Elevation in serum parathyroid hormone (PTH) often accompanies vitamin D deficiency and renal impairment. PTH elevation in renal failure is viewed as an unfavorable development. Evidence is increasing that PTH elevation may be associated with increased morbidity and mortality. In many instances these PTH effects appear to be independent of vitamin D status. PTH mediates its effects through the ubiquitous type 1 PTH/PTH-related peptide receptor, which is notably present in the cardiovascular system. Increased PTH may promote cardiovascular disease through diminished cardiac contractility, enhanced coronary risk, and cardiac valvular and vascular calcification. High PTH levels appear to be linked to the metabolic syndrome and are aligned with hyperlipidemia, decreased insulin sensitivity, and, perhaps, decreased insulin secretion. Increased PTH also is associated with neuroendocrine activation, increased sympathetic activity, and endothelial stress. The relation between PTH and vitamin D is complex and may show significant threshold variations, especially when calcium intake, age, and race are considered. Moreover, evidence is increasing that fragments of PTH may not only be hormonally active but also may have opposing effects to PTH. Despite these caveats, PTH values provide useful clinical diagnostic and prognostic information in monitoring many chronic ailments such as heart and renal failure and multiple sclerosis.

Purpose: Living in a rural region is associated with significant health disparities and increased medical costs. Vitamin D deficiency, which is increasingly common, is also associated with many adverse health outcomes. The purpose of this study was to determine whether rural-urban residence status of veterans was related to vitamin D levels, and to determine if this factor also influenced medical costs/service utilization. Additionally explored was whether vitamin D differences accounted for part of the association between area of residence and medical costs/service utilization. Methods: Medical records of 9,396 veterans from 6 Veterans Administration Medical Centers were reviewed for variables of interest including county of residence, vitamin D level, medical costs and service utilization, and background variables. Rurality status was classified as large metropolitan, urban, and rural. Findings: The 3 rurality status groups differed significantly in vitamin D levels, with the highest levels observed for urban residents, followed by rural residents, and the lowest for large metro residents. Compared with urban residents, large metro residents were 49% more likely, while rural residents were 20% more likely, to be vitamin D deficient. Both rural and large metro residents had higher medical costs, and they were significantly more likely to be hospitalized. Vitamin D levels explained a statistically significant amount of the relationship between rurality status and medical costs/service utilization. Conclusions: Vitamin D deficiency may be an additional health disparity experienced by both rural and inner-city veterans, and patients residing in these locations should be considered at increased risk for deficiency and routinely tested.

Aim: VitaminD deficiency is a global health issue associated with increased health-care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitaminD deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitaminD level were included. Initial and follow-up vitamin D values were recorded. The type of vitaminD supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitaminD were divided into separate inpatient and outpatient categories. Results: Veterans (n=108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitaminD level were studied. There were differences in follow-up vitaminD levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitaminD3 were less likely to use laboratory, pharmacy, radiology and fee-based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health-care costs and expenses in patients with inflammatory bowel disease.

Considerable disparities in cancer survival rates exist between African Americans (AAs) and white Americans (WAs). Various factors such as differences in socioeconomic status (SES), cancer stage at time of diagnosis, and treatment - which this analysis considers primary explanatory factors - have accounted for many of these differences. An additional factor not usually considered is vitamin D. Previous studies have inversely correlated higher solar ultraviolet-B (UVB) doses and serum 25-hydroxyvitamin D (25(OH)D) concentrations with incidence and/or mortality rates for about 20 types of cancer and improved survival rates for eight types of cancer. Because of darker skin pigmentation, AAs have 40% lower serum 25(OH)D concentrations than WAs. This study reviews the literature on disparities in cancer survival between AAs and WAs. The journal literature indicates that there are disparities for 13 types of cancer after consideration of SES, stage at diagnosis and treatment: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin lymphoma and melanoma. Solar UVB doses and/or serum 25(OH)D concentrations have been reported inversely correlated with incidence and/or mortality rates for all of these cancers. This finding suggests that future studies should consider serum 25(OH)D concentrations in addressing cancer survival disparities through both measurements of serum 25(OH)D concentrations and increasing serum 25(OH)D concentrations of those diagnosed with cancer, leading to improved survival rates and reduced disparities.

Health care-associated and hospital-acquired infections are two entities associated with increased morbidity and mortality. They are highly costly and constitute a great burden to the health care system. Vitamin D deficiency (< 20 ng/ml) is prevalent and may be a key contributor to both acute and chronic ill health. Vitamin D deficiency is associated with decreased innate immunity and increased risk for infections. Vitamin D can positively influence a wide variety of microbial infections. Herein we discuss hospital-acquired infections, such as pneumonia, bacteremias, urinary tract and surgical site infections, and the potential role vitamin D may play in ameliorating them. We also discuss how vitamin D might positively influence these infections and help contain health care costs. Pending further studies, we think it is prudent to check vitamin D status at hospital admission and to take immediate steps to address existing insufficient 25-hydroxyvitamin D levels.

