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A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow-up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994).Our objective was to repeat the analyses with 6 years additional follow-up to evaluate whether the association persists through 15 years of follow-up.The study included 15 099 participants aged ≥ 20 years with 3784 deaths.Relative risk (RR) of death from all causes was adjusted for age, sex, race/ethnicity, and season using 2 Poisson regression approaches: traditional categorical and cubic splines. Results were given for 9 25(OH)D levels:20, 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 74, 75 to 99 (reference), 100 to 119, and ≥ 120 nmol/L.The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels60 nmol/L were significantly1 compared with the reference group. The nadir of risk was 81 nmol/L (95% CI, 73-90 nmol/L). For 25(OH)D ≥ 120 nmol/L, results (RR, 95% CI) were slightly different using traditional categorical (1.5, 1.02-2.3) and cubic splines approaches (1.2, 0.9-1.4). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults. The study was too small to evaluate the association in non-Hispanic black and Mexican-American adults.A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal.

Background: The Vitamin D Standardization Program (VDSP) has developed protocols for standardizing procedures of 25-hydroxyvitamin D [25(OH)D] measurement in National Health/Nutrition Surveys to promote 25(OH)D measurements that are accurate and comparable over time, location, and laboratory procedure to improve public health practice. Objective: We applied VDSP protocols to existing ELISA-derived serum 25(OH)D data from the Irish National Adult Nutrition Survey (NANS) as a case-study survey and evaluated their effectiveness by comparison of the protocol-projected estimates with those from a reanalysis of survey serums by using liquid chromatography–tandem mass spectrometry (LC–tandem MS). Design: The VDSP reference system and protocols were applied to ELISA-based serum 25(OH)D data from the representative NANS sample (n = 1118). A reanalysis of 99 stored serums by using standardized LC–tandem MS and resulting regression equations yielded predicted standardized serum 25(OH)D values, which were then compared with LC–tandem MS reanalyzed values for all serums. Results: Year-round prevalence rates for serum 25(OH)D concentrations 125 nmol/L were 1.2%, 0.3%, and 0.6% by means of ELISA, VDSP protocols, and LC–tandem MS, respectively. Conclusion: VDSP protocols hold a major potential for national nutrition and health surveys in terms of the standardization of serum 25(OH)D data.

Concerns exist about the adequacy of vitamin D in pregnant and lactating women. This review assesses the evidence that maternal vitamin D status influences maternal, fetal, and breast-fed infant bone health; maternal adverse outcomes (preeclampsia, gestational diabetes, obstructed labor, and infectious disease); fetal adverse outcomes (growth, gestational age, and developmental programming); and infant adverse outcomes. The evidence for all of these outcomes is contradictory (except for maternal infectious disease) and lacking causality; thus, it is inconclusive. The 2011 Dietary Reference Intakes for vitamin D and their implications for assessing vitamin D status are discussed. An estimated 5% to 29% of American pregnant women may have inadequate vitamin D status, with the higher prevalence in African Americans. Little is known about the prevalence of inadequacy in American lactating women. Research needs are also identified, especially the need for rigorous and well-designed randomized clinical trials to determine the role of vitamin D in nonbone health outcomes in pregnancy and lactation.

A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999-2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991-1994 and NHANES 1999-2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007-2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA.

A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12 - related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES - serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy) - and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. Theroundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12 - related biomarkers. Theyagreed thatproblems with sensitivityandspecificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.

Three laboratories participated with their laboratory-specific microbiologic growth assays (MA) in the NHANES 2007–2008 to assess whether the distributions of serum (n = 2645) and RBC folate (n = 2613) for the same one-third sample of participants were comparable among laboratories. Laboratory (L) 2 produced the highest and L1 the lowest serum and RBC folate geometric means (nmol/L) in the NHANES sample (serum: L1, 39.5; L2, 59.2; L3, 47.7; and RBC: L1, 1120; L2, 1380; L3, 1380). Each laboratory produced different reference intervals for the central 95% of the population. Pearson correlation coefficients were highest between L3 and L1 (serum, r = 0.95; RBC, r = 0.92) and lowest between L2 and L1 (serum, r = 0.81; RBC, r = 0.65). Notable procedural differences among the laboratories were the Lactobacillus rhamnosus microorganism (L1 and L3: chloramphenicol resistant, L2: wild type) and the calibrator [L1: [6S]5-methyltetrahydrofolate (5-methylTHF), L2: [6R,S] 5-formyltetrahydrofolate ([6R,S] 5-formylTHF), L3: folic acid (FA)]. Compared with 5-methylTHF as calibrator, the folate results were 22–32% higher with FA as calibrator and 8% higher with 5-formylTHF as calibrator, regardless of the matrix (n = 30 serum, n = 28 RBC). The use of different calibrators explained most of the differences in results between L3 and L1 but not between L2 and L1. The use of the wild-type L. rhamnosus by L2 appeared to be the main reason for the differences in results between L2 and the other 2 laboratories. These findings indicate how assay variations influence MA folate results and how those variations can affect population data. To ensure data comparability, better assay harmonization is needed.

