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Vitamin D and mineral metabolism in the very low birth weight infant receiving 400 IU of vitamin D.

STUDY OBJECTIVE: To examine (1) the effect of vitamin D intake (380 to 480 IU daily) on plasma 25-hydroxyvitamin D (25-OHD) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) concentrations and (2) the relationship of 1,25-(OH)2D to calcium and phosphorus absorption and retention in the very low birth weight infant receiving a preterm infant formula. SUBJECTS: Eleven "well" infants with a birth weight and gestational age (mean +/- SD) of 1078 +/- 128 gm and 29 +/- 1.9 weeks, respectively, were studied for a 3-week period. Weight and postnatal age (mean +/- SD) at the beginning of the study were 1132 +/- 56 gm and 16 +/- 6 days, respectively. All infants were fed a preterm infant formula and tolerated a full enteral intake (120 kcal/kg/day) for the duration of the study. INTERVENTIONS: Plasma 25-OHD and 1,25-(OH)2D concentrations were measured at the beginning of the study and at the beginning of each 48-hour balance period. Calcium and phosphorus balance studies (n = 33) were performed weekly. MAIN RESULTS: Plasma 25-OHD (30 +/- 10 ng/ml) and 1,25-(OH)2D (54 +/- 14 pg/ml) concentrations were normal at the beginning of the study. Plasma 25-OHD values did not change, but 1,25-(OH)2D values increased (p less than 0.001) throughout the study. Plasma 1,25-(OH)2D concentrations were not related to calcium or phosphorus absorption and retention, but were a linear function of postconceptional age. CONCLUSIONS: Normal vitamin D status and activity are maintained in the very low birth weight infant fed a high calcium formula (380 to 480 IU of vitamin D daily). Plasma 1,25-(OH)2D concentrations are not related to calcium absorption but are linearly related to maturity.

Calcium↗

Bone mineral content, serum vitamin D metabolite concentrations, and ultraviolet B light exposure in infants fed human milk with and without vitamin D2 supplements.

OBJECTIVE: To monitor ultraviolet B light exposure in human milk-fed infants both with and without supplemental vitamin D2, and to measure longitudinally the bone mineral content, growth, and serum concentrations of calcium, phosphorus, 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D, and parathyroid hormone. DESIGN: Longitudinal, randomized, double-blind, placebo-controlled study of 6 months' duration. SETTING: Patients from private pediatric practice, Madison, Wisconsin. PATIENTS: Sequential sampling of 46 human milk-fed white infants; 24 received 400 IU/day of vitamin D2, and 22 received placebo. An additional 12 patients were followed who received standard infant formula. Eighty-three percent of patients completed a full 6 months of the study. MEASUREMENTS AND RESULTS: Ultraviolet B light exposure and measurements of growth did not differ between groups. At 6 months, the human milk groups did not differ significantly in bone mineral content or serum concentrations of parathyroid hormone or 1,25-dihydroxyvitamin D, although total 25-hydroxyvitamin D values were significantly less in the unsupplemented human milk group (23.53 +/- 9.94 vs 36.96 +/- 11.86 ng/ml; p less than 0.01). However, 25-hydroxyvitamin D3 serum concentrations were significantly higher in the unsupplemented human milk-fed group compared with the supplemented group (21.77 +/- 9.73 vs 11.74 +/- 10.27 ng/ml, p less than 0.01) by 6 months of age. CONCLUSION: Unsupplemented, human milk-fed infants had no evidence of vitamin D deficiency during the first 6 months of life.

25-Hydroxyvitamin D 2↗

Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.

