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1.  Homocysteine, Iron and Cardiovascular Disease: A Hypothesis 
Nutrients  2015;7(2):1108-1118.
Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.
PMCID: PMC4344578  PMID: 25668155
iron; homocysteine; cardiovascular disease; methionine; thioether
2.  13C-Enrichment of Urinary Uric Acid after l-[Ring-2-13C]Histidine Dose in Adult Humans 
Nutrients  2015;7(1):697-705.
We determined whether ring-2 carbon of histidine is folate-dependently transferred to carbons 8 (C8) and/or 2 (C2) in urinary uric acid in humans. Two adults collected each urine void for four days. Aliquots of urine for the first day were used for baseline values; then the subjects ingested 0.7 g (3.3 mmol) of l-[ring-2-13C]histidine and collected urine for three experimental days. Aliquots were analyzed for percentage 13C-content at C2 and C8 by a liquid-chromatography-mass spectrometry method. Percentage enrichment was determined by subtracting time-of-day paired baseline percentage 13C-content from experimental percentage 13C-content for each void. C2 was predominantly 13C-enriched in the majority of voids. The percentage enrichments at C2 for two subjects were 0.14 (±0.028 [SEM], n = 26) and 0.18 (±0.049, n = 21), whereas at C8, they were 0.008 (±0.006) and −0.005 (±0.008), respectively. The mean C2-enrichments were significantly greater than zero (p < 0.01), whereas those of C8 were not (p > 0.2). The enrichment had a diurnal rhythm peaking in the morning. Our results may be useful in the estimation of the timing for the administration of drugs that interfere with purine nucleotide biosynthesis in the treatment of cancer and autoimmune disease.
PMCID: PMC4303862  PMID: 25608940
C2 enrichment; uric acid; folate metabolism; humans; purine nucleotide biosynthesis; [ring-2-13C]histidine
3.  The second study of experimental human folate deficiency 
SpringerPlus  2014;3:719.
PMCID: PMC4320236  PMID: 25674459
4.  Plasma Zinc Concentrations of Mothers and the Risk of Oral Clefts in their Children in Utah 
The role of maternal zinc nutrition in human oral clefts (OCs) is unclear. We measured plasma zinc concentrations (PZn) of case- and control-mothers to evaluate the associations between PZn and risk of OCs with and without other malformations.
Case-mothers were ascertained by the Utah Birth Defects Network and control-mothers were selected from Utah birth certificates by matching for child gender and delivery month and year. Maternal blood was collected > 1 year after the last pregnancy. PZn was available for 410 case-mothers who were divided into four subgroups; isolated cleft lip with or without cleft palate (CL/P-I, n = 231), isolated cleft palate (CP-I, n = 74), CL/P with other malformations (CLP-M, n = 42), and CP with other malformations (CP-M, n = 63). PZn was available for 447 control-mothers. The mean age of children at blood sampling was 3.7 years for all cases combined and 4.3 years for controls.
Mean PZn of all groups were similar, and low PZn (< 11.0 μmol/l) was found in 59% of cases and 62% of controls. Risk of OCs did not vary significantly across PZn quartiles for the four subgroups individually and all OC groups combined.
We previously reported that poor maternal zinc status was a risk factor for OCs in the Philippines, where OC prevalence is high and maternal PZn is low. In Utah, however, no such association was found, suggesting that poor maternal zinc status may become a risk factor only when zinc status is highly compromised.
PMCID: PMC3712612  PMID: 19067407
zinc status; plasma zinc; cleft lip; cleft palate; malformations; human; Utah
5.  Biomarkers of folate status in NHANES: a roundtable summary123456 
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.
PMCID: PMC3127517  PMID: 21593502
6.  Biomarkers of vitamin B-12 status in NHANES: a roundtable summary123456 
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. The roundtable 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. They agreed that problems with sensitivity and specificity 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.
PMCID: PMC3127527  PMID: 21593512
7.  Effect of paternal folate deficiency on placental folate content and folate receptor α expression in rats 
Nutrition Research and Practice  2011;5(2):112-116.
We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor α (FRα) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FRα (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FRα expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport.
PMCID: PMC3085799  PMID: 21556224
Paternal folate status; placental folate; placental weight; folate receptor alpha
8.  Zinc status and growth of Korean infants fed human milk, casein-based, or soy-based formula: three-year longitudinal study 
To evaluate the effect of feeding methods on growth and zinc nutritional status of infants early in life, we monitored from birth to 36 months in 51 infants who were exclusively fed human milk (HM, n = 20), casein-based formula (CBF, n = 12), or soy-based formula (SBF, n = 19) during the first five months of life. Zinc status was assessed by analyzing serum zinc concentrations and zinc intakes. Zinc contents in HM and formulas were measured. Zinc intake was estimated by weighing infants before and after feeding in the HM group and by collecting formula-intake records in the CBF and SBF groups. After solid foods were introduced, all foods consumed were also included to estimate zinc intake. The growth of infants in all groups was similar to that established for normal Korean infants. Human milk zinc concentrations declined as lactation progressed. Zinc concentrations in all formulas tested in this study were higher than HM and were also higher than those claimed by the manufacturers. During the first twelve months, mean serum zinc concentrations of infants were similar in all groups, although infants in the HM group consistently had the lowest zinc intake among the groups, and the overall zinc intake in infants fed SBF was highest. This finding could be explained by the different zinc bioavailability of HM and formulas. In conclusion, infants fed HM, CBF or SBF has normal growth up to three years of age, although HM contained the lowest zinc concentration followed by CBF, then SBF.