Dietary supplement use has steadily increased over time since the 1970s; however, no current data exist for the U.S. population. Therefore, the purpose of this analysis was to estimate dietary supplement use using the NHANES 2003–2006, a nationally representative, cross-sectional survey. Dietary supplement use was analyzed for the U.S. population (≥1 y of age) by the DRI age groupings. Supplement use was measured through a questionnaire and was reported by 49% of the U.S. population (44% of males, 53% of females). Multivitamin-multimineral use was the most frequently reported dietary supplement (33%). The majority of people reported taking only 1 dietary supplement and did so on a daily basis. Dietary supplement use was lowest in obese adults and highest among non-Hispanic whites, older adults, and those with more than a high-school education. Between 28 and 30% reported using dietary supplements containing vitamins B-6, B-12, C, A, and E; 18–19% reported using iron, selenium, and chromium; and 26–27% reported using zinc- and magnesium-containing supplements. Botanical supplement use was more common in older than in younger age groups and was lowest in those aged 1–13 y but was reported by ~20% of adults. About one-half of the U.S. population and 70% of adults ≥ 71 y use dietary supplements; one-third use multivitamin-multimineral dietary supplements. Given the widespread use of supplements, data should be included with nutrient intakes from foods to correctly determine total nutrient exposure.

A roundtable to discuss monitoring of serum 25-hydroxyvitamin D [25(OH)D] in the NHANES was held in late July 2009. Topics included the following: 1) options for dealing with assay fluctuations in serum 25(OH)D in the NHANES conducted between 1988 and 2006; 2) approaches for transitioning between the RIA used in the NHANES between 1988 and 2006 to the liquid chromatography tandem MS (LC-MS/MS) measurement procedure to be used in NHANES 2007 and later; 3) approaches for integrating the recently available standard reference material for vitamin D in human serum (SRM 972) from the National Institute of Standards and Technology (NIST) into the NHANES; 4) questions regarding whether the C-3 epimer of 25-hydroxyvitamin D3 [3-epi-25(OH)D3] should be measured in NHANES 2007 and later; and 5) identification of research and educational needs. The roundtable experts agreed that the NHANES data needed to be adjusted to control for assay fluctuations and offered several options for addressing this issue. The experts suggested that the LC-MS/MS measurement procedure developed by NIST could serve as a higher order reference measurement procedure. They noted the need for a commutability study for the recently released NIST SRM 972 across a range of measurement procedures. They suggested that federal agencies and professional organizations work with manufacturers to improve the quality and comparability of measurement procedures across all laboratories. The experts noted the preliminary nature of the evidence of the 3-epi-25(OH)D3 but felt that it should be measured in 2007 NHANES and later.

Background: Unmetabolized serum folic acid (UMFA) has been detected in adults. Previous research indicates that high folic acid intakes may be associated with risk of cancer. Objective: The objective was to examine UMFA concentrations in relation to dietary and supplemental folate and status biomarkers in the US population aged 60 y. Design: Surplus sera were analyzed with the use of data from the National Health and Nutrition Examination Survey (NHANES) 2001–2002, a cross-sectional, nationally representative survey (n = 1121). Results: UMFAwas detected in 38% of the population, with a mean concentration of 4.4 6 0.6 nmol/L (median: 1.26 0.2 nmol/L). The group with UMFA (UMFA+) had a significantly higher proportion of folic acid supplement users than did the group without UMFA (60% compared with 41%). UMFA+ men and women also had higher supplemental and total (food + supplements) folic acid intakes than did their counterparts without UMFA. Forty percent of the UMFA+ group was in the highest quartile of total folic acid intake, but total folic acid intake was only moderately related to UMFA concentrations (r 2 = 0.07). Serum folate concentrations were significantly higher in the UMFA+ group and were predictive of UMFA concentrations (r 2 = 0.15). Serum 5-methyltetrahydrofolate and vitamin B-12 concentrations were higher in the UMFA+ group, whereas there was no difference between the 2 UMFA groups in red blood cell folate, serum homocysteine, or methylmalonic acid concentrations. Conclusions: Approximately 40% of older adults in the United States have UMFA that persists after a fast, and the presence of UMFA is not easily explained in NHANES by folic acid intakes alone. Given the possibility that excessive folic acid exposure may relate to cancer risk, monitoring of UMFA may be warranted. Am J Clin Nutr 2010;92:383–9.

Background: Total folate intake includes naturally occurring food folate and folic acid from fortified foods and dietary supplements. Recent reports have focused on total folate intakes of persons aged � 14 y. Information on total folate intakes of young children, however, is limited. Objective: The objective was to compute total folate and total folic acid intakes of US children aged 1‐13 y by using a statistical method that adjusts for within-person variability and to compare these intakes with the Dietary Reference Intake guidelines for adequacy and excess. Design: Data from the 2003‐2006 National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey, were analyzed. Total folate intakes were derived by combining intakes of food folate (naturally occurring and folic acid from fortified foods) on the basis of 24-h dietary recall results and folic acid intakes from dietary supplements on the basis of a 30-d questionnaire. Results: More than 95% of US children consumed at least the Estimated Average Requirement (EAR) for folate from foods alone. More than one-third (35%) of US children aged 1‐13 y used dietary supplements, and 28% used dietary supplements containing folic acid. Supplement users had significantly higher total folate and folic acid intakes than did nonusers. More than half (53%) of dietary supplement users exceeded the Tolerable Upper Intake Level (UL) for total folic acid (fortified food + supplements) as compared with 5% of nonusers. Conclusions: Total folate intakes of most US children aged 1‐13 y meet the EAR. Children who used dietary supplements had significantly higher total folate intakes and exceeded the UL by .50%. Am J Clin Nutr 2010;92:353‐8.