BACKGROUND: Susceptibility to disease after infection by Mycobacterium tuberculosis is influenced by environmental and host genetic factors. Vitamin D metabolism leads to activation of macrophages and restricts the intracellular growth of M. tuberculosis. This effect may be influenced by polymorphisms at three sites in the vitamin D receptor (VDR) gene. We investigated the interaction between serum vitamin D (25-hydroxycholecalciferol) concentrations and VDR genotype on susceptibility to tuberculosis. METHODS: This study was a hospital-based case-control analysis of Asians of Gujarati origin, a mainly vegetarian immigrant population with a high rate of tuberculosis. We typed three VDR polymorphisms (defined by the presence of restriction endonuclease sites for Taq1, Bsm1, and Fok1) in 91 of 126 untreated patients with tuberculosis and 116 healthy contacts who had been sensitised to tuberculosis. Serum 25-hydroxycholecalciferol was recorded in 42 contacts and 103 patients. FINDINGS: 25-hydroxycholecalciferol deficiency was associated with active tuberculosis (odds ratio 2.9 [95% CI 1.3-6.5], p=0.008), and undetectable serum 25-hydroxycholecalciferol (<7 nmol/L) carried a higher risk of tuberculosis (9.9 [1.3-76.2], p=0.009). Although there was no significant independent association between VDR genotype and tuberculosis, the combination of genotype TT/Tt and 25-hydroxycholecalciferol deficiency was associated with disease (2.8 [1.2-6.5]) and the presence of genotype ff or undetectable serum 25-hydroxycholecalciferol was strongly associated with disease (5.1 [1.4-18.4]). INTERPRETATION: 25-hydroxycholecalciferol deficiency may contribute to the high occurrence of tuberculosis in this population. Polymorphisms in the VDR gene also contribute to susceptibility when considered in combination with 25-hydroxycholecalciferol deficiency.

Calcifediol↗

Synergistic combination therapy of 5-fluorouracil, vitamin A, and cobalt-60 radiation for head and neck tumors--antitumor combination therapy with vitamin A.

Using cultured transformed fibroblasts, an antitumor agent, 5-fluorouracil (5-FU), was found to be potentiated in its inhibitory action on RNA formation by vitamin A. 5-FU in combination with vitamin A enhanced more effectively the cellular sensitivity to irradiation than when 5-FU was used alone. So we have applied a triple combination of 5-FU, vitamin A, and cobalt-60 radiation (FAR therapy) to clinical treatment of head and neck tumors since 1972. The treatment of 192 patients with cancer of the larynx, 60 patients with hypopharyngeal and cervical esophageal cancer, and 23 patients with epipharyngeal cancer with FAR therapy during 6 years from 1972 to 1977 resulted in highly effective synergism, and the improved points of this therapy were considered.

Adult↗

Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy.

We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and pyridoxal-5'-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and thermolabile genotypes of 5, 10-methylenetetrahydrofolate reductase (MTHFR) were also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of 20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia, whereas 85% of these had plasma folate concentrations below the normal range. However, erythrocyte folate concentrations were abnormally low in only 25% of the patients who received phenytoin. Valproate administration increased serum vitamin B-12 concentrations. Over 55% of the entire patients had PLP concentrations below the normal range, although the reason is unknown. Only three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis was not possible in this study. However, one patient with homozygous genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate nutritional status, and the other two had normal homocysteine concentrations with normal folate status. Our data suggest that hyperhomocysteinemia is not a serious clinical concern in epileptic patients when folate nutriture is adequate.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗

Colorimetric determination of tocopheryl acetate (vitamin E) in pure form and in multi-vitamin capsules.

A simple, accurate and sensitive method for the determination of micro amounts of vitamin E (V(E)) in pure form and in multi-vitamin capsules is described. The method is based on the reduction of tetrazolium blue in slightly alkaline medium by vitamin E after extraction from aqueous EDTA medium with petroleum ether and transesterification. The oxidation reduction reaction occurs after 10 min of heating in a water bath at 90+/-2 degrees C, leading to the formation of a highly coloured formazan derivative. Different variables affecting the colour development were investigated and optimized. Absorbance measurements were made at 526 nm and the calibration graph was linear for 0.2-11.0 microg/ml of (V(E)) with relative precision of about 0.7-1.5% when the standard additions method is used.

Antioxidants↗

Vitamin E and ATPases: protection of ATPase activities by vitamin E supplementation in various tissues of hypercholesterolemic rats.

It has been shown that the lipid composition of plasma membrane can be modified in vivo by dietary fat. It has also been observed that an increase in the cholesterol content of plasma membranes results in decreased activities of ATPases. In the present study, we evaluated the changes in the activities of ATPases from erythrocytes, hepatocytes, and kidney cortex caused by cholesterol-rich diet in rats and subsequently examined the role of vitamin E administration on the cholesterol-induced effects in these tissues. Administration of hypercholesterolemic diet to the rats for 4.5 months, significantly decreased membrane Na(+)-K(+)-ATPase and Ca+2-ATPase activities in comparison to the controls in all tissues studied. Vitamin E supplementation to the hypercholesterolemic rats led to a recovery in membrane ATPase activities. In conclusion, vitamin E supplementation to the rats provided protection against hypercholesterolemic diet-induced impairment of membrane-bound ATPases.

