation of a variety of cell types including adenocarcinoma of the prostate. The primary mechanism for the antiproliferative effects of 1,25-(OH)2D3 in prostate cancer cells is inhibition of G1 to S phase cell cycle progression. While 1,25-(OH)2D3-mediated growth inhibition requires the vitamin D receptor (VDR), a ligand activated transcription factor, expression of functional VDR is not sufficient. To define target genes that might participate in the antiproliferative actions of 1,25-(OH)2D3, we developed a derivative of the human prostate cancer cell line, LNCaP, which retains transcriptionally active VDRs but unlike parental LNCaP cells, is not growth inhibited by 1,25-(OH)2D3. Gene expression profiling of these resistant cells (termed VitD.R) compared to control LNCaP cells revealed two novel 1,25-(OH)2D3-inducible genes, GADD45G and MIG6. The expression of GADD45G and MIG6 genes was induced by 1,25-(OH)2D3 in LNCaP but not in the resistant VitD.R or in ALVA31 cells, human prostate cancer cells that exhibit natural resistance to growth inhibition by 1,25-(OH)2D3 despite expression of functional VDR. Ectopic expression of GADD45G but not MIG6 in either LNCaP or ALVA31 cells resulted in accumulation of cells in G1 and inhibition of proliferation equal to or greater than that caused by 1,25-(OH)2D3 treatment. While GADD45G is induced by androgens in prostate cancer cells, up-regulation of GADD45G by 1,25-(OH)2D3 was not dependent on androgen receptor signaling further refuting a requirement for androgens/androgen receptor in vitamin D-mediated growth inhibition in prostate cancer cells. These data introduce two novel 1,25-(OH)2D3-regulated genes and establish GADD45G as a growth inhibitory protein in prostate cancer. Further, defects in vitamin D-mediated induction of GADD45G may underlie vitamin D resistance in prostate cancer cells. We previously demonstrated that the antiproliferative actions of 1,25-(OH)2D3 in prostate cancer cells are associated with decreased CDK2 activity and increased stability of the cyclin dependent kinase inhibitor (CKI) p27KIP1. We defined a novel mechanism that may underlie these antiproliferative effects, 1,25-(OH)2D3 -mediated cytoplasmic relocalization of CDK2, which would provide a unifying mechanism for the observed effects of 1,25-(OH)2D3 on CDK2 and p27. In the present study, we investigated the role of CDK2 cytoplasmic relocalization in the antiproliferative effects of 1,25-(OH)2D3. CDK2 was found to be necessary for prostate cancer cell proliferation. In contrast, while p27KIP1 is induced by 1,25-(OH)2D3, this CKI was completely dispensable for 1,25-(OH)2D3-mediated growth inhibition. Reduction of CDK2 activity by 1,25-(OH)2D3 was associated with decreased T160 phosphorylation, a residue whose phosphorylation in the nucleus is essential for CDK2 activity. Since cyclin E is important for nuclear translocation of CDK2, we investigated cyclin E effects on 1,25D-mediated growth inhibition. Ectopic expression of cyclin E blocked 1,25-(OH)2D3-mediated cytoplasmic relocalization of CDK2 and all antiproliferative effects of 1,25-(OH)2D3, yet endogenous levels of cyclin E or binding to CDK2 were not affected by 1,25-(OH)2D3. Similarly, knockdown of the CDK2 substrate retinoblastoma (Rb), which causes cyclin E up-regulation, resulted in resistance to 1,25-(OH)2D3 mediated growth inhibition. VitD.R cells did not exhibit 1,25-(OH)2D3-mediated cytoplasmic relocalization of CDK2. Importantly, targeting CDK2 to the nucleus of LNCaP cells blocked G1 accumulation and growth inhibition by 1,25-(OH)2D3. These data establish central roles for CDK2 nuclear-cytoplasmic trafficking and uncoupling of VDR in the regulation of antiproliferative target genes in the mechanisms of 1,25-(OH)2D3-mediated growth inhibition in prostate cancer cells. Since 1,25-(OH)2D3 continues to be evaluated for its chemotherapeutic and chemopreventative potential, elucidating the mechanism of 1,25-(OH)2D3 antiproliferative effects is critical in the determination of 1,25-(OH)2D3 responsiveness and the design of individualized treatment strategies.