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Vitamin K deficiency and osteopenia in vitamin D-deficient elderly women with Parkinson's disease.

OBJECTIVE: To assess the influence of vitamin K on bone mineral density (BMD) in vitamin-D-deficient women with Parkinson's disease (PD). DESIGN: Cross-sectional study. SETTING: Neurology department at a university medical center in Japan. PARTICIPANTS: Sixty-two women with PD (mean age, 70.7yr) and 62 age-matched controls. Patients were divided into 2 groups according to their functional capabilities: group A (independent: stages I-II of Hoehn and Yahr stages of Parkinson's disease, n = 26); and group B (dependent: Hoehn and Yahr stages 3-5; n = 36). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sera were analyzed to relate vitamin K concentrations to bone-related biochemical indices. BMD was measured by computed radiograph densitometry. RESULTS: Group B had significantly lower metacarpal BMD (P <.0001) lower serum concentrations of vitamin K1 (P <.01) and 25-hydroxyvitamin D (25-OHD; P <.0001) than group A. Serum undercarboxylated osteocalcin levels were higher in group B than in group A (P <.0001). The serum concentration of vitamin K1 correlated positively with that of 25-OHD (r =.735, P <.0001), and negatively with undercarboxylated osteocalcin (r = -.751, P <.0001) and Hoehn and Yahr stages (r =.787, P <.0001). Multiple regression analysis identified Hoehn and Yahr stages, vitamin K1, 25-OHD, and undercarboxylated osteocalcin as independent determinants of BMD (P <.0364.0003). CONCLUSION: In functionally dependent women with PD, nutritional vitamin K1 deficiency is believed to reduce production of fully carboxylated osteocalcin, causing reduced BMD.

Aged↗

The effects of ascorbic acid, vitamin B6, vitamin B12, and folic acid supplementation on the breast milk and maternal nutritional status of low socioeconomic lactating women.

In this double-blind study, the effects of ascorbic acid, vitamin B6, vitamin B12, and folate supplementation on the maternal nutritional status and vitamin content of breast milk in 16 low socioeconomic lactating women were studied. Nine subjects were administered a commercial multivitamin-multimineral supplement and seven were given placebos. Milk samples were collected four times per day at 4-h intervals from 5 to 7 and 43 to 45 days postpartum. Fasting blood samples were taken from all mothers at the end of each milk collection period. Dietary records of all foods consumed were kept from 4 to 7 and 42 to 45 days postpartum. There were no significant differences in milk or plasma levels of ascorbic acid between the unsupplemented and supplemented groups. Both the EGPT index and milk concentration of vitamin B6 were significantly different (p less than 0.01) between the unsupplemented and supplemented groups. The milk concentrations of vitamin B12 increased significantly (p less than 0.05) in the supplemented group, as did the milk concentrations of folate (p less than 0.01). Because of consistently low levels of dietary vitamin B6 and folic acid in this group of low socioeconomic lactating women, either dietary changes or supplements could be necessary to maintain recommended levels of these vitamins in the womens' breast milk.

Ascorbic Acid↗

Physical or temporal separation of olestra and vitamins A, E and D intake decreases the effect of olestra on the status of the vitamins in the pig.

A study was conducted in the domestic pig to determine 1 ) whether feeding olestra mixed in the diet exaggerated olestra effects on fat-soluble vitamin status compared with the effects of feeding it in a typical snack food, and 2) whether separating olestra consumption temporally from vitamin consumption affected the influence of olestra on vitamin status. Groups of 10 pigs each, five castrated males and five females, were fed 2.2% (wt/wt) olestra for 4 wk in purified diet that provided 1 time the National Research Council's requirements for swine of all micronutrients. The olestra was either mixed in the purified diet or fed in potato chips. The potato chips were given to the pigs at all three feedings, at the noon feeding only, or between the noon and the evening feedings. A control group was fed the purified diet with no olestra. The effects of olestra on indices of vitamin A, D and E status were from 1.7 to 4.5 times greater when olestra was fed three times daily mixed in the diet than when it was fed three times daily in potato chips. Because the effect of olestra on the status of the fat-soluble vitamins was diminished substantially by feeding the olestra in potato chips, it was not possible to conclude definitively how the temporal separation of olestra and vitamin consumption affected the olestra effect on vitamin status.

25-Hydroxyvitamin D 2↗

What is an adequate dose of oral vitamin B12 in older people with poor vitamin B12 status?