The concentration or threshold of 25-hydroxyvitamin D [25(OH)D] needed to maximally suppress intact serum parathyroid hormone (iPTH) has been suggested as a measure of optimal vitamin D status. Depending upon the definition of maximal suppression of iPTH and the 2-phase regression approach used, 2 distinct clusters for a single 25(OH)D threshold have been reported: 16-20 ng/mL (40-50 nmol/L) and 30-32 ng/mL (75-80 nmol/L). To rationalize the apparently disparate published results, we compared thresholds from several regression models including a 3-phase one to estimate simultaneously 2 thresholds before and after adjusting for possible confounding for age, BMI, glomerular filtration rate, dietary calcium, and season (April-September vs. October-March) within a single data set, i.e. data from the Tufts University Sites Testing Osteoporosis Prevention/Intervention Treatment study, consisting of 181 men and 206 women (total n = 387) ages 65-87 y. Plasma 25(OH)D and serum iPTH concentrations were (mean +/- SD) 22.1 +/- 7.44 ng/mL (55.25 +/- 18.6 nmol/L) and 36.6 +/- 16.03 pg/mL (3.88 +/- 1.7 pmol/L), respectively. The 3-phase model identified 2 thresholds of 12 ng/mL (30 nmol/L) and 28 ng/mL (70 nmol/L); similar results were found from the 2-phase models evaluated, i.e. 13-20 and 27-30 ng/mL (32.5-50 and 67.5-75 nmol/L) and with previous results. Adjusting for confounding did not change the results substantially. Accordingly, the 3-phase model appears to be superior to the 2-phase approach, because it simultaneously estimates the 2 threshold clusters found from the 2-phase approaches along with estimating confidence limits. If replicated, it may be of both clinical and public health importance.

Low circulating pyridoxal 5'-phosphate (PLP) concentrations have been linked to inflammatory markers and the occurrence of inflammatory diseases. However, the implications of these findings are unclear. The measurement of PLP and C-reactive protein (CRP) in blood samples collected from participants in the 2003-2004 NHANES afforded us the opportunity to investigate this relationship in the general U.S. population. Dietary and laboratory data were available for 3864 of 5041 interviewed adults, 2686 of whom were eligible (i.e. provided reliable dietary data and were not diabetic, pregnant, lactating, or taking hormones or steroidal antiinflammatory drugs). Vitamin B-6 intake was assessed using 2 24-h diet recalls and supplement use data. After multivariate adjustment for demographics, smoking, BMI, alcohol use, antioxidant vitamin status, intakes of protein and energy, and serum concentrations of creatinine and albumin, high vitamin B-6 intake was associated with protection against serum CRP concentrations >10 mg/L compared with or =20 nmol/L compared with 10 mg/L (P < 0.001). In conclusion, higher vitamin B-6 intakes were linked to protection against inflammation and the vitamin B-6 intake associated with maximum protection against vitamin B-6 inadequacy was increased in the presence compared to absence of inflammation.

Background The term total folate intake is used to represent folate that occurs naturally in food as well as folic acid from fortified foods and dietary supplements. Folic acid has been referred to as a double-edged sword because of its beneficial role in the prevention of neural tube defects and yet possible deleterious effects on certain cancers and cognitive function. Previous monitoring efforts did not include folic acid from dietary supplements and are therefore not complete. Objective Our objective was to combine data on dietary folate (as measured by two 24-h recalls) and folic acid from dietary supplements (collected with a 30-d frequency questionnaire) with the use of the bias-corrected best power method to adjust for within-person variability. Design The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey. Linear contrasts were constructed to determine differences in dietary and total folate intake for age and racial-ethnic groups by sex; prevalence of inadequate and excessive intakes is presented. Results In 2003-2006, 53% of the US population used dietary supplements; 34.5% used dietary supplements that contained folic acid. Total folate intake (in dietary folate equivalents) was higher for men (813 +/- 14) than for women (724 +/- 16) and higher for non-Hispanic whites (827 +/- 19) than for Mexican Americans (615 +/- 11) and non-Hispanic blacks (597 +/- 12); 29% of non-Hispanic black women had inadequate intakes. Total folate and folic acid intakes are highest for those aged > or =50 y, and 5% exceed the Tolerable Upper Intake Level. Conclusions Improved total folate intake is warranted in targeted subgroups, which include women of childbearing age and non-Hispanic black women, whereas other population groups are at risk of excessive intake.

Folate is an essential B vitamin found naturally in a variety of foods such as leafy vegetables, citrus fruits, liver, and lentils. There are many forms of folate, and folic acid is the form used in folate supplements and food fortification. Folate is involved in many reactions requiring the transfer of 1-carbon units, being essential for both DNA and RNA synthesis. Although folate was first demonstrated to be important for human health more than 70 years ago, only recently have health professionals begun to understand the full range of its physiological functions. For example, several controlled clinical trials have shown that increased consumption of folic acid may decrease the risk of neural tube defects. Other observational studies suggest inverse relationships between folate and risk for a variety of chronic diseases such as cancer and cardiovascular disease; controlled clinical trials to confirm these associations, however, are either in process or have tended not to support a simple cause-and-effect relationship. Assessment of folate status can involve both biochemical and dietary data, and it is important that clinicians understand the appropriate uses and limitations of these assessment tools. Because of the potential public health benefit of higher folate intakes on decreasing risk of neural tube defects, the Food and Drug Administration launched a national folic acid food fortification program that became fully effective in 1998. Dietary and biochemical analysis suggests that folate status has increased since the initiation of this program, although there is concern that folate intake now may be too high in some individuals. Still others argue that folate intake remains too low to achieve the original intended effect. Clearly, continued monitoring of this program is warranted. Although much has been learned about folate during the past 80 years, there is still much to ascertain about the mechanisms by which it exerts its numerous effects on human health