Adenosine Triphosphatases↗

Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells.

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.

Acute Disease↗

Vitamin D receptor-mediated gene regulation mechanisms and current concepts of vitamin D analog selectivity.

Lipophilic hormones of steroidal origin such as the sex hormones and 1,25-dihydroxy vitamin D(3) (1,25[OH](2)D(3)) function by regulating patterns of gene expression in cells. The mediators of such actions are nuclear receptors that recognize these ligands with high affinity and selectivity and function through several mechanisms as gene specific transcription factors. As a result of the mechanistic complexity of nuclear receptor action, recent studies have revealed that both synthetic analogs as well as novel mimetics of a receptor's natural hormonal ligand are capable of modulating functional responses in both cell- and gene-selective manners. These findings have given rise to the term selective receptor modulators, typified by such synthetic estrogen receptor ligands as tamoxifen and raloxifene. A number of vitamin D analogs have been prepared that appear to exhibit tissue-selective activity--most notable through their inability to induce levels of hypercalcemia typical of the activity of the natural hormone 1,25(OH)(2)D(3). Because this debilitating yet normal feature of the natural ligand limits its usefulness in a variety of clinical indications, including its application to prevent bone disease caused by secondary hyperparathyroidism, this feature of many of the new analogs is especially welcome. This article discusses what constitutes a selective receptor modulator and whether the current vitamin D analogs represent such entities.

Gene Expression↗

A central dinucleotide within vitamin D response elements modulates DNA binding and transactivation by the vitamin D receptor in cellular response to natural and synthetic ligands.

There is considerable divergence in the sequences of steroid receptor response elements, including the vitamin D response elements (VDREs). Two major VDRE-containing and thus 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3))-regulated genes are the two non-collagenous, osteoblast-derived bone matrix proteins osteocalcin and osteopontin. We observed a stronger induction of osteopontin than osteocalcin mRNA expression by 1,25-(OH)(2)D(3). Subsequently, we have shown that vitamin D receptor/retinoid X receptor alpha (VDR/RXRalpha) heterodimers bind more tightly to the osteopontin VDRE than to the osteocalcin VDRE. Studies using point mutants revealed that the internal dinucleotide at positions 3 and 4 of the proximal steroid half-element are most important for modulating the strength of receptor binding. In addition, studies with VDRE-driven luciferase reporter gene constructs revealed that the central dinucleotide influences the transactivation potential of VDR/RXRalpha with the same order of magnitude as that observed in the DNA binding studies. The synthetic vitamin D analog KH1060 is a more potent stimulator of transcription and inducer of VDRE binding of VDR/RXR in the presence of nuclear factors isolated from ROS 17/2.8 osteoblast-like cells than the natural ligand 1,25-(OH)(2)D(3). Interestingly, however, KH1060 is comparable or even less potent than 1,25-(OH)(2)D(3) in stimulating VDRE binding of in vitro synthesized VDR/RXRalpha. Thus, the extent of 1,25-(OH)(2)D(3)- and KH1060-dependent binding of VDR/RXRalpha is specified by a central dinucleotide in the VDRE, and the ligand-induced effects on DNA binding are in part controlled by the cellular context of nuclear proteins.

Animals↗

Suppression of the human parathyroid hormone promoter by vitamin D involves displacement of NF-Y binding to the vitamin D response element.

An earlier report in the literature indicated the vitamin D response element (VDRE) in the human parathyroid hormone (hPTH) promoter could be specifically bound by an unidentified transcription factor in addition to the vitamin D receptor (VDR) complex. We confirmed that OK and HeLa cell nuclear extracts formed a specific complex with the hPTH VDRE that was insensitive to competition with other VDRE sequences. However, this factor could be competed for by a consensus NF-Y DNA-binding site, and an anti-NF-Y antibody was able to supershift the bound band. Mutational analysis indicated that the NF-Y-binding site partially overlapped the 3' portion of the VDRE. Transfection studies using an hPTH promoter construct in Drosophila SL2 cells demonstrated strong synergistic transactivation by NF-Y interactions with both the VDRE site and a previously described distal NF-Y-binding site. Finally, mobility shift studies indicated that the VDR heterodimer competed with NF-Y for binding to the VDRE sequence, and NF-Y-stimulated activity of the hPTH promoter could be suppressed in a hormone-dependent manner when the VDR heterodimer complex was coexpressed in SL2 cells. In summary, these findings establish the presence of a proximal NF-Y-binding site in the hPTH promoter and highlight the potential for synergism between distal and proximal NF-Y DNA elements to strongly enhance transcription. Furthermore, findings suggest that the repressive effects of vitamin D on hPTH gene transcription may involve displacement of NF-Y binding to the proximal site by the VDR heterodimer, which subsequently attenuates synergistic transactivation.

