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Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )

OBJECTIVES: To determine the effect of four vitamin D supplement doses on falls risk in elderly nursing home residents. DESIGN: Secondary data analysis of a previously conducted randomized clinical trial. SETTING: Seven hundred twenty-five-bed long-term care facility. PARTICIPANTS: One hundred twenty-four nursing home residents (average age 89). INTERVENTION: Participants were randomly assigned to receive one of four vitamin D supplement doses (200IU, 400IU, 600IU, or 800IU) or placebo daily for 5 months. MEASUREMENTS: Number of fallersand number offalls assessed using facility incident tracking database. RESULTS: Over the 5-month study period, the proportion of participants with falls was 44% in the placebo group (11/ 25), 58% (15/26) in the 200IU group, 60% (15/25) in the 400IU group, 60% (15/25) in the 600IU group, and 20% (5/23) in the 800IU group. Participants in the 800IU group had a 72% lower adjusted-incidence rate ratio of falls than those taking placebo over the 5 months (rate ratio 50.28; 95% confidence interval 50.11‐0.75). No significant differences were observed for the adjusted fall rates compared to placebo in any of the other supplement groups. CONCLUSION: Nursing home residents in the highest vitamin D group (800IU) had a lower number of fallers and a lower incidence rate of falls over 5 months than those taking lower doses. Adequate vitamin D supplementation in elderly nursing home residents could reduce the number of falls experienced by this high falls risk group. JA m Geriatr Soc 55:234–239, 2007.

To investigate the relation of circulating concentrations of vascular endothelial growth factor (VEGF) for the risk of developing cardiovascular disease (CVD) in a large community-based sample.We prospectively assessed the relation of circulating VEGF concentrations with the incidence of CVD among 3041 Framingham Heart Study participants (mean age 63.4±11.1 years, 59% women). Multivariable Cox proportional hazards models were estimated adjusting for standard risk factors to VEGF quartiles to incident CVD. Restricted cubic splines were used to examine the linearity of the association.After a mean follow-up of 8.8 (±2.8) years, 527 individuals experienced a first CVD event. Compared with participants in the first VEGF quartile, individuals in the second VEGF quartile had a 34% increased risk for future CVD (HR 1.34, 95% CI 1.03 to 1.74; p value=0.03) and individuals in third quartile had a 59% higher risk (HR 1.59; 95% CI 1.23 to 2.05, p value=0.0003). Individuals in the highest VEGF quartile had a similar cardiovascular risk as compared with those in the lowest VEGF quartile (HR 1.18, 95% CI 0.91 to 1.53, p value=0.21). Evaluation of restricted cubic splines confirmed the nonlinear, inverted U-shaped relation of serum VEGF and CVD events (p0.0001 for model fit, p=0.006 for non-linearity).Circulating VEGF concentrations exhibit a complex non-linear (inverted U-shaped) relation with the risk of developing CVD events, with the lowest risk experienced at the lower and upper end of the distribution. The underlying pathophysiological mechanisms remain to be elucidated.

It is well recognized that vitamin D plays an important role not only in bone health but also in the prevention of various chronic diseases, including obesity, diabetes, cardiovascular disease and ...

To determine vitamin D status and bone mineral density (BMD) in patients admitted to a subacute rehabilitation facility.Cross-sectional cohort study.Subacute rehabilitation facility.Fifty-three community-dwelling patients admitted from June through February 2005.Not applicable.BMD, 25-hydroxyvitamin D (25[OH]D), C-telopeptide (CTX), osteocalcin, and dietary milk intake.Prevalence of vitamin D deficiency (25[OH]D20 ng/mL) was 49.1%, while a total of 83% of patients were either vitamin D deficient or insufficient (25[OH]D30 ng/mL). The prevalence of osteopenia (T score,-1) was 52.8%; osteoporosis (T score,-2.5) was 17.0%. CTX (bone resorption marker) was elevated in 60.4% of patients. Osteocalcin (bone formation marker) was elevated in 13.2% of patients. Measurements of bone resorption and formation positively correlated (R2 = .22) indicating increased bone remodeling.Vitamin D deficiency and osteopenia and osteoporosis were highly prevalent in patients admitted for rehabilitation. Elevated bone resorption and remodeling were evident. This could be due to vitamin D deficiency that should be corrected before antiresorptive therapy is considered. The study emphasizes the need for vigilance for vitamin D status and BMD testing in patients admitted to rehabilitation facilities.

We compared the natural ultraviolet B (UV‐B) exposure, dietary vitamin D, and skin‐generated vitamin D synthesis for adult males of two species of Jamaican anoles. The more shade‐tolerant and thermal‐conforming Anolis lineotopus merope, rarely exposed to full sun, experienced less UV‐B irradiation in its shady environment than the more heliophilic and thermophilic Anolis sagrei, which frequently basked in full sun during the morning hours (0800–1100 hours). Both species obtained detectable levels of vitamin D3 in their diet, but the heliophilic A. sagrei obtained more. To compensate for less availability of UV‐B and dietary vitamin D, the skin of A. lineotopus merope seems to have acquired a greater sensitivity than that of A. sagrei regarding UV‐B‐induced vitamin D3 photobiosynthesis. We assessed this by observing a greater conversion of provitamin D to photoproducts in skin exposed to UV‐B from a sunlamp. The reduced skin sensitivity of A. sagrei regarding vitamin D photobiosynthesis may reflec...

We have previously documented that chronic UVB exposure of female panther chameleons within a specified dose range is critical for hatching success of their eggs. We have also documented that the mechanism of this effect includes the enhancement of vitamin D3 production in the skin. Here we report that the mechanism for this effect includes enhancement of egg vitamin D3 content. Hatch success in this species can be predicted not only by UVB dose of the mother but by egg vitamin D levels above 65 ng/g at the beginning of incubation, although lower levels can sometimes be associated with hatch success. Vitamin D status of the mother (circulating 25-hydroxyvitamin D3; calcidiol) may also be useful to predict hatching success but our sample size was too small to determine a predictive linear or threshold effect. Finally, we document that egg vitamin D3 content is steadily reduced during the prolonged 260 d incubation period, so one must assay at the beginning of incubation or state when vitamin D3 is...

The 25-hydroxyvitamin D3 (25-OH-D3) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We hypothesized that covalent attachment of a 25-OH-D3 analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D3 biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D3 into its analog. We showed earlier that 25-hydroxyvitamin D3-3-bromoacetate (25-OH-D3-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10−6 mol/L of 25-OH-D3-3-BE inhibited the growth of keratinocytes, LNCaP, and LAPC-4 androgen-sensitive and PC-3 and DU145 androgen-refractory prostate cancer cells, and PZ-HPV-7 immortalized normal prostate cells with similar or stronger efficacy as 1,25(OH)2D3. But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D3-3-BE was toxic to these prostate cancer cells and caused these cells to undergo apoptosis as shown by DNA-fragmentation and caspase-activation assays. In a reporter assay with COS-7 cells, transfected with a 1α,25-dihydroxyvitamin D3-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D3-3-BE induced 24-OHase promoter activity. In a “pull down assay” with PC-3 cells, 25-OH-D3-3-BE induced strong interaction between VDR and general transcription factors, retinoid X receptor, and GRIP-1. Collectively, these results strongly suggested that the cellular effects of 25-OH-D3-3-BE were manifested via 1,25(OH)2D3/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 μg/kg of 25-OH-D3-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D3-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.

Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female-to-male transsexuals are genetic females who suffer from gender dysphoria and thus take supra-physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton.A group of 15 female-to-male transsexuals was prospectively enrolled for observation over a 2-year period. The subjects had a mean age of 37.0 +/- 3.0 years. All of the subjects self-administered testosterone esters intramuscularly at a mean dose of 70.7 +/- 4.5 mg weekly.The subjects had measurements of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) of the femoral neck and spine (L2-L4) at 12-month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N-telopeptide (NTX) at the date of enrolment and at the end of 2 years. results There was a significant positive increase in mean BMD of 7.8% at the femoral neck and a nonsignificant increase in mean BMD of 3.1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female-to-male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study.We conclude that supra-physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis.

The hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D [1 alpha,25(OH)(2)D] promotes the differentiation and inhibits the proliferation, invasiveness and metastasis of prostate cells. However, 1 alpha,25(OH)(2)D is not suitable as a chemopreventive agent because its administration can cause hypercalcemia. Serum levels of 1 alpha,25(OH)(2)D are tightly regulated by the renal enzyme, 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase), which synthesizes 1 alpha,25(OH)(2)D from the prohormone, 25-hydroxyvitamin D [25(OH)D]. Normal prostate epithelial cells in primary culture, as well as several prostate cancer cell lines, also express 1 alpha-OHase and synthesize the hormone intracellularly. We now investigated the regulation of the prostate 1 alpha-OHase by the three most important regulators of the renal 1 alpha-OHase: calcium, 1 alpha,25(OH)(2)D and parathyroid hormone (PTH). The 1 alpha-OHase activity in the primary cultures of prostate epithelial cells was inhibited by 1 alpha,25(OH)(2)D(3) at 10 and 100 nM, whereas PTH at 10 and 100 nM had no significant effect. Calcium at 1.2 and 2.4 mM had no significant effect on the enzyme activity in the PZ-HPV-7 cell line, a prostate epithelial cell line derived from normal prostate tissue. Conversely, 1.2 or 2.4 mM calcium markedly inhibited 1 alpha-OHase activity in a human kidney cell line used as a positive control. Furthermore, PTH at 100 nM and calcium at 1.2 and 2.4 mM had no effect on the 1 alpha-OHase gene promoter activity in prostate cells, whereas the promoter activity was inhibited 48 +/- 5% by 100 nM 1 alpha,25(OH)(2)D(3). Our findings suggest that, unlike the renal enzyme, the prostate 1 alpha-OHase appears to be largely unregulated by serum levels of PTH and calcium. These findings support the hypothesis that vitamin D or 25(OH)D may be useful as chemopreventive agents for prostate cancer because their administration should cause an increased synthesis of 1 alpha,25(OH)(2)D within prostate cells.

Three types of broadband ultraviolet-B (UVB) radiometers were shown to display different irradiances from the same light source. Also, natural light and different lamp types were shown to have different vitamin D–synthesizing potential. Equations relating the irradiance readings from UVB radiometers from Gigahertz-Optik Inc., UVP Inc., and Spectronics Corp. to in vitro vitamin D–synthesizing potential are reported for four UVB sources. Zoo Biol 23:355–363, 2004. © 2004 Wiley-Liss, Inc.

We postulated that dietary ingestion of vitamin D may be used by some Alaskan Arctic marine mammal species in addition to, or instead of, cutaneous production to meet nutritional requirements. Zooplankton (n=5) sampled near Kaktovik, Alaska, contained no measurable vitamin D2 or D3, but did contain provitamin D (7-dehydrocholesterol), the cutaneous precursor for previtamin D3 in mammals. Fillets and livers from five fish species were sampled near Barrow, Alaska, and evaluated for vitamin D3 content (no vitamin D2 was detected). Differences in vitamin D3 content appeared significant (P≤0.10) among fish livers (Kruskal-Wallis [H test]=8.25, df=4, P=0.08) and among fish fillets (H=7.80, df=4, P=0.01). We also found significant differences in several pairwise comparisons (Mann-Whitney U-test) of vitamin D3 levels in fillets and livers. Blubber from six species of marine mammals had no detectable vitamin D2. The H test results for blubber vitamin D3 concentration were highly significant: 28.12, df=5, P

Background: Fortification of milk with vitamin D may not be adequate for satisfying the vitamin D requirement because of variability in vitamin D content after fortification and because many persons have milk allergy or lactose intolerance. Additional foods need to be fortified with vitamin D. Objective: We determined whether vitamin D, a fat-soluble vitamin, is bioavailable in orange juice and skim milk, 2 nonfat beverages. Design: On 3 separate occasions, 18 adults ingested 25 000 IU vitamin D 2 in 240 mL whole milk or skim milk or in 0.1 mL corn oil applied to toast. A separate, double-blind, randomized, controlled trial investigated whether the consumption of orange juice fortified with vitamin D 3 would increase serum 25-hydroxyvitamin D [25(OH)D] concentrations: 14 subjects ingested 240 mL orange juice fortified with 1000 IU vitamin D, and 12 subjects ingested a control orange juice daily for 12 wk. Results: Peak serum vitamin D 2 concentrations did not differ significantly after the ingestion of vitamin D 2 in whole milk, skim milk, or corn oil on toast. After subjects consumed orange juice fortified with 1000 IU vitamin D 3 daily for 12 wk, serum 25(OH)D 3 concentrations increased by 150%, and serum parathyroid hormone concentrations decreased by 25% compared with baseline; control subjects had a seasonal increase of 45% in 25(OH)D and no significant change in serum parathyroid hormone. Conclusions: The fat content of milk does not affect vitamin D bioavailability. Vitamin D fortification at 1000 IU/240 mL orange juice for 12 wk safely increased 25(OH)D 3 concentrations in adults. Am J Clin Nutr 2003;77:1478‐83.

The objective was to test a method of assessing sun exposure for use in stratifying adolescent girls according to potential for vitamin D 3 synthesis in the skin. Thirty-five girls wore polysulphone ultraviolet (UV) dosimeters and kept diaries of their activities on August 17, 2000. Minutes spent outdoors during each hour of the day were tabulated and adjusted for the fractional strength of ultraviolet B (UVB) radiation relative to peak hour. Total adjusted minutes outdoors were compared with UV dosimeter readings. A series of ampules containing 7-dehydrocholesterol were exposed on a flat plane to further investigate the potential for skin synthesis of previtamin D 3 with a given sun exposure. The correlation between measured UVB exposure and self-reported minutes outdoors adjusted for the time of day was r = 0.64. In vitro previtamin D 3 synthesis at midday was reduced by 50% on a cloudy day compared with a sunny day.