Background Changes in serum 25-hydroxyvitamin D [25(OH)D] concentrations in the US population have not been described. Objective We used data from the National Health and Nutrition Examination Surveys (NHANES) to compare serum 25(OH)D concentrations in the US population in 2000-2004 with those in 1988-1994 and to identify contributing factors. Design Serum 25(OH)D was measured with a radioimmunoassay kit in 20 289 participants in NHANES 2000-2004 and in 18 158 participants in NHANES III (1988-1994). Body mass index (BMI) was calculated from measured height and weight. Milk intake and sun protection were assessed by questionnaire. Assay differences were assessed by re-analyzing 150 stored serum specimens from NHANES III with the current assay. Results Age-adjusted mean serum 25(OH)D concentrations were 5-20 nmol/L lower in NHANES 2000-2004 than in NHANES III. After adjustment for assay shifts, age-adjusted means in NHANES 2000-2004 remained significantly lower (by 5-9 nmol/L) in most males, but not in most females. In a study subsample, adjustment for the confounding effects of assay differences changed mean serum 25(OH)D concentrations by approximately 10 nmol/L, and adjustment for changes in the factors likely related to real changes in vitamin D status (ie, BMI, milk intake, and sun protection) changed mean serum 25(OH)D concentrations by 1-1.6 nmol/L. Conclusions Overall, mean serum 25(OH)D was lower in 2000-2004 than 1988-1994. Assay changes unrelated to changes in vitamin D status accounted for much of the difference in most population groups. In an adult subgroup, combined changes in BMI, milk intake, and sun protection appeared to contribute to a real decline in vitamin D status.

We summarize the key findings, strength of the evidence, and research needs identified in the National Institutes of Health conference “Vitamin D and Health in the 21st Century: an Update,” which was held in September 2007; a systematic evidence-based review; and a National Institutes of Health roundtable discussion held after the conference by scientists with relevant expertise. The evidencebased review addressed 5 questions on 25-hydroxyvitamin D [25(OH)D] and functional outcomes across the life cycle and responsetoexposure,bonehealthoutcomesofsupplementation,risks andbenefitsofsunexposure,andadverseoutcomes.Thesequestions alsoframedtheconferenceandroundtablediscussions.Researchers have made considerable progress in understanding the relation of 25(OH)D to bone health outcomes in the elderly and in postmenopausal women, but we know less about its impact on other stages of the life cycle and in racial and ethnic groups. Limitations of the existing data include the failure of many studies to control for important confounders [baseline 25(OH)D concentration, skin pigmentation, body mass index, compliance, etc], sparse data on key vulnerablepopulations(dark-skinnedpersons,reproducingwomen, infants,children,andadolescents),problemsofaccuracyandexcessive variability in measuring 25(OH)D, lack of established relation of 25(OH)D with functional outcomes except in the elderly, and limited information on the effects of vitamin D independent of calcium,magnesium,andphosphate.Futureresearchshoulddetermine andvalidateacrossthelifecyclerelevantfunctionaloutcomesfor bone and other health factors as well as adverse outcomes for the biomarker of exposure, 25(OH)D, to enable assessment of the role of vitamin D status in health maintenance and disease prevention. Am J Clin Nutr 2008;88(suppl):483S–90S.

No large-scale, population-based study has considered the descriptive epidemiology of vitamin B-6 status with use of plasma pyridoxal 5'-phosphate (PLP), the indicator of vitamin B-6 adequacy used to set the current Recommended Dietary Allowance, which isor = 2 mg/d for all subgroups.We sought to examine the epidemiology of vitamin B-6 status in the US population.In6000 participants agedor = 1 y in the National Health and Nutrition Examination Survey (2003-2004), we considered relations between plasma PLP and various subject characteristics and examined trends in plasma PLP and homocysteine with vitamin B-6 intake, both overall and in selected subgroups.In males, plasma PLP decreased with age after adolescence only in nonusers of supplemental vitamin B-6. Regardless of supplement use, plasma PLP concentrations of women of childbearing age were significantly lower than those of comparably aged men, and most oral contraceptive users had plasma PLP20 nmol/L. The prevalence of low plasma PLP was significantly3% at vitamin B-6 intakes from 2 to 2.9 mg/d in all subgroups and at intakes from 3 to 4.9 mg/d in smokers, the elderly, non-Hispanic blacks, and current and former oral contraceptive users. Intakes from 3 to 4.9 mg/d compared with2 mg/d were associated with significant protection from low plasma PLP in most subgroups and from hyperhomocysteinemia in the elderly.Vitamin B-6 intakes of 3 to 4.9 mg/d appear consistent with the definition of a Recommended Dietary Allowance for most Americans. However, at that intake level, substantial proportions of some population subgroups may not meet accepted criteria for adequate vitamin B-6 status.

This article illustrates the importance of having analytical data on the vitamin and mineral contents of dietary supplements in nutrition studies, and describes efforts to develop an analytically validated dietary supplement ingredient database (DSID) by a consortium of federal agencies in the USA. Preliminary studies of multivitamin mineral supplements marketed in the USA that were analyzed as candidates for the DSID are summarized. Challenges are summarized, possible future directions are outlined, and some related programs at the Office of Dietary Supplements, National Institutes of Health are described. The DSID should be helpful to researchers in assessing relationships between intakes of vitamins and minerals and health outcomes.