Animals↗

Serum carotene, vitamin A, and vitamin C levels in breast cancer and cancer of the uterine cervix.

Levels of carotene, vitamin A, and vitamin C measured in the serum of patients with cancer of the breast and uterine cervix were compared with levels in healthy controls and patients with benign diseases of the breast and cervix. Serum ascorbate levels were significantly lower in patients with benign diseases of the breast and cervix than in controls. In cancer patients, there was a significant trend of lower serum vitamin levels with increasing stage of the disease.

Ascorbic Acid↗

Influence of vitamin C, vitamin E and beta-carotene on the osmotic fragility and the primary antioxidant system of erythrocytes in zinc-deficient rats.

The present study was designed to investigate the effect of antioxidant supplementation on the in vitro osmotic fragility of erythrocytes from zinc-deficient rats. Rats were fed either a zinc-adequate diet, zinc-deficient diet or a zinc-deficient diet enriched either with vitamin C or vitamin E or beta-carotene. Components of the primary antioxidant system of erythrocytes, parameters of hemolysis in vivo and indicators of liver injuries were also examined. In order to ensure adequate and identical food intake rats were force-fed by intragastric tube. The supplementation with antioxidants led to a marked improvement of the osmotic fragility without having influenced zinc status of the animals and components of the antioxidant system. The strongest effect was exerted by vitamin E. The rats fed the zinc-adequate diet (control group) showed unusually high values of erythrocytes osmotic fragility. Therefore there was no difference between control group and zinc-deficient group. A possible reason for this is discussed. Zinc deficiency led to a reduction of serum zinc concentration and alkaline phosphatase activity as well as to changes in the antioxidant system of erythrocytes characterized by a decrease of glutathione and an increase of glutathione S-transferase activity. Superoxide dismutase activity in serum decreased. There was no indication for hemolysis in vivo and for liver injuries.

Alkaline Phosphatase↗

Dietary levels of vitamin E and polyunsaturated fatty acids and plasma vitamin E.

Seventeen daily diets (breakfast, lunch, and dinner) were analyzed from a 35-day menu cycle fed to students, under contract in the University dining halls. This 35-day menu cycle was repeated 6.6 times over the course of two 15-week semesters and registration and final examination periods. The average 2, 500 kcal diet collected during the sixth and seventh menu cycles contained 96 plus or minus 26 g fat of which 19.5 plus or minus 1.8% was linoleate and 28.7 plus or minus 14.2 mg total tocopherol of which 7.5 plus or minus 3.5 mg was RRR-alpha-tocopherol. Blood samples obtained from 26 female undergraduate student volunteers contained adequate levels of plasma total vitamin E, 1.09 plus or minus 0.25 mg/100 ml, despite the observation that 71% and 65% of the diets analyzed did not meet the value tabluated in the eighth edition of "Recommended Dietary Allowances" for adult females in terms of RRR-alpha-tocopherol or total vitamin E activity, respectively. These data emphasize the importance of the average long-term consumption of this fat-soluble vitamin rather than daily intake.

Adult↗

Determination of vitamin A in blood. Some practical considerations on the time of collection of the specimens and the stability of the vitamin.

The stability of vitamin A and retinol-binding protein (RBP) in serum separated from the clot at different times after blood extraction and the effect of ingesting a vitamin A-rich breakfast on postprandial serum levels of retinol, carotenoids, and RBP were investigated. In the stability trials, venous blood was drawn from 12 well-nourished young adult subjects and sample aliquots were maintained, respectively, at 4 degree C or at room temperature (26 to 28 degrees C). The serum was separated from the clot either immediately after blood clotting or at 2, 4, 6, 12, and 24 h after blood extraction. Serum retinol and RBP were stable either at 4 degrees C or at room temperature, even if the serum was separated from the clot 24 h after blood extraction. In the breakfast experiment, seven young adult subjects ingested a meal containing 291 microgram of retinol equivalents. The serum levels of retinol, carotenoids, and RBP were measured pre- and postprandially up to a period of 4 h. The ingestion of the breakfast meal did not alter significantly the postprandial serum levels of retinol, carotenoids, or RBP. These results are of practical importance for the performance of vitamin A nutrition surveys involving field work, when as is common, blood specimens cannot be collected under fasting and, in addition, they have to be transported from far away localities to the laboratory.