The prevalence of vitamin B12 deficiency increases in the elderly, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish, and dairy foods. Depending on the biochemical criterion that is used, 5% to more than 20% of older adults have marginal or frank vitamin B12 deficiency. Adults over 50 years of age should meet the Recommended Dietary Allowance by consuming vitamin B12 in the crystalline form, which does not require gastric acid or enzymes for initial digestion. A recent clinical trial suggests that an oral dose of 500 microg/d of crystalline vitamin B12 is needed to reverse biochemical signs of vitamin B12 deficiency in older adults.

Aged↗

Intestinal absorption of mixed micellar phylloquinone (vitamin K1) is unreliable in infants with conjugated hyperbilirubinaemia: implications for oral prophylaxis of vitamin K deficiency bleeding.

OBJECTIVE: To compare the pharmacokinetics and efficacy of oral versus intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic liver disease, a known risk factor for vitamin K deficiency bleeding. DESIGN: Prospective randomised controlled study. SETTING: Paediatric Liver Unit. PATIENTS: Forty four infants less than 6 months of age with conjugated hyperbilirubinaemia. MAIN OUTCOME MEASURES: Serum concentrations of vitamin K(1) and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of vitamin K status) before and for up to four days after a single dose of mixed micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24 hours after oral K(1) with those from 14 healthy newborns given the same dose. RESULTS: At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K deficiency. Median serum K(1) concentrations were similar in the oral and intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml) of serum K(1) compared unfavourably with the much higher levels (median 77, range 11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested impaired and erratic intestinal absorption in cholestatic infants. The severity of malabsorption was such that only 4/24 (17%) achieved an incremental rise in serum K(1) > 10 ng/ml. CONCLUSIONS: The intestinal absorption of mixed micellar K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the strong association between cholestasis and late vitamin K deficiency bleeding, these data provide an explanation for the failure of some oral vitamin K(1) prophylaxis regimens in infants with latent cholestasis.

Administration, Oral↗

The second international standard for vitamin D: crystalline vitamin D3.

This report was presented to the Subcommittee on Fat-Soluble Vitamins of the WHO Expert Committee on Biological Standardization in 1949 by the Vitamin D Sub-Committee of the Accessory Food Factors Committee of the Medical Research Council of Great Britain and formed the evidence on which the first-mentioned subcommittee based its recommendation of the adoption of crystalline vitamin D(3) as the International Standard for Vitamin D, replacing the solution of irradiated ergosterol which had been adopted as Standard in 1931.The Vitamin D Sub-Committee organized a collaborative assay in which 32 laboratories in seven countries participated. In addition to 29g of crystalline vitamin D(3) generously contributed by five firms, the following preparations were compared for vitamin D activity by biological tests on rats or chicks or both: the then current International Standard, a preparation of the purest calciferol obtainable, the British Standards Institution (BSI) Standard, the United States Pharmacopeia (USP) Reference Cod Liver Oil, and the Swedish provisional standard.Altogether 29 rat assays and 25 chick assays were carried out, and the results were subjected to standard methods of analysis. The BSI Standard and the pure calciferol were found less potent than the Old Standard (potency ratios: 0.916 and 0.933, respectively); and the New Standard may be slightly less potent (0.981), but it is more potent than the BSI Standard (1.071). The USP Reference Oil is less potent than the BSI Standard (0.949), the Old Standard (0.896), and the New Standard (0.886). The fiducial range is generally less than 10%, but even where it is greater, it is still satisfactory for a biological test.

Animals↗

Effect of vitamin C upon gastric mucosal O6-alkyltransferase activity and on gastric vitamin C levels.

The repair enzyme O6-alkyltransferase will repair O6-methylguanine adducts in human DNA. In gastric mucosal DNA these adducts may be formed as a result of exposure to nitrosamines within the gastric lumen. The formation of these nitrosamines may be inhibited by vitamin C. We have examined the effect of oral vitamin C supplementation upon intragastric vitamin C levels and gastric mucosal O6-alkyltransferase levels in 48 patients. Intragastric vitamin C levels were significantly elevated in those patients with normal gastric mucosal histology after treatment, although a variable response in intragastric vitamin C to supplementation was seen in the presence of chronic atrophic gastritis. Gastric mucosal O6-alkyltransferase activities ranged from 100 to 950 fmol/mg protein before vitamin C administration. The range of enzyme activity was similar after the course of vitamin C (62-1137 fmol/mg) but O6-alkyltransferase activities were found to be higher in 33 of the 48 patients following treatment (P < 0.01). Once again this effect was more pronounced in patients with normal gastric mucosa than those displaying evidence of chronic atrophic gastritis. We speculate that inhibition of intragastric nitrosation by vitamin C results in decreased formation of O6-methylguanine-DNA. In consequence, less O6-alkyltransferase is consumed in repairing these adducts resulting in higher tissue levels of this enzyme.