Several activities of the Office of Dietary Supplements (ODS) at the National Institutes of Health involve enhancement of dietary supplement databases. These include an initiative with US Department of Agriculture to develop an analytically substantiated dietary supplement ingredient database (DSID) and collaboration with the National Center for Health Statistics to enhance the dietary supplement label database in the National Health and Nutrition Examination Survey (NHANES). The many challenges that must be dealt with in developing an analytically supported DSID include categorizing product types in the database, identifying nutrients, and other components of public health interest in these products and prioritizing which will be entered in the database first. Additional tasks include developing methods and reference materials for quantifying the constituents, finding qualified laboratories to measure the constituents, developing appropriate sample handling procedures, and finally developing representative sampling plans. Developing the NHANES dietary supplement label database has other challenges such as collecting information on dietary supplement use from NHANES respondents, constant updating and refining of information obtained, developing default values that can be used if the respondent cannot supply the exact supplement or strength that was consumed, and developing a publicly available label database. Federal partners and the research community are assisting in making an analytically supported dietary supplement database a reality.

The influence of folate nutritional status on various pregnancy outcomes has long been recognized. Studies conducted in the 1950s and 1960s led to the recognition of prenatal folic acid supplementation as a means to prevent pregnancy-induced megaloblastic anemia. In the 1990s, the utility of periconceptional folic acid supplementation and folic acid food fortification emerged when they were proven to prevent the occurrence of neural tube defects. These distinctively different uses of folic acid may well be ranked among the most significant public health measures for the prevention of pregnancy-related disorders. Folate is now viewed not only as a nutrient needed to prevent megaloblastic anemia in pregnancy but also as a vitamin essential for reproductive health. This review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins, and we identify issues for future research.

This study investigated the homocysteine lowering potential of garlic in rats rendered folic acid (FA) deficient. Rats fed AIN-93G diet devoid of FA exhibited mild folate deficiency and had a plasma level of total homocysteine higher than that for those fed AIN-93G diet containing FA (9 vs 5 μ mol/L). Supplementation with aged garlic extract (AGE, 4%) to either diet did not alter plasma homocysteine levels. Subsequently, rats were made severely deficient in folate by feeding a folate-deficient l-amino acid diet containing succinyl sulfathiazole. Although folate concentrations in plasma, erythrocytes, liver, and kidneys were markedly depressed, plasma total homocysteine was increased to 32 μ mol/L by the severe deficiency. Supplementation of AGE to the deficient diet reduced plasma protein-bound, free, and total homocysteine by 28% to 33%. The supplementation did not change plasma cysteine, cysteinylglycine, or glutathione concentrations. Liver concentration of S -adenosylmethionine was elevated by 26%, and S -adenosylhomocysteine was lowered by 15% in the AGE-supplemented group. It is speculated that the reduction of plasma homocysteine level by AGE stems, in part, from stimulation of transsulfuration via cystathionine β -synthase and inhibition of remethylation of homocysteine resulting from inactivated N 5 , N 10 -methylenehydrofolate reductase.

The purpose of this study was to investigate the usefulness of soluble serum transferrin receptor (TfR) concentration, TfR index and log TfR:ferritin ratio (TfR outcomes) in detecting tissue Fe deficiency among breast-feeding Otomi women residing in Capulhuac, Mexico (2800 m above sea level) and to determine whether folate deficiency modifies the interpretation of these data. Lactating women (n = 68) provided blood samples at 22 +/- 13 d (mean +/- SD) postpartum. Using the 3-index Fe assessment model with and without Hb, 2 women (3%) had Fe-deficient erythropoiesis, 24 (36%) Fe deficiency anemia, and 19 (29%) indeterminate Fe status; 29 (43%) and 5 (7.5%) women had plasma and erythrocyte folate concentrations below normative cutoff values, respectively. Mean values for TfR outcomes were higher among women classified as Fe deficient than those who were Fe sufficient, but did not differ with low or normal blood folate concentrations. Similarly, TfR outcomes did not differ among women with normocytic or macrocytic erythrocytes. Receiver-operating characteristic (ROC) curves generated for TfR outcomes yielded areas under the curve from 0.62 to 0.68, indicating that each of these measures, on its own, is a poor predictor of tissue Fe deficiency in lactating women. In conclusion, low blood folate concentrations or the presence of macrocytosis in Otomi women from Capulhuac, Mexico (moderate altitude) did not influence the utility of TfR outcomes for the detection of Fe deficiency during early lactation. Further, on their own, TfR, TfR index, and TfR:ferritin ratio were poor predictors of tissue Fe deficiency for any given individual.

Background: The findings of animal and human studies suggest that a certain component in milk enhances food folate bioavailability. Objective: The objective was to evaluate whether cow milk enhances the bioavailability of food folate in humans. Design: Thirty-one young women were fed low-folate diets on a 4-d rotation with (n = 17) or without (n = 14) cow milk for 8 wk. Plasma and erythrocyte folate and plasma total homocysteine (tHcy) concentrations were monitored. Results: Plasma folate concentrations steadily declined in both the milk and the nonmilk groups; however, the declines were not significantly different between groups (P = 0.09). In contrast, erythrocyte folate concentrations declined only in the nonmilk group and remained unchanged in the milk group; the difference between the 2 groups was significant (P = 0.01). Plasma tHcy concentrations significantly increased in the nonmilk group and remained unchanged in the milk group; the difference between the 2 groups was significant (P = 0.02). Conclusion: The inclusion of cow milk in the diet enhanced the bioavailability of food folate as assessed by the changes in erythrocyte folate and plasma tHcy concentrations but not in plasma folate concentrations. The mechanisms of action by the components of cow milk remain to be investigated.