Background: The cholecalciferol inputs required to achieve or maintain any given serum 25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to the probable physiologic supply of the vitamin. Objectives: The objectives were to establish the quantitative relation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferol concentration and to estimate the proportion of the daily requirement during winter that is met by cholecalciferol reserves in body tissue stores. Design: Cholecalciferol was administered daily in controlled oral doses labeled at 0, 25, 125, and 250 � g cholecalciferol for � 20 wk during the winter to 67 men living in Omaha (41.2� N latitude). The time course of serum 25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment. Results: From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum 25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slope of � 0.70 nmol/L for each additional 1 � g cholecalciferol input. The calculated oral input required to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in the autumn) was 12.5 � g (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated at � 96 � g( � 3800 IU)/ d. By difference, the tissue stores provided � 78‐82 � g/d. Conclusions: Healthy men seem to use 3000‐5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D. Am J Clin Nutr 2003;77:204‐10.

The purpose of this work was to measure important nutritional status parameters for a group of free-ranging Mexican mantled howler monkeys (A. palliata mexicana) and compare those data to published data for primates. The nutritional status of six free-ranging Mexican mantled howler monkeys was examined using biochemical analysis. Blood samples were analyzed for serum chemistry; lipids; vitamins D, A, and E; carotenoids; and minerals. Serum chemistries were somewhat different from published values, but did not indicate clear abnormalities. Circulating lipids were not different from those in captive primates. Circulating vitamin D metabolites (83±16.3 for 25(OH)D ng/mL; 563±53.8 for 1,25(OH)2D pg/mL) were similar to those in wild-caught tamarins (Saguinus oedipus), lower than some published data for captive Cebidae and Callitrichidae, and higher than for Old World primates. Serum concentrations of retinol (16.5±1.64 μg/dl) were similar to those in captive spider monkeys (Ateles geoffroyi). Retinyl palmitate and retinyl stearate was present in howler samples and may have reflected recent dietary intake. Circulating α-tocopherol (997±97.6 μg/dl) was similar to published values for other primates. Carotenoid levels in howlers were within the ranges reported for many primates. A significant finding was the presence of cadmium in samples that should be further studied. The number of individuals sampled was limited, and further investigation into the effects of seasonality is needed. However, this information provides new data for howler monkeys and for free-ranging primates in general. Zoo Biol 22:239–251, 2003. © 2003 Wiley-Liss, Inc.

Two studies were conducted to determine the suitability of the Westron Corp. self-ballasted mercury vapor lamps in the captive maintenance of the chuckwalla lizard, Sauromalus obesus. Initially, preference for basking under either a Westron lamp or an incandescent flood lamp was measured in a separate enclosure involving five individuals selected from a group of eight juveniles. Following this, the eight chuckwallas were divided into two groups and maintained for fifteen months in indoor enclosures illuminated with either an incandescent flood lamp and fluorescent Sylvania 350 BL combination or a single Westron self-ballasted mercury vapor lamp. Snout-to-vent length (SVL), body mass, and cloacal body temperatures were measured every two weeks. After nine months, the lizards were radiographed to assess bone density and blood was collected for assay of 25-hydroxyvitamin D. No significant differences in SVL and body mass growth rates, cloacal body temperatures or bone densities were observed between...

Hepatocellular carcinoma (HCC) is the most diagnosed liver cancer without effective treatments available for advanced HCC. Vitamin D is getting popular due to its anti-cancer characteristics. However, the clinical application of 1α,25(OH)2D, the active form of vitamin, is hampered by its hypercalcemia side effect. 1α,25(OH)2D is converted from 25(OH)D, the index of serum vitamin D status, by CYP27B1, which is originally found in kidneys but recently detected in non-renal tissues. 25(OH)D has been shown to repress some cancers expressing CYP27B1 due to the local conversion of 25(OH)D to 1α,25(OH)2D, which works in a intra-, auto-, or paracrine manner and thus minimizes the risk of hypercalcemia. In this study, we found CYP27B1 expression in human hepatocyte, HCC, and HepG2 cells. As we treated HepG2 cells with 25(OH)D, the 1α,25(OH)2D target gene CYP24A1 expression was increased and was further upregulated as CYP27B1 transfection or downregulated as CYP27B1 knockdown. Other 1α,25(OH)2D target genes in HepG2 cells, p21 and p27 were also stimulated by 25(OH)D after CYP27B1 transfection. Further, 25(OH)D could inhibit HepG2 cells growth, which was potentiated by CYP27B1 transfection. Collectively, we showed for the first time that HCC expressed CYP27B1 and was able to covert 25(OH)D to 1α,25(OH)2D in vitro, thus responsive to 25(OH)D treatment. Our data justifies the application of 25(OH)D and CYP27B1 gene transfection therapy in further HCC treatment studies.

Evidence suggests that vitamin D may have a protective role for prostate cancer. 1α,25-Dihydroxyvitamin D [1α,25(OH)2D] inhibits growth and induces differentiation of prostate cells. 25-Hydroxyvitamin D-1α-hydroxylase [1α-OHase], the enzyme that is responsible for the synthesis of 1α,25(OH)2D, is expressed in cultured prostate cells. We observed a marked decrease in 1α-OHase activity in prostate cancer cells, suggesting some defect of the 1α-OHase in these cells. To investigate whether the defect was due to dysregulation of the enzyme at the promoter level, a series of deletion constructs of the promoter was synthesized and incorporated upstream into the luciferase reporter gene. Two regions were identified with high basal activity in transfected normal prostate cell line (PZHPV-7), −1100 bp (AN2), and −394 bp (AN5) upstream of ATG start site of the 1α-OHase gene. When the reporter gene with either AN2 or AN5 was transfected into prostate cancer cell lines, we observed a lower basal promoter activity in PC-3 cells and DU145 cells than that found in PZHPV-7 cells for both constructs, and a loss of promoter activity in LNCaP cells. Thus, the results suggest that the defect in enzyme activity may result from the decreased promoter activity in prostate cancer cells. J. Cell. Biochem. 88: 315–322, 2003. © 2002 Wiley-Liss, Inc.

Long-term vitamin D insufficiency can cause secondary hyperparathyroidism and osteomalacia (1). In addition, there is increasing evidence that vitamin D may protect against common cancers, such as cancer of the colon (2–4), prostate (5), and breast (6). Young adults aged 17 to 35 years drink inadequate amounts of milk (7) and are concerned about exposure to the sun because of the fear of developing skin cancer (8,9), which increases the risk of vitamin D insufficiency (10). We sought to examine the prevalence of vitamin D insufficiency in a group of free-living healthy young adults, consisting of mostly health care professionals, in Boston, Massachusetts.