Ascorbic Acid↗

Differences in the metabolism of vitamin D2 and vitamin D3 by subcellular fractions from rat liver.

The 25-hydroxylation of vitamin D2 and vitamin D3 was studied in the mitochondrial fraction from rat liver and in a reconstituted system containing cytochrome P-450 from rat liver microsomes. The mitochondrial fraction catalyzed the 25-hydroxylation of vitamin D3 at least two times more effectively than the 25-hydroxylation of vitamin D2. Microsomal cytochrome P-450 catalyzed an efficient 25-hydroxylation of vitamin D3, but no 25-hydroxylation of vitamin D2 could be detected. The present results show a difference in the 25-hydroxylation of vitamin D2 and vitamin D3 in rat liver in vitro.

Animals↗

Modulation of vitamin D receptor and estrogen receptor by 1,25(OH)2-vitamin D3 in T-47D human breast cancer cells.

1,25(OH)2-Vitamin D3 inhibits breast cancer cell proliferation through interaction with the vitamin D receptor (VDR). Regulation of VDR is under the influence of several factors which include the functional ligand for this receptor (1,25(OH)2-vitamin D3) as well as heterologous steroid hormones. We evaluated the nature of homologous regulation in T-47D human breast cancer cells with a radiolabelled ligand binding assay and a ribonuclease protection assay for VDR. Significant VDR up-regulation, as measured by hormone binding assays, occurred with pre-incubations with 10(-9)M through 10(-6)M 1,25(OH)2-vitamin D3 (P < 0.05). A 7-fold VDR up-regulation with 10(-8)M 1,25(OH)2-vitamin D3 occurred at 4 h treatment and was not associated with an increase in VDR mRNA expression on ribonuclease protection assay. This supports the hypothesis that up-regulation of VDR is probably the result of ligand-induced stabilization of pre-existing receptor. All-trans-retinoic acid, the progesterone analog R-5020, and prednisone were found to induce heterologous up-regulation of the VDR. We then determined with ligand binding assays whether 1,25(OH)2-vitamin D3 could influence receptor levels for another hormone in a manner analogous to the heterologous regulation of VDR. Regulation of estrogen receptor (ER) by 1,25(OH)2-vitamin D3 was studied in T-47D and MDA-MB-231 breast cancer cells. Incubation of T-47D cells, which are ER (+), with 10(-8)M 1,25(OH)2-vitamin D3 did not result in up-regulation of ER. Yet estrogen binding was significantly up-regulated in a cell line that is ER(-), MDA-MB-231. The increased estrogen binding was associated with a shift in binding affinity and ribonuclease protection assay showed absence of ER mRNA in these cells, suggesting an up-regulation of estrogen binding proteins and not of the ER itself.

Breast Neoplasms↗

Antioxidant vitamin levels in term and preterm infants and their relation to maternal vitamin status.

BACKGROUND: Lipid peroxidation plays a vital role in the pathogenesis of many neonatal complications. Preterm babies are especially predisposed to lung diseases and retinopathy, probably due to a deficiency in their antioxidant systems. Vitamins E, A, and C are part of the natural antioxidant defense systems. We aimed to determine the levels of vitamins E, A, and C in maternal and cord blood plasma of term and preterm infants and to investigate the relationships between these levels. METHODS: In the present study we determined vitamin E, A, and C levels in the umbilical cord blood of term (n = 30) and preterm (n = 22) infants and their mothers by HPLC. Blood samples were taken during delivery. RESULTS: Levels of lipid soluble antioxidant vitamin E and A in cord blood were lower than maternal values (p <0.01, p <0.05, respectively). Conversely, the level of water-soluble vitamin C was higher in cord blood than in maternal level (p <0.05). Significantly higher levels of vitamins E, A, and C were found in term babies as compared with those born preterm (p <0.05). CONCLUSIONS: There was a positive correlation between maternal and cord blood levels of vitamins E and A (r = 0.775, r = 0.725, respectively). In conclusion, preterm babies have fewer lipid-soluble antioxidant vitamins in their serum compared to term infants. Therefore, it is possible to postulate that preterm infants are more susceptible to oxidative stress.

Antioxidants↗

An evaluation of the biologic activity and vitamin D receptor binding affinity of the photoisomers of vitamin D3 and previtamin D3.

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.