Major initiatives of the US National Institutes of Health Office of Dietary Supplements (ODS) include development of analytical methods and reference materials to make the development of analytically substantiated dietary supplement databases possible in the future. ODS has an active evidence-based review program focused on efficacy and safety of dietary supplements. It also sponsors basic and clinical research, and information and educational resources, including continuing education conferences and training efforts.

This guide was compiled after recommendations by the American Institute for Cancer Research (AICR) Cancer Resource Advisory Council. It encompasses the AICR position on current issues in nutrition for cancer survivors during treatment and is intended to provide advice about dietary supplements for cancer survivors who are still being treated. Current scientific findings about the safety and effectiveness of some commonly used dietary antioxidants and nonantioxidant supplements during chemotherapy are presented and assessed. Use of dietary supplements during cancer treatment remains controversial. Patients are cautioned that vitamin and mineral supplements as therapies are not substitutes for established medicine. The current recommendation for cancer patients is to only take moderate doses of supplements because evidence from human clinical studies that confirm their safety and benefits is limited. A daily multivitamin containing supplements at the levels of the Dietary Reference Intakes can be used safely as part of a program of healthy nutrition. In addition, the AICR Cancer Resource Advisory Council concluded that further scientific research is needed to provide a set of firm guidelines for the use of vitamin and mineral supplements by cancer patients during treatment.

Over the past several decades, great progress has been made in developing national nutrition policies and research agendas that address numerous problems faced by various segments of our population. Despite the success of these initiatives and our understanding of the importance of nutrition throughout the life cycle, ongoing nutrition-related problems have been identified and still need to be adequately addressed through research and policy. The recognition of these various issues inspired the development of an agenda for the National Nutrition Summit held in May 2000, jointly sponsored by the U.S. Departments of Agriculture and of Health and Human Services. The major goal of the Summit was to forge partnerships among policy makers and program planners at the federal, state, and community levels to examine what accomplishments were made since 1969 and to identify existing gaps in the areas of food, nutrition and health. This review provides an overview of the purpose and overarching themes that emerged from the Summit, along with a review of additional resources from the Summit available on a website sponsored by the U.S. Departments of Health and Human Services and Agriculture.

Nutritional needs are increased during pregnancy and lactation for support of fetal and infant growth and development along with alterations in maternal tissues and metabolism. Total nutrient needs are not necessarily the sum of those accumulated in maternal tissues, products of pregnancy and lactation and those attributable to the maintenance of nonreproducing women. Maternal metabolism is adjusted through the elaboration of hormones that serve as mediators, redirecting nutrients to highly specialized maternal tissues specific to reproduction (i.e., placenta and mammary gland). It is most unlikely that the heightened nutrient needs for successful reproduction can always be met from the maternal diet. Requirements for energy-yielding macronutrients increase modestly compared with several micronutrients that are unevenly distributed among foods. Altered nutrient utilization and mobilization of reserves often offset enhanced needs but sometimes nutrient deficiencies are precipitated by reproduction. There are only limited data from well-controlled intervention studies with dietary supplements and with few exceptions (iron during pregnancy and folate during the periconceptional period), the evidence is not strong that nutrient supplements confer measurable benefit. More research is needed and in future studies attention must be given to subject characteristics that may influence ability to meet maternal and infant demands (genetic and environmental), nutrient-nutrient interactions, sensitivity and selectivity of measured outcomes and proper use of proxy measures. Consideration of these factors in future studies of pregnancy and lactation are necessary to provide an understanding of the links among maternal diet; nutritional supplementation; and fetal, infant and maternal health.

Usual intakes of nutrients are reliable indicators for making associations between diet and health or disease risks. Estimates of consumption of specific foods and food groups are also important for evaluating the progress in meeting key objectives in such national public health initiatives as Healthy People 2010. Reliable and valid estimates of intakes of particular foods, food ingredients, dietary supplements and other bioactive substances are also needed for dietary assessment and regulatory purposes. The ability to generate useful estimates of these constituents often requires much larger sample sizes than are needed for estimating nutrient intakes. Statistical methods recommended by the National Academy of Sciences are described that provide estimates of distributions of usual nutrient intakes and permit dietary assessment and planning at the population level. Statistical and modeling approaches for estimating intakes of foods, dietary supplements and other bioactive substances are also summarized. Based on the deliberations of discussion groups consisting of members of key stakeholder groups involved in the planning, implementation and utilization of national survey data, a high priority was placed on the need for more research to determine the best approaches for applying these methods to dietary data in the integrated What We Eat in America-National Health and Nutrition Examination Survey (NHANES).

This paper describes the collection process for the integrated dietary component of the National Health and Nutrition Examination Survey(NHANES) 2002 (entitled What We Eat in America-NHANES), referred to here as the integrated survey. The dietary components of previous NHANES cycles and the Continuing Survey of Food Intake in Individuals (CSFII) are also described. The collection process for foods in the integrated survey consists of an in-person 24-h recall using a computerized 5-step method and a second nonconsecutive 24-h recall via telephone. A food frequency questionnaire is being pilot-tested to provide information on the propensity to consume certain foods. Dietary supplement intakes over the past 30 d are assessed for all persons during the household interview. Other diet-related data are also obtained. Strengths of the integrated survey include information on food and supplement intakes in a representative sample of the civilian noninstitutionalized population of the United States that can be linked to anthropometric, biochemical, clinical and disease history information in NHANES. After reviewing the current state of the art on dietary and dietary supplement data collection, discussion groups consisting of members of key stakeholder community concluded that, although the most advanced methods for dietary data collection available are being used, the differences between how information on food and dietary supplement intakes is collected make it challenging to combine data describing nutrients from both sources to obtain estimates of total nutrient intakes. The discussion groups concluded that more research is needed on these issues and provided key recommendations for future efforts in this important area of public health surveillance.

