1. Prospective study of plasma vitamin B6 and risk of colorectal cancer in men

Lee JE , Li H , Giovannucci E , Lee IM , Selhub J , Stampfer M , Ma J .

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA

Cancer Epidemiol Biomarkers Prev. 2009

Vitamin B(6) may lower risk of colorectal cancer by preventing aberrations in one-carbon metabolism or by anti-inflammatory effects. We prospectively evaluated the association between plasma levels of pyridoxal 5'-phosphate (PLP; the active form of vitamin B(6)) and risk of colorectal cancer in a nested case-control study within the Physicians' Health Study. Among 14,916 men who provided blood specimens in 1982 to 1984, we identified 197 incident colorectal cancer cases through 2000 and individually matched them to 371 controls by age and smoking status. Plasma PLP levels were positively correlated with cold cereal intake and plasma levels of folate and vitamin B(12) (age- and smoking-adjusted partial correction r = 0.28-0.48) and slightly inversely correlated with body mass index (r = -0.11) and plasma levels of homocysteine, C-reactive protein, tumor necrosis factor-alpha receptor 2, and interleukin-6 (r = -0.23 to -0.14). With control for these factors and known risk factors for colorectal cancer, plasma PLP levels were significantly inversely associated with risk of colorectal cancer; compared with men in the lowest quartile, those with PLP in quartiles 2 to 4 had relative risks (95% confidence interval) of 0.92 (0.55-1.56), 0.42 (0.23-0.75), and 0.49 (0.26-0.92; P(trend) = 0.01), respectively. In conclusion, vitamin B(6) may protect against colorectal cancer independent of other one-carbon metabolites and inflammatory biomarkers.

2. NAD+ and vitamin B3: from metabolism to therapies

Sauve AA .

Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA

J Pharmacol Exp Ther. 2008

The role of NAD(+) metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD(+) metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD(+) metabolism regulates important biological effects, including lifespan. NAD(+) exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADP-ribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD(+) metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD(+) metabolism in humans and microbes, including new insights into mechanisms that regulate NAD(+) biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD(+) biosynthesis for treatment of human disorders and infections.

3. Dietary intake of folate, other B vitamins, and omega-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults.

Murakami K , Mizoue T , Sasaki S , Ohta M , Sato M , Matsushita Y , Mishima N .

Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, Tokyo, Japan

Nutrition. 2008

OBJECTIVE: Although a favorable effect of dietary folate and omega-3 polyunsaturated fatty acids (PUFAs) on depression is suggested from epidemiologic studies in Western countries, evidence from non-Western populations is lacking. We examined cross-sectional associations between the intake of folate, other B vitamins, and omega-3 PUFAs and depressive symptoms in Japanese adults. METHODS: Subjects were 309 Japanese men and 208 Japanese women 21-67 y of age. Dietary intake was assessed with a validated, brief, self-administered diet history questionnaire. Depressive symptoms were defined as present when subjects had a Center for Epidemiologic Studies Depression scale score > or =16. Adjustment was made for age, body mass index, work place, marital status, occupational physical activity, leisure-time physical activity, current smoking, current alcohol drinking, and job stress score. RESULTS: The prevalences of depressive symptoms were 36% for men and 37% for women. Folate intake showed a statistically significant, inverse, and linear association with depressive symptoms in men but not in women. The multivariate odds ratios (95% confidence intervals) for depressive symptoms for men in the first, second, third, and fourth quartiles of folate intake were 1.00 (reference), 0.78 (0.38-1.63), 0.57 (0.27-1.18), and 0.50 (0.23-1.06), respectively (P for trend = 0.045). No statistically significant linear association was observed for the intake of riboflavin, pyridoxine, cobalamin, total omega-3 PUFAs, alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid in either sex. CONCLUSION: Higher dietary intake of folate was associated with a lower prevalence of depressive symptoms in Japanese men but not women.

4. Folate-responsive neurologic diseases

Djukic A .

Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Pediatr Neurol. 2007

Folate is a water-soluble vitamin of the B complex group, and is required for optimal health, growth, and development. In humans, it cannot be synthesized de novo. As a cofactor or coenzyme, folate plays key biological roles in a variety of physiologic processes: maintenance and repair of the genome, regulation of gene expression, amino-acid metabolism, neurotransmitter synthesis, and the formation of myelin. Dietary folates must undergo multiple, tightly regulated absorption and metabolic processes before their cellular utilization occurs. Clinical conditions associated with abnormal body folate status are very diverse. They range from genetic syndromes defined prior to conception, to malformations that develop during embryogenesis (neural tube defects), to disorders that are postnatally acquired and progressive (e.g., cerebral folate deficiency, or folinic acid-responsive seizures). Central nervous system folate deficiency or impaired availability can occur in the settings of normal or decreased systemic folate levels. Because the majority of patients respond to treatment with folinic acid, pediatric neurologists should remain vigilant to the possibility of deficiencies of folate in patients with unexplained neurologic disorders. The deleterious outcomes of untreated patients underscore the importance of making an early diagnosis.

5. Biotin

Zempleni J , Wijeratne SS , Hassan YI .

Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806, USA.

Biofactors. 2009

Biotin is a water-soluble vitamin and serves as a coenzyme for five carboxylases in humans. Biotin is also covalently attached to distinct lysine residues in histones, affecting chromatin structure and mediating gene regulation. This review describes mammalian biotin metabolism, biotin analysis, markers of biotin status, and biological functions of biotin. Proteins such as holocarboxylase synthetase, biotinidase, and the biotin transporters SMVT and MCT1 play crucial roles in biotin homeostasis, and these roles are reviewed here. Possible effects of inadequate biotin intake, drug interactions, and inborn errors of metabolism are discussed, including putative effects on birth defects

6. Update on the role of vitamin K in skeletal health

Shea MK , Booth SL .