Calcitriol↗

Syntheses and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60).

Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidioxyvitamin D (vitamin D endoperoxides, 2 and 2'), were chemically synthesized, and their biological activity in inducing differentiation of a human myeloid leukemia cell line (HL-60 cells) was examined. The potency of the endoperoxides derived from vitamin D derivatives possessing the 1 alpha-hydroxyl group such as 1 alpha, 25-dihydroxyvitamin D3 endoperoxides (2b and 2b') was markedly (10(-2)) diminished relative to the respective parent vitamin D compounds. In contrast, 25-hydroxyvitamin D3 endoperoxides [25-(OH)D3 endoperoxides, 2a and 2a'] and their analogues fluorinated at the 24- or 26- and 27-positions were 2.5-10 times more potent than 25-hydroxyvitamin D3 (1a) in spite of the absence of the conjugated triene structure typical of vitamin D compounds. The potency of these vitamin D endoperoxides (2 and 2'), especially those lacking the 1 alpha-hydroxyl group, in inducing differentiation of HL-60 cells was not correlated with their activity in binding to the cytosol receptor for 1 alpha, 25-dihydroxyvitamin D3 (1b). The binding efficiency to the receptor was relatively lower than the differentiating activity. To examine the action of vitamin D endoperoxides, carbon analogues of 25-(OH)D3 endoperoxides, two C-6 epimers of 25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3 (6 and 6'), were synthesized. The carbon analogues (6 and 6') had no potential to induce differentiation of HL-60 cells. These results suggest that vitamin D endoperoxides (2 and 2') express their biological activity probably after being converted to some other compounds.

Binding, Competitive↗

Sp1 and NF-Y synergistically mediate the effect of vitamin D(3) in the p27(Kip1) gene promoter that lacks vitamin D response elements.

Vitamin D(3) promotes myeloid leukemic cell lines to differentiate terminally into monocytes/macrophages. It has been reported that overexpression of the cdk inhibitor p27(Kip1) results in the differentiation of the myelomonocytic U937 cell line and that this gene is the target of vitamin D(3). To identify the sequences required for the positive regulation of p27(Kip1) transcription by vitamin D(3), a 3.6-kilobase 5'-flanking region of the human p27(Kip1) gene was examined by transiently transfecting luciferase reporter constructs into U937 cells. The transcriptional activity of this construct was activated by vitamin D(3). Deletion and mutational analysis revealed that both a GGGCGG sequence (-545/-539) and a CCAAT sequence (-525/-520) were necessary to induce p27(Kip1) gene expression. Importantly, the region containing both of these elements conferred positive responsiveness to vitamin D(3) to a heterologous promoter. Gel shift assays showed that Sp1 binds to the GGGCGG sequence and that NF-Y binds to the CCAAT sequence. Consistent with the roles of these transcription factors, treatment with vitamin D(3) stimulated the DNA binding activities of these factors to each element and induced the change of one NF-Y subunit. We conclude that vitamin D(3) stimulates transcription of the p27(Kip1) gene by a novel mechanism involving Sp1 and NF-Y, but not the vitamin D receptor, during the early stages of U937 cell differentiation.

Base Sequence↗

Stable isotope-labelled vitamin C as a probe for vitamin C absorption by human subjects.

Factors affecting absorption of physiological doses of vitamin C in man have not been widely studied, partly because few suitable tools exist to distinguish recently absorbed vitamin C from endogenous vitamin. Stable isotope-labelled vitamin C provides such a tool. Fifteen healthy non-smoking subjects aged 26-59 years were studied. Each received 30 mg l-[1-(13)C]ascorbic acid orally on two occasions, 3-4 weeks apart. The ascorbate was given alone or with Fe (100 mg as ferrous fumarate) or with red grape juice, which is rich in polyphenols. Blood was collected at frequent intervals for 1 h, and then each hour for a further 3 h. Total concentration of vitamin C was measured fluorometrically and its (13)C-isotope enrichment was measured by GC-MS after conversion to volatile trimethylsilyl esters. Peak plasma enrichment occurred within 25-50 min. No kinetic variables were significantly altered by the iron fumarate supplement. Grape juice attenuated vitamin C absorption, reaching significance at the 20 min time point. There were weak correlations between isotope enrichment and body weight or endogenous ascorbate concentration. The increment in total plasma ascorbate was smaller if calculated from isotope enrichment than from vitamin C concentration increase. The dilution pool was much larger than the plasma ascorbate pool. Further studies are needed to resolve these paradoxes. Stable isotope-labelled ascorbate is potentially useful for measurement of vitamin C absorption by human subjects.