This study was designed to determine if oral sodium selenite supplementation to Se-depleted rat pups furnishes protection against hyperoxic lung injury. Twelve female rats were bred and fed a Se-deficient (0.04 ppm Se) diet during pregnancy and lactation. Pups were supplemented either with 0 or 3.2 ng Se/g body weight daily from days 2 to 7. On day 4, two litters were mixed, with half of the pooled litter assigned to an air environment and the other half to an oxygen environment. Dams cross-fostered pups for 4 d. Selenite supplementation increased pup plasma and liver selenium concentration and the liver activity of glutathione peroxidase (GPx). However, lung GPx activity was more affected by oxygen exposure than selenite supplementation. While oral Se supplementation of the pups showed a tendency for decreased incidence of lung injury with oxygen exposure, this apparent effect was not statistically significant. Selenium-supplemented pups also showed a trend toward larger internal surface area and lung volume than selenium-depleted pups. These data indicate that early postnatal selenium repletion via direct oral selenite supplementation may be beneficial to rat pups against hyperoxic lung injury.

Objective: To identify portion sizes (quantity ingested at a meal/snack) of foods commonly consumed in early childhood, temporal stability, and relations to energy intake, weight status, and sociodemographic characteristics. Study design: Three samples were evaluated: the Continuing Survey of Food Intakes by Individuals, 1994 to 1996, 1998 (CSFII 94-96, 98) (n = 1039), the Nationwide Food Consumption Survey, 1977 to 1978 (NFCS 77-78) (n = 1045), and a longitudinal sample (n = 55) studied from 12 to 18 months. The CSFII 94-96, 98, and NFCS 77-78 samples were compared to evaluate secular trends. Change from 12 to 18 months was assessed in the longitudinal sample. Relations of portion size to other relevant variables were evaluated in the CSFII 94-96, 98 sample. Results: In recent decades, portions remained remarkably similar for most foods. An exception was for meat portions, which were smaller in recent samples. Portions were longitudinally stable for most foods but increased for milk, bread, cereal, juice, and peanut butter. Body weight was positively related to energy intake and portion size but not number of eating occasions and/or foods. Sociodemographically, portion size was inversely related to number of eating occasions and/or foods. Conclusions: Children regulate energy intake largely through portion size. Sociodemographic patterns may have implications for later weight status. (J Pediatr 2002;140:340-7)

International agencies and various US health organizations uniformly recommend breastfeeding as the preferred method of infant feeding for the entire first year of life and thereafter as long as is beneficial to the mother–infant dyad. 1,52 These recommendations are based on knowledge that term infants nursed by nutritionally adequate mothers are provided with sufficient energy and the proper profile of nutrients to support normal growth and development without any additional foods through the first 4 to 6 months of life. After 6 months, complimentary foods are needed to furnish nutrients likely to become limiting. Also, human milk furnishes an array of nonnutrient growth factors, immune factors, hormones, and other bioactive components that can act as biological signals and confer protection against illness in infancy and later in life. 20,43 From a nutritional perspective, infancy is a critical and vulnerable period. At no other stage of life is a single food adequate as the sole source of nutrition. This phenomenon occurs when immaturity in tissues and organs involved in nutrient metabolism (i.e., the gastrointestinal tract, liver, and kidneys) limits the ability of an infant to respond to excesses or deficiencies in nutrient intakes. Human milk is species specific, and many of the nutrients it contains are secreted as bound components that can offer protection from digestion and facilitate absorption and utilization. In this article, the characteristic nutritional features of human milk and influencing factors are reviewed. Knowledge of human-milk composition and nutrient intakes of thriving human milk–fed infants are central to the understanding of infant nutritional requirements and the nutritional cost of lactation for mothers.

A primary consideration in longitudinal growth studies is the identification of growth from error components. While previous research has considered matters of measurement accuracy and reproducibility in detail, few reports have investigated the errors of measurement due to aspects of the physiology and cooperation of the child. The present study directly assesses this source of measurement undependability for the first time. Investigation of total measurement error variance in 925 recumbent length replicates taken over stasis intervals in growth identifies that between 60% and 70% of total measurement unreliability is due to a child factor undependability. Individual differences are significant and longitudinal growth analyses should consider two to three times the technical error of measurement statistic as a reasonable estimate of the total unreliability for any single measurement of an infant's recumbent length. These results raise issues regarding analytic methods as applied to serial growth data.