Vitamin K Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA

Nutr Rev. 2008

A protective role for vitamin K in bone health has been suggested based on its role as an enzymatic cofactor. In observational studies, vitamin K insufficiency is generally associated with lower bone mass and increased hip fracture risk. However, these findings are not supported in randomized controlled trials (RCT) of phylloquinone (vitamin K(1)) supplementation and bone loss at the hip in the elderly. This suggests that increased vegetable and legume intakes may simultaneously improve measures of vitamin K status and skeletal health, even though the mechanisms underlying these improvements may be independent of each other. Menaquinone-4 (vitamin K(2)), when given at pharmacological doses, appears to protect against fracture risk and bone loss at the spine. However, there are emerging data that suggest the efficacy of vitamin K supplementation on bone loss is inconclusive.

7. Effect of vitamin K supplementation on bone loss in elderly men and women

Booth SL , Dallal G , Shea MK , Gundberg C , Peterson JW , Dawson-Hughes B .

U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, Massachusetts 02111, USA

J Clin Endocrinol Metab. 2008

CONTEXT: Vitamin K has been implicated in bone health, primarily in observational studies. However, little is known about the role of phylloquinone supplementation on prevention of bone loss in men and women. OBJECTIVE: The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density (BMD) of the femoral neck bone in older men and women who were calcium and vitamin D replete. DESIGN, PARTICIPANTS, AND INTERVENTION: In this 3-yr, double-blind, controlled trial, 452 men and women (60-80 yr) were randomized equally to receive a multivitamin that contained either 500 mug/d or no phylloquinone plus a daily calcium (600 mg elemental calcium) and vitamin D (400 IU) supplement. MAIN OUTCOME MEASURES: Measurements of the femoral neck, spine (L2-L4), and total-body BMD, bone turnover, and vitamins K and D status were measured every 6-12 months. Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial. RESULTS: There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups. The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone. No other biochemical measures differed between the two groups. CONCLUSIONS: Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin D.

8. Micronutrient status, cognition and behavioral problems in childhood

Benton D ; ILSI Europe a.i.s.b.l .

Department of Psychology, University of Swansea, Swansea, Wales, SA2 8PP, UK

Eur J Nutr. 2008

It is widely accepted that the rapid rate of growth of the brain during the last third of gestation and the early postnatal stage makes it vulnerable to an inadequate diet, although brain development continues into adulthood and micronutrient status can influence functioning beyond infancy. A deficiency of various micro-nutrients in developing countries has been found to have long-term implication for cognitive development. Vitamin A plays a critical role in visual perception and a deficiency is the leading cause of childhood blindness. A lack of iodine during a critical period in brain development is associated with reduced intellectual ability. Iron shortage is a widespread problem in the developing world but also in industrialized countries. There is evidence that iron deficiency in early life adversely effects brain development. In addition in industrialized countries a role for folate in the prevention of neural tube defects is well established and in a few individuals impaired cognitive functioning is associated with the inadequate provision of vitamin B(12. )The controversial suggestions that sub-clinical deficiencies of micronutrients may in industrialized societies influence anti-social behavior and intelligence are also discussed.

9. Effectiveness and safety of vitamin D in relation to bone health

Cranney A , Horsley T , O'Donnell S , Weiler H , Puil L , Ooi D , Atkinson S , Ward L , Moher D , Hanley D , Fang M , Yazdi F , Garritty C , Sampson M , Barrowman N , Tsertsvadze A , Mamaladze V .

Evid Rep Technol Assess (Full Rep). 2007 Aug;(158):1-235

OBJECTIVES: To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. DATA SOURCES: MEDLINE(R) (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). REVIEW METHODS: Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. RESULTS: 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of <400 IU to doses >/= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. CONCLUSIONS: The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

10. Zinc: mechanisms of host defense

Prasad AS .

Department of Internal Medicine, Division of Hematology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

J Nutr. 2007 May

Zinc deficiency in humans decreases the activity of serum thymulin (a thymic hormone), which is required for maturation of T-helper cells. T-helper 1 (Th(1)) cytokines are decreased but T-helper 2 (Th(2)) cytokines are not affected by zinc deficiency in humans. This shift of Th (1) to Th (2) function results in cell-mediated immune dysfunction. Because IL-2 production (Th (1) cytokine) is decreased, this leads to decreased activities of natural-killer cell and T cytolytic cells, which are involved in killing viruses, bacteria, and tumor cells. In humans, zinc deficiency may decrease the generation of new CD4+ T cells from the thymus. In cell culture studies (HUT-78, a Th(0) human malignant lymphoblastoid cell line), as a result of zinc deficiency, nuclear factor-kappaB (NF-kappaB) activation, phosphorylation of IkappaB, and binding of NF-kappaB to DNA are decreased and this results in decreased Th(1) cytokine production. In another study, zinc supplementation to humans decreased the gene expression and production of pro-inflammatory cytokines and decreased oxidative stress markers. In HL-60 cells (a human pro-myelocytic leukemia cell line), zinc deficiency increased the levels of TNF-alpha , IL -1beta, and IL-8 cytokines and mRNA. In these cells, zinc induced A20, a zinc finger protein that inhibited NF-kappaB activation via tumor necrosis factor receptor associated factor pathway, and this decreased gene expression of pro-inflammatory cytokines and oxidative stress markers. We conclude that zinc has an important role in cell-mediated immune functions and also functions as antiinflammatory and antioxidant agent.