Several disease syndromes in captive rhinoceroses have been linked to low vitamin status. Blood samples from captive and free-ranging black (Diceros bicornis) and white rhinoceros (Ceratotherium simum) and tissue samples of captive individuals from four rhinoceros species were analysed for vitamins A and E. Circulating vitamin A levels measured as retinol for free-ranging versus captive black and white rhinoceros were 0.04 (+/- 0.03 SD) vs. 0.08 (+/- 0.08) and 0.07 (+/- 0.04) vs. 0.06 (+/- 0.02) microgram/ml, respectively. Circulating vitamin E levels measured as alpha-tocopherol were 0.58 (+/- 0.30) vs. 0.84 (+/- 0.96) and 0.62 (+/- 0.48) vs. 0.77 (+/- 0.32) microgram/ml, respectively. In contrast to earlier findings, there was no significant difference in vitamin E concentration between captive and free-ranging black rhinoceros. When the samples of captive black rhinoceros were grouped into those taken before 1990 and after 1990, however, those collected before 1990 had significantly lower (P < 0.001) vitamin E levels (0.46 +/- 0.83 microgram/ml) and those collected in 1990 or later significantly higher (P < 0.001) vitamin E levels (1.03 +/- 1.04 micrograms/ml) than the captive population as a whole. This is probably due to increased dietary supplementation. There were significant differences in circulating vitamin concentrations in black rhinoceroses from different regions in the wild. Serum 25-hydroxy (OH) vitamin D3 averaged 55.7 ng/ml in free-ranging rhinoceroses; no carotenoids were detected in any blood samples. Captive black and white rhinoceroses appear to be adequately supplemented in vitamin A and E. Captive Indian rhinoceroses (Rhinoceros unicornis) had significantly lower vitamin A concentrations in blood (P < 0.001) and higher vitamin A concentrations in liver tissue samples (P < 0.001) than other rhinoceros species. Equine requirements are not recommended as a model for rhinoceros vitamin requirements.

Nutrition most certainly affects health and may play a role in the etiology of growth and reproductive problems in captive cheetah (Acinonyxjubatus) populations. The objective of our research was to examine nutritional differences between two dietary regimens and quantify their physiologic effects on cheetahs held in captivity. Twelve cheetahs were randomly assigned to either a commercial diet (COM) or a supplemented meat diet (SMD) group. These cats were physically examined and had blood samples taken three times over the course of a year. Representative samples of COM and four separate components of the SMD treatment were analyzed over the same time frame for proximate nutrient composition, digestibility, and concentrations of taurine, fat-soluble vitamins, and selected minerals. Concentrations of fat, vitamins A and E, Se, Fe, Cu, Na, and Mn were significantly higher in COM compared with those in SMD samples, with the exception of fat content in turkey. Mg content was lower in COM than in SMD; other nutrients did not differ. Mean concentrations of vitamins A and E in COM were markedly higher than in SMD samples (408,140 vs. 29,696 IU/kg dry matter [DM] and 431 vs. 48 IU/kg DM, respectively) and varied dramatically between sampling periods. Percent crude protein and protein-to-fat ratios were high for SMD compared with either whole prey-based or commercial food preparations. Blood urea nitrogen and serum creatinine levels were above normal reference means for domestic cats. Plasma concentrations of vitamins A, D, and E were significantly higher in COM-fed than in SMD-fed cheetahs. Both plasma retinol and tocopherol levels were almost three times higher in COM-fed cats (1.26 +/- 0.06 vs. 0.53 +/- 0.03 microg/ml and 17.5 +/- 0.7 vs. 6.4 +/- 0.02 microg/ml, respectively) and exceeded the normal ranges expected for domestic felids. Significant differences between male and female cheetahs were found for plasma concentrations of vitamin E, Se, and Fe after allowing for effects of diet and time of collection. Excess fat-soluble dietary vitamins can result in direct toxicities as well as nutrient antagonisms and may be linked to reproductive and health issues in captive cheetahs. The high protein levels found in SMD may be linked to chronic renal disease, which was detected in some of these cheetahs.

Having previously documented experimentally the need for ultraviolet B (UVB) irradiation (290–315 nm) in the light environment of captive female panther chameleons (Furcifer pardalis) to ensure hatching success of their eggs, we investigated optimal UVB irradiation levels. From 1996–1998 28 hatchling female panther chameleons were raised to maturity and bred (using vitamin and mineral-fortified insect diets low in vitamin D) in nine different artificial UVB light environments. Seven of the environments included long (12 hr/day) low irradia-tion exposures ranging from 1.7 to 22 μW/cm2 UVB, with a corresponding conversion of provitamin D3 to photoproducts in in vitro models of 0.18 to 1.52% in 2 hr. Two environments included short (0.5 and 1.0 hr/day), high irradiation exposures of 55 and 49 μW/cm2 UVB, respectively, with a corres-ponding conversion of provitamin D3 to photoproducts in in vitro models of 8.3% to 14.6% in the respective 0.5- and 1.0-hr time periods. Females raised with the mid-level long/low exposures (5–15 μW/cm2 UVB; 0.52–1.32% conversion to photoproducts in in vitro models) produced viable eggs with a significantly higher percentage of hatching compared to those with the extreme (highest or lowest) long/low exposures. Those raised with the short-/high-exposure environments produced viable eggs with a generally high percentage of hatching, but success was variable. The results and techniques for light quality assessment are interpreted, with recommendations for practical application by the herpetoculturist desiring to successfully breed panther chameleons in captivity. Zoo Biol 21:525–537, 2002. © 2002 Wiley-Liss, Inc.

Pancreatic cancer (PDA) is a devastating disease and there is no effective treatment available at present. To develop new regiments against PDA is urgently needed. Previously we have shown that vitamin D analog, MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), exerted potent antiproliferative effect on PDA in vitro and in vivo without causing hypercalcemia. Since metastasis is the major cause of PDA-related death, we therefore investigate the anti-metastasis effect of MART-10 on PDA. Our results showed that both 1α,25(OH)2D3 and MART-10 repressed migration and invasion of BxPC-3 and PANC cells with MART-10 much more potent than 1α,25(OH)2D3. 1α,25(OH)2D3 and MART-10 inhibited epithelial-mesenchymal transition (EMT) in pancreatic cancer cells through downregulation of Snail, Slug, and Vimentin expression in BxPC-3 and PANC cells. MART-10 further blocked cadherin switch (from E-cadherin to N-cadherin) in BxPC-3 cells. The F-actin synthesis in the cytoplasm of BxPC-3 cells was also repressed by 1α,25(OH)2D3 and MART-10 as determined by immunofluorescence stain. Both 1α,25(OH)2D3 and MART-10 decreased MMP-2 and -9 secretion in BxPC-3 cells as determined by western blot and zymography. Collectively, MART-10 should be deemed as a promising regimen against PDA.