Adult↗

Serum vitamin A distribution curve for children aged 2-6 y known to have adequate vitamin A status: a reference population.

Serum vitamin A was determined before and 30-45 d after the administration of 60.6 mg (212 mumol) vitamin A to 544 Brazilian children residing in slum areas of Recife. The frequency-distribution curves were compared in a subgroup of children whose vitamin A status was assessed initially by the relative-dose-response (RDR) test. The curves of children with negative (adequate status) and positive (inadequate status) RDR tests were different. The difference disappeared after supplementation. The shape of the distribution curve after supplementation was close to normal with a mean, median, and 95% confidence interval of 1.78 +/- 0.49, 1.68, and 1.02-2.90 mumol/L, respectively. The postsupplementation curve derived from this underprivileged child population may serve as a reference for diagnostic, surveillance, and program-evaluation purposes.

Brazil↗

Effect of the maternal vitamin D status at parturition on the vitamin D status of the neonatal calf.

The plasma concentrations of calcium, phosphorus, magnesium, hydroxyproline, vitamin D, and vitamin D metabolites were determined in cows and their colostrum-deprived calves. At birth, calf plasma calcium, phosphorus, and hydroxyproline concentrations were not correlated (P greater than 0.05) with the maternal plasma concentrations of these substances. There was a high degree of correlation between maternal and neonatal calf plasma concentrations of 25-hydroxyergocalciferol (r = 0.733), 25-dydroxycholecalciferol (r = 0.888), 24,25-dihydroxyergocalciferol (r = 0.770), 24,25-dihydroxycholecalciferol (r = 0.629), and 25,26-dihydroxycholecalciferol (r = 0.840). Neonatal calf plasma concentrations of 1,25-dihydroxyvitamin D were low (41.2 +/- 3.4 pg/ml) and had no correlation with maternal concentrations (r = 0.219, P greater than 0.05). Neonatal plasma calcium and inorganic phosphorus concentrations were correlated (P less than 0.05) with maternal plasma concentrations of 1,25-dihydroxyvitamin D (r = 0.559 and 0.525, respectively). Vitamin D status of the dam, therefore, appears to be important in determining neonatal calf plasma concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25,26-dihydroxyvitamin D, and, in addition, the plasma calcium and inorganic phosphorus status of the neonatal calf is apparently dependent on maternal concentrations of 1,25-dihydroxyvitamin D.

Animals↗

Dietary (n-3) fatty acid and vitamin E interactions in rats: effects on vitamin E status, immune cell prostaglandin E production and primary antibody response.

To examine the interaction between dietary fat and vitamin E at the level of the rat immune system, a 2 x 3 factorial study was designed. Weanling female Sprague Dawley rats were fed for 8-9 wk diets that contained either corn oil (CO diet) or fish oil (FO diet) and one of three levels (30, 300, 900 mg/kg) of all-rac-alpha-tocopheryl acetate. At the lowest level of dietary vitamin E, alpha-tocopherol content of splenocytes from FO-fed rats was approximately 40% lower (P less than 0.05) than in those from CO-fed rats. Supplementation with all-rac-alpha-tocopheryl acetate elevated alpha-tocopherol in splenocytes from FO-fed rats but not in those from CO-fed rats, and reduced the relative proportion of arachidonic acid and eicosapentaenoic acid in the serum of CO-fed and FO-fed rats, respectively. Prostaglandin E production by isolated immune cells was not affected by all-rac-alpha-tocopheryl acetate supplementation. However, feeding the FO diet consistently reduced prostaglandin E synthesis by 70-80% as compared with the CO diet. Antibody production against sheep RBC was highest in rats fed the FO diet supplemented with 900 mg all-rac-alpha-tocopheryl acetate/kg of diet. However, antibody response was not directly correlated to diet-induced changes in immune cell prostaglandin E production or alpha-tocopherol content. Our data suggest that there are significant interactions between vitamin E and (n-3) fatty acids that affect the immune system and that further research in this area is warranted.

Animals↗