Absorption↗

Measurement of vitamin B12 in the livers and sera of sheep and cattle and an investigation of factors influencing serum vitamin B12 levels in sheep.

Modifications of a radioassay method for the analysis of vitamin B12 using chicken serum as the binder are described. This obviates the need to use individual serum blanks to correct for non-specific binding in vitamin B12 assays of the sera and livers of sheep and cattle. Samples with high vitamin B12 levels can be diluted prior to assay without loss of linearity. Recoveries of added cyanocobalamin or hydroxocobalamin were better than 95% and results correlated significantly with those obtained using a microbiological assay (Poteriochromonas malhamensis). Sera and liver samples stored for four weeks at temperatures ranging from -20 degrees to 22 degrees showed no change in vitamin B12 levels. Withholding food from sheep for 44 hours led to a marked increase in serum vitamin B12. This effect was also evident in sheep eating a limited amount of cut grass. In sheep at pasture there was no evidence of a diurnal variation in serum vitamin B12 levels. Serum vitamin B12 levels in sheep at pasture were shown to be an unreliable indicator of liver vitamin B12.

Journal Article↗

[Vitamin B1 content of liver, brain and muscles of pregnant and nonpregnant rats with different vitamin B1 supplies].

The purpose of this publication was to examine the effects of a wide variation of dietary vitamin B1 supply (0-12,000 mg vitamin B1 per kg diet) to gravid and non gravid rats on their vitamin B1 content in liver, brain and muscle. The experiment was designed with 176 (2 x 11 x 8) female Sprague-Dawley-rats. Additionally, the organs and tissues were tested as criteria for requirement recommendations. The animals were sacrificed on the 20th day of gravidity of the pregnant rats. Before gravidity the vitamin-B1-contents were 4.7 micrograms/g liver, 2.5 micrograms/g brain and 1.5 micrograms/g muscle. At the end of the experiment the gravid rats had a 19 per cent higher liver content than the non gravids. With a dietary supply of 8-10 ppm vitamin B1 the liver content plateaued until about 120 ppm. Vitamin B1 concentration in brain was about 2 micrograms/g and gravidity was of no effect. Vitamin B1 concentration in muscle was significantly influenced by both factors and saturation was reached at 1.3 and 1.7 micrograms/g muscle. These data showed that the response of the liver to dietary supply was the most sensitive and should therefore be considered in requirements. The requirement for non gravid animals is therefore 4 mg vitamin B1 per kg diet at minimum, gravid animals should be supplied by 7 mg per kg diet.

Animals↗

Differences in vitamin B6 status indicator responses between young and middle-aged women fed constant diets with two levels of vitamin B6.

The responses of adult women to two levels of vitamin B6, was conducted with five young and eight middle-aged subjects. A constant diet (2.3-2.4 mg vitamin B6 per day) was fed for four weeks followed by three weeks of the same diet supplemented with 8.0 mg pyridoxine. Plasma pyridoxal 5'-phosphate (PLP), plasma and urinary vitamin B6, and urinary 4-pyridoxic acid (4-PA) were determined. The older women had significantly lower plasma PLP, plasma and urinary vitamin B6 and slightly higher urinary 4-PA values on normal vitamin B6 intakes. With supplementation, only the difference in urinary total vitamin B6 remained significant. Tryptophan load tests revealed no significant between-group differences in xanthurenic acid or kynurenic acid excretion. These results demonstrate an age-related difference in vitamin B6 status indicators in women under controlled dietary intake of vitamin B6.

Adult↗

Different metabolism of vitamin D2 and vitamin D3 in epileptic patients on carbamazepine.

Serum concentrations of vitamin D metabolites were measured in 30 epileptic outpatients on monotherapy with carbamazepine before and during treatment with either vitamin D2 or vitamin D3, 4000 IU per day for 24 weeks. Vitamin D2 treatment increased the serum concentration of 25OHD2, but a corresponding decrease in 25OHD3 resulted in an unchanged serum value of total 25OHD. Vitamin D3 treatment increased the serum concentration of 25OHD3. The resulting serum level of 25OHD was consequently twice the level of that in the D2-treated group. The serum concentrations of the dihydroxy metabolites showed a similar difference between the 2 treatment groups. We conclude that treatment with vitamins D2 and D3 in the same doses produces considerably different serum concentrations of vitamin D metabolites. If the present findings can be extrapolated to normal subjects, it is important to consider more carefully which D-vitamin should be used, both with regard to therapy and supplementation.

Adult↗