// Kun-Chun Chiang 1,* , Chun-Nan Yeh 2,* , Kun-Ju Lin 3 , Li-Jen Su 4 , Tzu-Chen Yen 3 , Jong-Hwei S. Pang 5 , Atsushi Kittaka 6 , Chi-Chin Sun 7 , Miin-Fu Chen 2 , Yi-Yin Jan 2 , Tai C. Chen 8 , Horng-Heng Juang 9 and Ta-Sen Yeh 2 1 General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC 2 General Surgery Department, Chang Gung Memorial Hospital, Linkoul, Taoyuan, Taiwan, ROC 3 Nuclear medicine department, Chang Gung Memorial Hospital, Linkoul, Taoyuan, Taiwan, ROC 4 Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taoyuan, Taiwan, ROC 5 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC 6 Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1Kaga, Itabashi, Tokyo, Japan 7 Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC 8 Boston University School of Medicine, Boston, MA, USA 9 Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C * These Authors contributed equally to this work Correspondence: Tai C. Chen, email: // Horng-Heng Juang, email: // Ta-SenYeh, email: // Keywords : cholangiocarcinoma; vitamin D; chemoprevention; LCN2; NGAL Received : March 25, 2014 Accepted : May 20, 2014 Published : May 22, 2014 Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D supplementation is getting popular due to its anti-tumor functions after conversion to its active form, 1α,25(OH) 2 D. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH) 2 D 3 , LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analogs against ICC are warranted.

Objective: To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages. Methods: Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE e4, plasma homocysteine, waist-hip ratio, and physical activity. Results: Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p Conclusion: Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.

In Crohn's disease, severe skeletal demineralization, secondary hyperparathyroidism, and muscle weakness can occur. This may be caused by impaired vitamin D absorption, resulting from extensive intestinal disease and resection of duodenum and jejunum, where vitamin D is absorbed. We report a 57-year-old woman with a long history of Crohn's disease and short-bowel syndrome who had only 2 feet of small intestine remaining after 3 bowel resections. She was taking a daily multivitamin containing 400 IU of vitamin D(3) and was dependent on total parenteral nutrition that contained 200 IU of vitamin D and calcium (18 mEq in a 1-L bag infused over 8 hours daily) for a period of 36 months. Despite the above replacement, she complained of bone pain and muscle weakness, and she continued to be vitamin D-deficient with a 25(OH)D level

Estrogen metabolism in women with SLE is weighted towards 16alpha-hydroxyestrone, an estrogenic compound that might fuel disease activity. Indole-3-carbinol (I3C) is a nutritional compound that can shift estrogen metabolism towards less estrogenic metabolites. However, the effects of I3C in women with SLE have not been studied. Open-label 1-week metabolic study of 375 mg/day I3C was carried out in women with SLE, followed by a 3-month observational period for disease activity. The primary outcome measure was the change in ratio of urinary 2:16alpha hydroxyestrone levels. Secondary measures included the SLE Disease Activity Index. Seventeen clinically premenopausal women fulfilling ACR criteria for probable/definite SLE (mean age 37.9 y, range 20-49 y, mean disease duration 4.3 y, range 0.5-15) completed the 1-week metabolic study; 12 took I3C for 3 months. The mean 2:16alpha hydroxyestrone ratio increased by 1.84 to 3.15 (P = 0.0001). Mean SLEDAI scores were 10.0 (baseline); 6.25 (3 months); and 8.8 (3 months after withdrawal; P = NS). Women with SLE can manifest a metabolic response to I3C and might benefit from its antiestrogenic effects. We did not observe any striking effects on SLE disease activity during the 3-month observational period.

1 alpha,25-Dihydroxyvitamin D(3) (1 alpha,25(OH(2))D(3)) and its analogs are used to treat psoriasis because of their potent antiproliferative activity. They have the potential for causing hypercalcemia, however, and patients often become resistant to the drug. We examined the feasibility of enhancing the cutaneous production of 1 alpha,25(OH(2))D(3) using a human 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase) plasmid. The 1 alpha-OHase gene was fused to the green fluorescent protein gene (1 alpha-OHase-GFP) driven by the cytomegalovirus promoter. Transfection of cultured normal human keratinocytes with the 1 alpha-OHase-GFP plasmid resulted in a marked increase in the expression of 1 alpha-OHase-GFP in the mitochondria. Transfection of keratinocytes with 1 alpha-OHase-GFP or 1 alpha-OHase plasmids in vitro enhanced the 1 alpha-OHase activity substantially and increased the sensitivity of the keratinocytes to the antiproliferative effect of 25(OH)D(3). The 1 alpha-OHase-GFP plasmid was topically applied to shaved C57/BL6 mice. Twenty-four hours after topical application, immunohistochemical analysis of the skin for 1 alpha-OHase-GFP revealed the presence of 1 alpha-OHase-GFP in the epidermis and epidermal appendages including the hair follicles. The results from this study offer a unique new approach for the topical treatment of hyperproliferative disorders such as psoriasis and skin cancer using the 1 alpha-OHase gene that could locally increase the production of 1 alpha,25(OH(2))D(3) without causing hypercalcemia or resistance.

Most bats of the suborder Microchiroptera are nocturnal, actively avoid sunlight, and eat mineral-poor diets. In those bats previously studied with respect to mineral metabolism, extensive bone remodeling occurs, and it has been suggested that calcium has been an important constraint on reproduction. There have been no previous studies of vitamin D or its metabolites in microchiropteran bats with respect to calcium metabolism. Reported is the utilization of current advances for the determination of serum levels of the vitamin D metabolite 25-hyroxyvitamin D (25-OH-D) in a neotropical bat, Artibeus jamaicensis. Serum from wild-caught animals contained low levels of 25-OH-D (5.6 +/- 3.0 ng/ml, n = 8). Bats maintained on a vitamin-D-supplemented diet had higher serum 25-OH-D levels and when the diet containing vitamin D was discontinued, mean serum 25-OH-D levels declined significantly after 6 months. Serum calcium concentrations in wild-caught bats (8.5 +/- 0.4 mg%) showed very little variation and were not significantly different in any of the vitamin-D-supplemented animals. A pairwise correlation analysis between 25-OH-D and serum calcium levels revealed no linear correlation. The results indicate either that 25-OH-D does not appear to play a key role or that low levels of 25-OH-D may be adequate in regulating serum calcium levels in this bat.