PMCID: PMC3061270  PMID: 21487496
Zinc status; human milk; casein-based formula; soy-based formula; infant growth
9.  13C-Enrichment at carbons 8 and 2 of uric acid after 13C-labeled folate dose in man 
To evaluate folate-dependent carbon incorporation into the purine ring, we measured 13C-enrichment independently at C2 and C8 of urinary uric acid (the final catabolite of purines) in a healthy male after an independent oral dose of [6RS]-5-[13C]-formyltetrahydrofolate ([6RS]-5-H13CO-H4folate) or 10-H13CO-7,8-dihydrofolate (10-H13CO-H2folate). The C2 position was 13C-enriched more than C8 after [6RS]-5-H13CO-H4folate, and C2 was exclusively enriched after 10-H13CO-H2folate. The enrichment of C2 was greater from [6RS]-5-H13CO-H4folate than 10-H13CO-H2folate using equimolar bioactive doses. Our data suggest that formyl C of [6RS]-10-H13CO-H4folate was not equally utilized by glycinamide ribotide transformylase (enriches C8) and aminoimidazolecarboxamide ribotide (AICAR) transformylase (enriches C2), and the formyl C of 10-H13CO-H2folate was exclusively used by AICAR transformylase. 10-HCO-H2folate may function in vivo as the predominant substrate for AICAR transformylase in humans.
PMCID: PMC2151848  PMID: 17643394
Folate; Stable isotope; Purine biosynthesis; Uric acid; Human; Mass spectrometry; AICAR transformylase; GAR transformylase; Dihydrofolate reductase; 10-Formyldihydrofolate
10.  13C Enrichment of Carbons 2 and 8 of Purine by Folate-Dependent Reactions After [13C]Formate and [2-13C]Glycine Dosing in Adult Humans 
The 10-formyl moiety of 10-formyltetrahydrofolate is the source of carbons at the positions 8 (C8) and 2 (C2) of the purine ring, originating from formate and a few amino acids. Uric acid is the final catabolic product of purines. In adult humans, we independently measured the 13C enrichment of the C2 and C8 positions of urinary uric acid after an oral dose of [13C]sodium formate and that of the C2 and C8 plus C5 positions after [2-13C]glycine. A liquid-chromatography mass-spectrometric method was used to measure the 13C enrichment of uric acid in urine which was collected for 3 - 4 days. Purine catabolism to uric acid does not alter the positions of carbons in the ring. After the formate dose, the 13C-enrichment at C2 was greater that at C8, and a circadian rhythm was observed in the enrichment at C2. After the glycine dose, the C8 plus C5 positions were enriched, whereas no significant enrichment at C2 was found. These 13C enrichment patterns are not consistent with previous accepted metabolism. To our knowledge, this is the first study to investigate 13C enrichment from formate and glycine independently into the C2 and C8 positions of purine in the same subjects. Possible mechanisms explaining our findings are discussed. Oral [13C]formate or [2-13C]glycine dosing and urine collection can be used to study purine biosynthesis in humans.
PMCID: PMC1931417  PMID: 17445548
13C isotope; formate; glycine; purine nucleotide biosynthesis; humans
11.  Measurement of Amniotic Fluid Interleukin-6 Using Commercial Kits 
Objective: The association between increased amniotic fluid interleukin-6 (IL-6) concentrations and preterm labor has received increasing attention. Several research groups have evaluated this association using commercial IL-6 kits, which principally use the sandwich-enzyme-immunoassay method, and were originally created to measure IL-6 in plasma, serum, or culture media. We evaluated commercial kits for the determination of IL-6 in amniotic fluid.
Methods: Seven commercial kits were used to determine IL-6 concentrations in three amniotic fluid samples which were obtained from patients with clinical chorioamnionitis during labor and five from normal pregnancies at mid-trimester.
Results: Amniotic fluid IL-6 values differed significantly with some having over a 50-fold discrepancy and the recovery of known IL-6 added to amniotic fluid ranged from 12 to 123%. However, by all kits we were able to identify that amniotic fluid from patients with chorioamnionitis contained significantly higher IL-6 concentrations than those from normal mid-trimester pregnancies.
Conclusion: Our data indicate that standardization of the method for measuring IL-6 in amniotic fluid is desirable for the comparison of values from various laboratories.
PMCID: PMC2364548  PMID: 18476141

Results 1-11 (11)