Objective: Vitamin D deficiency remains a poorly recognized pandemic and is closely linked to increased health care costs in veterans. Projected health care needs in veterans are expected to increase over the next decade. Intensive care unit (ICU) costs contribute significantly to hospital costs and stem from intervention services and management of sepsis including nosocomial infections. Vitamin D has immunomodulating and antimicrobial properties through antimicrobial peptides such as cathelicidin. Design/Methods: A retrospective study was undertaken to evaluate if vitamin D deficiency was associated with less than optimal ICU outcomes in veterans. The study included 136 veterans with 25(OH)D levels drawn within a month of admission to ICU. Results: The average 25(OH)D level was 24.6 ng/mL (normal range 30-100) with 38% of patients falling in the vitamin D-deficient category (<20 ng/mL). ICU survivors had a significantly lower rate of vitamin D deficiency compared with nonsurvivors (28% versus 53%). Twenty-nine percent of vitamin D-replete patients were in ICU 3 days or more, whereas 58% of patients with vitamin D deficiency stayed in ICU 3 days or longer. This difference was highly significant translating to twofold increased risk (2.0 Relative Risk [RR]) for 3-day or longer stay in ICU for patients with vitamin D deficiency. Moreover, the risk of death was significantly higher in ICU patients with vitamin D deficiency (RR 1.81). Conclusion: A vitamin D-replete state may reduce costs and confer survival advantages in critical illness. We recommend that 25(OH)D levels be routinely checked and deficiencies treated in ICU patients.

Vitamin D is essential to optimizing health; vitamin D deficiency (VDD) can increase risk of hypertension, cardiovascular disease, and insulin resistance. VDD occurs when individuals do not receive sufficient oral intake or obtain adequate sun exposure. Previous researchers indicated there is a relationship between VDD and depression, while others have indicated there is no relationship. The purpose of this study was to examine the relationship between vitamin D levels and depression, and how this relationship might be moderated by an individual's demographic characteristics (gender, age, smoking status, or marital status). This study was a quantitative data analysis of archival data from the 2005-2006 National Health and Nutrition Examination Survey. The Health Belief Model was the theoretical framework. An ex-post facto exploratory analysis was used to test 2,623 adults located throughout the United States. Employing moderated multiple regression, a significant relationship was found between vitamin D levels and depression (p. < .001); however, the relationship was not moderated by demographic characteristics (gender, age, smoking status, or marital status). This study supports prior researchers who affirmed a correlation between vitamin D levels and depression. Given the definitive findings, practitioners should continue to recommend intake of vitamin D to individuals not meeting recommended daily dosages, but recommendations should not be based on gender, age, smoking status, or marital status. Understanding the connection between VDD and depression provides a basis on which to foster positive social change at the individual, family, organizational, and societal level.

The steroid hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] rapidly stimulates the uptake of phosphate in isolated chick intestinal cells, while the steroid 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] inhibits the rapid stimulation by 1,25(OH)2D3. Previous work in this laboratory has indicated that 24,25(OH)2D3 inhibits phosphate uptake in isolated intestinal cells and perfused duodenal loops. It is critical to show this effect in the whole animal to determine the presence of any confounding factors. Studies were therefore undertaken to determine if 24,25(OH)2D3 had a similar effect in vivo. 24,25(OH)2D3 has two isomers which are 24R, 25dihydroxyvitamin D3 [24R,25(OH)2D3] and 24S, 25dihydroxyvitamin D3 [24S,25(OH)2D3]. We studied these two isomers separately and tested them over a time course of 1, 5, 10, 15, and 18 h after steroid using chicks on regular diet, but fasted, and chicks on a lower vitamin D diet. All chicks were anesthetized prior to surgical exposure of the duodenal loop and injection of a solution containing H3 32PO4 into the lumen. An initial time course study of phosphate transport determined that 3 to 9 min of absorption in vivo was in a linear range, as judged by serum levels of radioactivity. Chicks were then injected with either 200 μg of 24R,25(OH)2D3, 20 μg of 24S,25(OH)2D3, or vehicle for control groups within the same time course studies. We found that the isomers had different effects on phosphate absorption. 24R,25(OH)2D3 had a hypophosphatemic effect in vivo. The serum levels of radionuclide revealed hypophosphatemic effects at 1, 5, 15, and 18 h time points with a decrease of 20%, 42%, 39%, and 43%, respectively, (P< 0.05) compared with controls; chicks raised on a low vitamin D diet also showed a decrease in phosphate absorption at 10 h time point by 33%. In contrast, 24S,25(OH)2D3 stimulated intestinal phosphate absorption at the 5-h time point by 64%, but had no other effects at the other time points tested. Because 24S,25(OH)2D3 was largely ineffective, dose-response studies were undertaken with only the 24R,25(OH)2D3 isomer. In comparing phosphate absorption in chicks fasted 18 h, and dosed with vehicle, 100 μg, 200 μg, or 300 μg of steroid 1 h prior to experimentation it was found that the lowest dose increased absorption to 99% of controls, while the 200 μg and 300 μg doses decreased phosphate absorption. (48 pages)