Background Although topical 1,25-dihydroxyvitamin D3 (calcitriol, 1,25(OH) 2 D 3 ) and its analogues, calcipotriol and tacalcitol, are effective for patients with psoriasis, some patients show little or no response, There is a need to develop more potent analogues of 1,25(OH) 2 D 3 . Hexafluoro-1,25(OH) 2 D 3 (F 6 -1,25(OH) 2 D 3 ) is at least 10 times more potent than 1,25(OH) 2 D 3 on calcium metabolism. Objectives We were interested in whether F 6 -1,25(OH) 2 D 3 was also more potent than 1,25(OH) 2 D 3 in inhibiting normal human and psoriatic keratinocyte proliferation. Methods The antiproliferative activity of F 6 -1,25(OH) 2 D 3 and 1,25(OH) 2 D 3 was determined by 3 H-thymidine incorporation into keratinocyte DNA and by counting basal cells. Results F 6 -1,25(OH) 2 D 3 was approximately 10-fold more active and had a longer lasting antiproliferative effect than 1,25(OH) 2 D 3 on normal human keratinocytes, and was about 100-fold more potent than 1,25(OH) 2 D 3 on human psoriatic keratinocytes as determined by 3 H-thymidine incorporation. F 6 -1,25(OH) 2 D 3 also caused a dose-dependent decrease in the number of basal cells and was 100-fold more active than 1,25(OH) 2 D 3 . Conclusions The increased potency and the long-lasting effects of F 6 -1,25(OH) 2 D 3 suggest that F 6 -1,25(OH) 2 D 3 may be a potent candidate agent for treating psoriasis.

Skin is in the site of previtamin D3 and vitamin D3 synthesis and their isomerization in response to ultraviolet irradiation. At present, little is known about the function of the photoisomers of previtamin D3 and the vitamin D3 in skin cells. In this study we investigated the antiproliferative activity of the major photoisomers and their metabolites in the cultured human keratinocytes by determining their influence on 3H-thymidine incorporation into DNA. Our results demonstrated at both 10(-8) and 10(-6) M in a dose-dependent manner. Lumisterol, tachysterol3, 5,6-trans-vitamin D3, and 25-hydroxy-5,6-trans-vitamin D3 only induced significant inhibition at 10(-6) M. 25-Hydroxytachysterol3 was approximately 10- to 100-fold more active than tachysterol3. 7-Dehydrocholesterol was not active even at 10(-6) M. The dissociation constants of vitamin D receptor (VDR) for 25-hydroxytachysterol3, 25-hydroxy-5,6-trans-vitamin D3, and 5,6-trans-vitamin D3 were 22, 58, and 560 nM, respectively. The dissociation constants for 7-dehydrocholesterol, tachysterol, and lumisterol were greater than 20 microM. In conclusion, vitamin D3, its photoisomers and the photoisomers of previtamin D3 have antiproliferative activity in cultured human keratinocytes. However, the antiproliferative activity did not correlate with their binding affinity for VDR. The results suggest that some of the photoproducts may be metabolized to their 25-hydroxylated and 1 alpha,25-dihydroxylated counterparts before acting on VDR. Alternatively, a different receptor may recognize these photoproducts or another mechanism may be involved in modulating the antiproliferative activity of the photoisomers examined.

The opportunity and ability to photobiosynthesize vitamin D3 by exposing skin to ultraviolet-B (UVB) irradiation from the sun was compared using the nocturnal/crepuscular Mediterranean House Gecko Hemidactylus turcicus and the diurnal Texas Spiny Lizard Sceloporus olivaceous. Texas spiny lizards had a greater opportunity for photobiosynthetic production of vitamin D3 than geckos. This was revealed by vitamin D3 photoproduct production in models (ampoules containing an alcohol solution of vitamin D3 precursor) placed at locations inhabited by free-living lizards at similar times of occupancy. Alternatively, geckos seemed able to maximize their limited photobiosynthetic opportunity with a higher rate of conversion of provitamin D3 to photoproducts. This was revealed by photoproduct conversion in patches of lizard skin exposed to ultraviolet lamps in the laboratory. Stomach-content analysis showed the spiny lizards to have dietary sources of vitamin D3, the geckos may or may not. This is the first d...

Rickets and osteomalacia have been reported frequently in captive callitrichids. Some have assumed that these conditions are a consequence of unmet, unusually high requirements for vitamin D and that these high requirements are characteristic of all New World primates. As a consequence, certain commercial diets formulated for New World primates contain such high concentrations of vitamin D that their consumption by other species has resulted in signs of vitamin D toxicity. This study was conducted to assess the vitamin D status of captive cotton-top tamarins consuming diets providing either 2,500 or 26,000 IU of vitamin D3/kg dry matter. These diets had been consumed for at least 2 years before the study, with the lower vitamin D intakes by six tamarins (0.5 to 9 years old) in a zoo colony and the higher vitamin D intakes by 24 tamarins (2 to 12 years old) in a pharmaceutical research laboratory. Although not measured in this study, none of the dietary ingredients has been shown to contain vitamin D2. Serum 25-hydroxyvitamin D (25(OH)D) concentrations in the captive tamarins were compared with serum 25(OH)D concentrations (range, 25.5–120 ng/mL; 64–300 nmol/L) reported by others in healthy wild tamarins in Colombia, South America. Concentrations of 25(OH)D in serum from zoo tamarins consuming 2,500 IU vitamin D3/kg dietary dry matter ranged from 48 to 236 ng/mL (120–590 nmol/L), whereas those in serum from laboratory tamarins fed 26,000 IU vitamin D3/kg dietary dry matter ranged from 11 to 560 ng/mL (28–1,400 nmol/L), with no significant (P > 0.05) association between serum 25(OH)D concentration and sex or age. However, in the laboratory tamarins, serum 25(OH)D concentrations ranged from 46 to 60 ng/mL (115–150 nmol/L) in one 8-year-old male and four 12-year-old females that had four to nine pregnancies each. Younger females (2–5 years old) that had zero or one pregnancy and the other males (3–12 years old) generally had serum 25(OH)D concentrations above 126 ng/mL (315 nmol/L). None of the individuals in the zoo colony showed signs of colitis. Of the two tamarins in the laboratory group with 25(OH)D levels below 50 ng/mL (125 nmol/L), one was a 4-year-old male with anorexia and cachexia associated with severe colitis. The second was a 7-year-old clinically normal, multiparous (five) female with normal hematology and clinical chemistry but histologic evidence of severe colitis. Because all other individuals in this group had histologic evidence of moderate to severe colitis but were normal in other respects, an unequivocal association between low serum 25(OH)D concentrations and colitis was not apparent. A dietary vitamin D3 concentration of 2,500 IU/kg dry matter was more than sufficient to support serum 25(OH)D concentrations equivalent to those found in the wild and, although the number of observations was small, supported apparently normal growth and adult weights, reproduction through five parities, and general health in a zoo colony showing no evidence of colitis. Zoo Biol 18:473–480, 1999. © 1999 Wiley-Liss, Inc.