Objective Current recommendations for infant feeding encourage breast-feeding through the first year. This research was conducted to evaluate associations among breast-feeding, maternal control of child-feeding, and the dietary intake of toddlers during the second year of life. In particular, we sought to determine whether breast-feeding through the first year and subsequent toddler intake was mediated via maternal control of child feeding. Design/subjects Fiftyfive white infants and their mothers were monitored longitudinally from age 12 or 13 months to age 18 months. Main outcome measures Breast-feeding through the first year and maternal control in infant feeding were evaluated as predictors of energy intake at age 18 months. Statistical analyses performed Regression analysis was used to evaluate predictors of toddler energy intake at age 18 months. A mediation model tested if the relationship between breast-feeding and infant intake was mediated by maternal control in feeding. Results Breast-feeding through the first year was associated with higher toddler energy intakes at age 18 months through its influence on maternal control in feeding. Mothers who breast-fed their infants for at least 12 months used lower levels of control in feeding. Lower levels of maternal control in feeding were associated with higher toddler energy intakes. The highest energy intakes among children aged 18 months were observed among taller and leaner toddlers. Applications/conclusions Our findings suggest that breast-feeding through the first year may have an effect on children's energy intake by shaping mothers' child-feeding practices. These findings may be used by clinicians to assist parents in making informed decisions about choice of infant-feeding method and to provide anticipatory guidance regarding infant-feeding style when initiating dietary diversity. J Am Diet Assoc. 2000;100:641-646.

BACKGROUND Folate requirements during lactation are not well established. OBJECTIVE We assessed the effects of dietary and supplemental folate intakes during extended lactation. DESIGN Lactating women (n = 42) were enrolled in a double-blind, randomized, longitudinal supplementation trial and received either 0 or 1 mg folic acid/d. At 3 and 6 mo postpartum, maternal folate status was assessed by measuring erythrocyte, plasma, milk, and dietary folate concentrations; plasma homocysteine; and hematologic indexes. Infant anthropometric measures of growth, milk intake, and folate intake were also assessed. RESULTS In supplemented women, values at 6 mo for erythrocyte and milk folate concentrations and for plasma homocysteine were not significantly different from those at 3 mo. In supplemented women compared with unsupplemented women at 6 mo, values for erythrocyte folate (840 compared with 667 nmol/L; P < 0.05), hemoglobin (140 compared with 134 g/L; P < 0.02), and hematocrit (0.41 compared with 0.39; P < 0.02) were higher and values for reticulocytes were lower. In unsupplemented women, milk folate declined from 224 to 187 nmol/L (99 to 82 ng/mL), whereas plasma homocysteine increased from 6.7 to 7.4 micromol/L. Dietary folate intake was not significantly different between groups (380+/-19 microg/d) and at 6 mo was correlated with plasma homocysteine in unsupplemented women (r = -0.53, P < 0.01) and with plasma folate in supplemented women (r = 0.49, P < 0.02). CONCLUSIONS A dietary folate intake of approximately 380 microg/d may not be sufficient to prevent mobilization of maternal folate stores during lactation.

The application of trienzyme treatment prior to microbiological assay using Lactobacillus casei for the measurement of folate in human milk was evaluated. Trienzyme treatment consisted of α-amylase, protease, and folate conjugase. Human milk samples (n = 84) were heat treated for 5 min at 100 °C in 0.1 m potassium phosphate buffer containing 0.05 mol liter−1 ascorbic acid, pH 4.1, then incubated with the enzymes by stepwise addition. Following trienzyme treatment, folate was measured microbiologically using a 96-well microplate method. The results show that treatment at 37 °C with α-amylase for 4 h followed by protease for 8 h, and finally by folate conjugase for 3 h significantly increased the measurable folate in human milk by an average of 85% compared with values after folate conjugase treatment alone (p < 0.001). Neither the pH of the extraction buffer, the source of folate conjugase, nor the method/length of heat treatment of the samples were significant variables influencing the values of human milk folate. Data indicate that folate in human milk can be underestimated unless samples are treated with α-amylase, protease, and folate conjugase prior to microbiological assay using L. casei.

▪ Abstract Triacylglycerols make up 98% of the lipid content of milk, ranging in different species from 0 to 50% of the total milk volume. The fatty aid composition of the triacylglycerols depends on the species, the dietary fatty acid composition, and the carbohydrate-to-lipid ratio of the diet. The rate of lipid synthesis in the lactating mammary gland depends on the stage of mammary development and is decreased by fasting and starvation in ruminants and rodents but not in species that fast during lactation, such as seals and hibernating bears. Regulatory agents include insulin, prolactin, and non-esterified fatty acids. Dietary trans fatty acids may depress milk lipid synthesis under certain conditions. Evidence is presented that fatty acids may play a major regulatory role in acute changes in de novo mammary fatty acid synthesis, acting primarily on the activity of acetyl coenzyme A carboxylase.

Folate plays an essential role in DNA, RNA, and protein biosynthesis. For this reason, the physiological need for this vitamin is increased during periods of rapid anabolic activity such as pregnancy and lactation. Although the importance of folate and the consequences of suboptimal folate status during pregnancy, especially during the periconceptional period, are well appreciated, little is known about the value of folate during lactation. The limited number of studies available on folate intake during lactation suggest that many women do not consume an adequate amount of folate and that recommended target intakes may be too low. Although inadequate maternal folate intake does not affect milk folate concentration unless maternal deficiency is severe, potential consequences of suboptimal folate nutrition to both the mother and her future offspring should also be considered.

The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health's Office of Dietary Supplements (NIH-ODS), has developed a Standard Reference Material (SRM) for the determination of 25-hydroxyvitamin D [25(OH)D] in serum. SRM 972 Vitamin D in Human Serum consists of four serum pools with different levels of vitamin D metabolites and has certified and reference values for 25(OH)D(2), 25(OH)D(3), and 3-epi-25(OH)D(3). Value assignment of this SRM was accomplished using a combination of three isotope-dilution mass spectrometry approaches, with measurements performed at NIST and at the Centers for Disease Control and Prevention (CDC). Chromatographic resolution of the 3-epimer of 25(OH)D(3) proved to be essential for accurate determination of the metabolites.