Most of the load-bearing demand placed on the human body is transduced by skeletal tissue, and the capacity of the skeleton to articulate in various opposing directions is essential for body movement and locomotion. Consequently, cartilage and bone defects due to trauma, disease, and developmental abnormalities result in disabling pain and immobility for millions of people worldwide. A novel way of promoting cartilage and bone regeneration is through the incorporation of either primary cells or multipotent progenitor cells in a three-dimensional (3D) biomaterial scaffold, and/or the addition of exogenous growth and differentiation factors. The first part of this study reports a protocol for using freshly isolated mature chondrocytes seeded in a 3D hydrogel biomaterial scaffold, developed to explore mechanotransduction of engineered cartilage constructs cultured in a designed bioreactor. The bioreactor was designed to allow the application of physiological mechanical forces (compression and fluid flow), as well as a non-invasive/non-destructive method for analyzing regenerating tissue in real time through ultrasound transducers and a computerized monitoring system. In the second part of this study, an engineered immortalized osteoprecursor cell line, designated OPC1 (osteoblastic precursor cell line 1), was used as a culture model system for exploring the effects of exogenous growth and differentiation factors, mainly vitamin D, on early bone development. OPC1 was previously designed to provide a consistent reproducible culture system for direct comparisons of engineered bone constructs, evaluating bone development and cell/biomaterial interactions, and for investigating putative bone differentiating factors. One of the objectives of this research effort was to explore tissue development and regeneration by culturing OPC1 in the presence of vitamin D metabolites vitaD3 and 1,25OH2D3, while assaying the concomitant biological response. Results indicate that OPC1 is capable of metabolizing the parental metabolite vitaD3, and thus 25OHD3, to the active vitamin D form 1,25OH2D3. The metabolism of vita3 resulted in an anti-proliferative and pro-differentiative influence on OPC-1. These results support the hypothesis that extra-endocrine synthesis of 1,25OH2D3 functions in a tissue specific manner to regulate growth and differentiation, in addition to the classic calcimic actions of the vitamin D endocrine pathway. Understanding the influence of vitamin D on bone development will have significant implications on healthy aging, including the susceptibility to skeletal disorders involved in development and aging, such as osteoarthritis (OA) and osteoporosis.

The active form of Vitamin D (VD3) has been shown to induce pro-apoptotic and anti-proliferative effects in several mammalian cancer cell types. The molecular mechanisms of tumor suppression, however, are not clearly understood. Previous research has shown that head and neck squamous cell carcinoma (HNSCC) responds to VD3. This thesis used both in vivo and in vitro models to examine the effect of VD3 in HNSCC. Former work in the Albala laboratory showed that hamsters that received systemic VD3 and topical treatment of 7,12-dimethylbenz(a)anthracene (DMBA) to the buccal pouch showed no or delayed carcinogenesis over the 14-week study compared to DMBA-only treated hamsters. This research further investigated the effect of VD3 in this hamster model. Using immunohistochemical (IHC) and western blot analysis, we demonstrate that systemic application of VD3to hamsters downregulates Rad51 expression in the buccal pouch and hinders the onset of tumor formation. Rad51 is a protein that plays a critical role in cell proliferation and homologous recombinational DNA repair. In the in vitro model, we show that Rad51 expression decreased in response to 100nM VD3 in HNSCC cell lines. The dose and time-dependence of VD3 on these cells was also examined. Western blot analysis and comet assay investigations confirmed that the SCC25 cell line is most sensitive to 100nM VD3 than to other doses tested, and that VD3 impairs the DNA-damage response. SiRNA and co-immunoprecipitation studies examined the potential of Chk 1 and p38 MAPK as upstream regulators of Rad51. Rad51 protein expression was found to be associated with early carcinogenesis from HNSCC cancer patients using IHC studies of human carcinomas from the oral cavity. This study focused on further identifying the role of Rad51 in response to VD3 in HNSCC.