Plasma 25-hydroxyvitamin D was measured in 40 healthy, mostly Black, mother-infant pairs. Although a majority of mothers received a daily prenatal multivitamin, vitamin D deficiency (

Elderly women are at increased risk for bone loss and fractures. In previous cross-sectional and longitudinal studies of women residing in northern latitudes, bone loss was most pronounced during winter months and in those consuming less than 1 g calcium per day. In this study we sought to test the hypothesis that calcium supplementation by either calcium carbonate or dietary means would prevent seasonal bone loss and preserve bone mass. Sixty older postmenopausal women without osteoporosis were randomized to one of three treatment arms: Dietary milk supplementation (D-4 glasses of milk/day), Calcium carbonate (CaCO3-1000 mg/day in two divided doses), or placebo (P). After 2 yr, placebo-treated women consumed a mean of 683 mg/day of calcium and lost 3.0% of their greater trochanteric (GT) bone mineral density (BMD) (P < 0.03 vs. baseline); Dietary supplemented women averaged a calcium intake of 1028 mg/day and sustained minimal loss from the GT (-1.5%; P = 0.30), whereas CaCO3-treated women (total Ca intake, 1633 mg/day) suffered no bone loss from the GT and showed a significant increase in spinal and femoral neck BMD (P < 0.05). Femoral bone loss occurred exclusively during the two winters of the study (i.e. total loss, -3.2%; P < 0.02 in placebo-treated women) with virtually no change in GT BMD during summer. Serum 25-OH vitamin D declined by more than 20% (P < 0.001) in all groups during the winter months but returned to baseline in summer; PTH levels rose approximately 20% (P < 0.001) during winter but did not return to baseline during the summers. Urine N-telopeptide and osteocalcin levels increased significantly but only in the P-treated women and only during winter. Serum insulin growth factor binding protein 4, an inhibitory insulin growth factor binding protein, rose 15% (P < 0.03) from summer to winter, but this increase was significant only in those women consuming

Objectives: Because several serum studies of vitamin D metabolites have produced equivocal results on their relation to prostate cancer risk, the purpose of this study is to evaluate this association further. Methods: A nested case-control study in a cohort of 3,737 Japanese-American men examined from 1967 to 1970 was conducted in Hawaii (United States). At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of over 23 years, 136 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 136 matched controls were measured for the following: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, phosphorus, and parathyroid hormone. Results: There were no notable differences between cases and controls in their median serum levels of the five laboratory measurements. Odds ratios (OR) for prostate cancer, based on the quartiles of serum levels in controls, were also determined. The ORs for the highest quartiles relative to the lowest were 0.8 (95 percent confidence interval [CI] = 0.4-1.8) for 25-hydroxyvitamin D and 1.0 (CI = 0.5-2.1) for 1,25-dihydroxyvitamin D. Conclusion: It is possible that the lack of sufficient numbers of study subjects with low vitamin D levels affected the results. Nonetheless, the findings suggest that there is a lack of a strong association between vitamin D and prostate cancer.

The difference between serum levels from 36 captive and 56 free-ranging polar bears (Ursus maritimus) for 25-hydroxyvitamin D (25-OH-D) was found not to be significant (mean ± SD = 348 ± 215 nmol/L [captive], 360 ± 135 nmol/L [free-ranging], t = 0.30, df = 52.8, P = 0.76), whereas the difference for retinol and α-tocopherol was significant (retinol, 1.37 ± 0.67 μmol/L [captive] 1.89 ± 0.63 μmol/L [free-ranging], t = 3.88, df = 72.4, P

The potency of 25-hydroxyvitamin D3 (25(OH)D3) is increased by several fold through its metabolism into 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) by cytochrome P450 27B1 (CYP27B1). Thus, the pivotal role of 1α-hydroxylation in the activation of vitamin D compounds is well known. Here, we examined the metabolism of 25-hydroxy-16-ene-23-yne-vitamin D3 (25(OH)-16-ene-23-yne-D3), a synthetic analog of 25(OH)D3 in a cell-free system and demonstrated that 25(OH)-16-ene-23-yne-D3 is neither activated by CYP27B1 nor inactivated by cytochrome P450 24A1 (CYP24A1). These findings were also confirmed in immortalized normal human prostate epithelial cells (PZ-HPV-7) which are known to express both CYP27B1 and CYP24A1, indicating that the structural modifications featured in 25(OH)-16-ene-23-yne-D3 enable the analog to resist the actions of both CYP27B1 and CYP24A1. To provide intelligible structure-function information, we also performed molecular docking analysis between the analog and CYP27B1. Furthermore, 25(OH)-16-ene-23-yne-D3 was found to suppress the growth of PZ-HPV-7 cells with a potency equivalent to 1α,25(OH)2D3. The antiproliferative activity of 25(OH)-16-ene-23-yne-D3 was found to be vitamin D receptor (VDR)-dependent as it failed to inhibit the growth of mammary tumor cells derived from VDR-knockout mice. Furthermore, stable introduction of VDR into VDR-knockout cells restored the growth inhibition by 25(OH)-16-ene-23-yne-D3. Thus, we identified 25-hydroxy-16-ene-23-yne-vitamin D3 as a novel non-1α-hydroxylated vitamin D analog which is equipotent to 1α,25(OH)2D3 in its antiproliferative activity. We now propose that the low potency of the intrinsic VDR-mediated activities of 25(OH)D3 can be augmented to the level of 1α,25(OH)2D3 without its activation through 1α-hydroxylation by CYP27B1, but by simply preventing its inactivation by CYP24A1.

We determined the association of vitamin D deficiency and the FokI polymorphism of the vitamin D receptor (VDR) gene in 760 patients who underwent angiography due to suspected coronary artery disease (CAD). Angiography and the Rentrop scoring system were used to classify the severity of CAD in each patient and to grade the extent of collateral development, respectively. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the FokI VDR gene polymorphism. The prevalence of severe vitamin D deficiency (serum 25(OH)D < 10 ng/mL) was significantly higher in patients with at least one stenotic coronary artery compared to those without any stenotic coronary arteries. Severe vitamin D deficiency was not independently associated with collateralization, but it was significantly associated with the VDR genotypes. In turn, VDR genotype was independently associated with the degree of collateralization; the Rentrop scores were the highest in FF, intermediate in Ff, and the lowest in the ff genotype. The results show that FokI polymorphism is independently associated with collateralization. Additionally, vitamin D deficiency is more prevalent in patients with CAD that may result from FokI polymorphism. Therefore, maintaining a normal vitamin D status should be a high priority for patients with CAD.

The absorptive response to graded doses of vitamin D3, 25(OH)D, and 1,25(OH)2D was measured in healthy adult men after treatment periods of eight, four, and two weeks, respectively. While no relationship was found between baseline absorption and serum vitamin D metabolite levels, all three vitamin D compounds significantly elevated 45Ca absorption from a 300 mg calcium load given as part of a standard test meal. 1,25(OH)2D was active even at the lowest dose (0.5 microgram/day), and the slope was such that doubling of absorption would occur at an oral dose of approximately 3 micrograms/day. 25(OH)D was also active in elevating absorption and did so without raising total 1,25(OH)2D levels. On the basis of the dose response curves for 1,25(OH)2D and 25(OH)D, the two compounds exhibited a molar ratio for physiological potency of approximately 100:1. The absorptive effect of vitamin D3 was seen only at the highest dose level (1250 micrograms, or 50,000 IU/day) and was apparently mediated by conversion to 25(OH)D. Analysis of the pooled 25(OH)D data from both the 25(OH)D- and vitamin D3-treated groups suggests that approximately one eighth of circulating vitamin D-like absorptive activity under untreated conditions in winter may reside in 25(OH)D. This is a substantially larger share than has been predicted from studies of in vitro receptor binding.

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as "squirting papilla". Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 micrograms/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e-, CDw49f-, CD29-, and CD44(std.)-immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.

We hypothesized the vitamin D-deficient green iguanas with depleted calcium stores would seek to augment calcium intake by self-selection of a high calcium source. Eight green iguanas were offered free-choice ground oystershell in addition to their regular diet. Of these, two had not been exposed to ultraviolet (UV-B) radiation for > 5 years and were demonstrated to be vitamin D-deficient by low circulating levels of the principal vitamin D metabolite, calcidiol (25-hydroxy-cholecalciferol). The six others had been exposed to a UV-B emitting bulb for the previous 3 years and had high circulating calcidiol levels. Average daily food intake (expressed as dry matter per kg body mass) did not differ between the Low-D and High-D iguanas. The daily oystershell intake of the Low-D iguanas (0.02–0.03 g/kg) was lower than that of the High-D iguanas (0.06–0.70 g/kg), leading to a significant difference in calcium intake. The failure of iguanas to increase calcium intake in response to vitamin D-deficiency was puzzling and suggests that vitamin D, as a steroid hormone, may play some role in the expression of calcium appetite. Zoo Biol 16:201–207, 1997. © 1997 Wiley-Liss, Inc.

Bone disease related to vitamin D deficiency is an insidious problem in captive colonies of callitrichids. Currently a diagnosis of vitamin D deficiency may be made after the appearance of clinical pathology, usually bone deformities or fractures. The development of assays for vitamin D metabolites suggests it may be possible to detect incipient vitamin D deficiency before animals are adversely affected. However, there are few data on normative levels of these metabolites in any nonhuman primates. We collected blood samples from 18 wild cotton-top tamarins (Saguinus oedipus) from Colombia and assayed them for 25-hydroxy vitamin D(25-OH-D), the major circulating form of the vitamin, which is believed to be a good indicator of status. Serum concentrations of 25-OH-D averaged 76.4 ng/ml (range 25.5–120 ng/ml). This is high compared with human norms (10–55 ng/ml), but the range is lower than that reported in the literature for captive callitrichids. Juveniles had higher serum concentrations than did adults, and pregnant females had lower concentrations than did nonpregnant females. These data confirm that healthy callitrichids have higher circulating levels of 25-OH-D than do humans, but they suggest that the extremely high levels found in some captive animals (300–600 ng/ml) may be above normal. We propose that serum concentrations of 25-OH-D of 50–120 ng/ml can be considered normal for cotton-top tamarins and perhaps other callitrichids. If serum values much below 50 ng/ml are found during clinical evaluation, the possibility of incipient vitamin D deficiency should be considered. Zoo Biol 16:39–46, 1997. © 1997 Wiley-Liss, Inc.

With the recent advance in breast cancer therapy, the survival rate of breast cancer patients has improved greatly. In spite of the progress, 25–50% of breast cancer patients eventually will develop metastasis. Due to limited early detection methods, metastasis is usually diagnosed at the late stages beyond recovery likely due to resistance to currently available breast cancer therapies. Thus, a new strategy to prevent cancer cell growth and repress tumor metastasis is desirable. The active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ], has anti-invasion and anti-migration properties in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemic side effect. Previously, we have demonstrated that a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D 3 (MART-10), is 1000-fold more active than 1α,25(OH) 2 D 3 in suppressing MCF-7 cells growth through cell cycle arrest and apoptosis induction. In the current study, we show for the first time that MART-10 is more active than 1α,25(OH) 2 D 3 in preventing MCF-7 cell invasion and migration likely mediated through the upregulation of E-cadherin, and the downregulation of Snail, Slug, and Twist, the transcription factors implicated in epithelial–mesenchymal transition (EMT), as well as MMP-13. Based on the current in vitro and the highly anti-tumor characteristics of MART-10 in a pancreatic xenograft model, MART-10 is deemed as a promising candidate for breast cancer treatment. Further in vivo animal study comparing MART-10 with 1α,25(OH) 2 D 3 and other potent and less calcemic analogs of vitamin D is warranted.

Convergent evidence from human and non-human animal studies suggests aerobic exercise and increased aerobic capacity may be beneficial for brain health and cognition. It is thought growth factors may mediate this putative relationship, particularly by augmenting plasticity mechanisms in the hippocampus, a brain region critical for learning and memory. Among these factors, glucocorticoids, brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), hormones that have considerable and diverse physiological importance, are thought to effect normal and exercise-induced hippocampal plasticity. Despite these predictions, relatively few published human studies have tested hypotheses that relate exercise and fitness to the hippocampus, and none have considered the potential links to all of these hormonal components. Here we present cross-sectional data from a study of recognition memory; serum BDNF, cortisol, IGF-1, and VEGF levels; and aerobic capacity in healthy young adults. We measured circulating levels of these hormones together with performance on a recognition memory task, and a standard graded treadmill test of aerobic fitness. Regression analyses demonstrated BDNF and aerobic fitness predict recognition memory in an interactive manner. In addition, IGF-1 was positively associated with aerobic fitness, but not with recognition memory. Our results may suggest an exercise adaptation-related change in the BDNF dose-response curve that relates to hippocampal memory.

Pancreatic cancer is a lethal disease with no known effective chemotherapy and radiotherapy, and most patients are diagnosed in the late stage, making them unsuitable for surgery. Therefore, new therapeutic strategies are urgently needed. 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is known to possess antitumor actions in many cancer cells in vitro and in vivo models. However, its clinical use is hampered by hypercalcemia. In this study, we investigated the effectiveness and safety of a new generation, less calcemic analog of 1α,25(OH)2D3, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), in BxPC-3 human pancreatic carcinoma cells in vitro and in vivo. We demonstrate that MART-10 is at least 100-fold more potent than 1α,25(OH)2D3 in inhibiting BxPC-3 cell proliferation in a time- and dose-dependent manner, accompanied by a greater upregulation of cyclin-dependent kinase inhibitors p21 and p27 and a greater downregulation of cyclin D3 and cyclin-dependent kinases 4 and 5, leading to a greater increase in the fraction of cells in G0/G1 phase. No induction of apoptosis and no effect on Cdc25 phosphatases A and C were observed in the presence of either MART-10 or 1α,25(OH)2D3. In a xenograft mouse model, treatment with 0.3 µg/kg body weight of MART-10 twice/week for 3 weeks caused a greater suppression of BxPC-3 tumor growth than the same dose of 1α,25(OH)2D3 without inducing hypercalcemia and weight loss. In conclusion, MART-10 is a promising agent against pancreatic cancer growth. Further clinical trial is warranted.