Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine ß-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.

STUDY OBJECTIVE: A phase 1/2 clinical trial was performed in individuals with cystathionine ß synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment. METHODS: Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 µM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days. RESULTS: Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 µM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 µM, pertinent to endothelial function. CONCLUSION: Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function.

Nonheme-iron absorption in first-degree relatives is highly correlated: a stable-isotope study in mother-child pairs.

BACKGROUND: Iron absorption in humans is highly variable even after iron status and dietary components that influence iron absorption are controlled for. Inherited factors may help explain this variance. OBJECTIVE: Our objective was to compare nonheme-iron absorption from a noninhibitory, stable-isotope-labeled test meal in preschool-aged children and their mothers. DESIGN: We provided 72 test meals based on degermed maize flour and milk powder and fortified with [(57)Fe]ferrous fumarate or [(58)Fe]ferrous sulfate to healthy Mexican preschool children [n = 18; mean (+/-SD) age: 3.6 +/- 1.0 y] and their mothers [n = 18; mean (+/-SD) age: 28.0 +/- 5.2 y]. Iron absorption was calculated on the basis of incorporation of isotopes into erythrocytes after 14 d and was adjusted for differences in iron status. RESULTS: There was a wide variation in iron absorption from the test meals: in the mothers and children, the median fractional absorption of ferrous sulfate was 22.55% (range: 1.65-54.83%) and 5.51% (range: 2.23-17.20%), respectively (P < 0.0001). After adjustment for serum ferritin, the significant difference in absorption between mothers and their children disappeared. Despite this broad range of iron absorption, corrected fractional iron absorption from the ferrous fumarate-fortified (r(2) = 0.582) and the ferrous sulfate-fortified test meals (r(2) = 0.557) was strongly correlated in mothers and their children (P < 0.0001). There was a striking positive correlation between the mean corrected fractional iron absorption from both test meals in mothers and their children (r(2) = 0.782, P < 0.0001). In regression analyses that included age, sex, and hemoglobin, the only significant predictor of corrected fractional iron absorption in children was corrected fractional iron absorption in their mothers (standardized beta = 0.884, P < 0.001). CONCLUSIONS: Nonheme-iron absorption exhibits a strong familial tendency. After differences in meal matrix and serum ferritin are accounted for, these data suggest that inheritance and/or shared environmental factors explain most of the variance in dietary iron absorption.

Vitamin D status assessed by a validated HPLC method: within and between variation in subjects supplemented with vitamin D3.

OBJECTIVE: The aim of this study was to develop and validate a high-pressure liquid chromatography (HPLC) method for assessing vitamin D status as 25-hydroxyvitamin D(2) (S-25OHD(2)) and 25-hydroxyvitamin D(3) (S-25OHD(3)) in serum. MATERIAL AND METHODS: We assessed the within- and between-subject variation of vitamin D status in serum samples from four different dietary intervention studies in which subjects (n = 92) were supplemented with different doses of vitamin D(3) (5-12 microg/day) and for different durations (4-20 months). RESULTS: The HPLC method was applicable for 4.0-200 nmol S-25OHD/L, while the within-day and between-days variations were 3.8 % and 5.7 %, respectively. There was a concentration-dependent difference between results obtained by a commercial radioimmunoassay and results from the HPLC method of -5 to 20 nmol 25OHD/L in the range 10-100 nmol 25OHD/L. The between-subject variation estimated in each of the four human intervention studies did not differ significantly (p = 0.55). Hence, the pooled standard deviation was 15.3 nmol 25OHD(3)/L. In the studies with 6-8 samplings during 7-20 months of supplementation, the within-subject variation was 3.9-7.2 nmol 25OHD(3)/L, while vitamin D status was in the range 47-120 nmol/L. CONCLUSIONS: The validated HPLC method was applied in samples from human intervention studies in which subjects were supplemented with vitamin D(3). The estimated standard deviation between and within subjects is useful in the forthcoming decision on setting limits for optimal vitamin D status.

Comparison of the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced elemental iron: randomized, double-blind, controlled trial in Thai women.

BACKGROUND: Although elemental iron powders are widely used to fortify cereal products, little data exist on their efficacy in humans. OBJECTIVE: We compared the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in Thai women with low iron stores. DESIGN: A double-blind intervention was conducted in 18-50-y-old women (n = 330) randomly assigned into 4 groups to receive either no fortification iron or 12 mg Fe/d for 6 d/wk for 35 wk as ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in a baked, wheat-flour-based snack. Snacks were not consumed with meals, and consumption was monitored. At baseline, 20 wk, and 35 wk, hemoglobin status and iron were measured and the groups were compared. RESULTS: Between baseline and 35 wk, geometric mean serum ferritin (SF) increased significantly in all 3 groups receiving iron (P < 0.01), and geometric mean serum transferrin receptor (TfR) decreased significantly in the groups receiving ferrous sulfate and electrolytic iron (P < 0.05). Calculated mean (+/-SD) body iron stores increased from 1.5 +/- 2.8 to 5.4 +/- 2.9 mg/kg in the ferrous sulfate group, from 1.5 +/- 3.5 to 4.4 +/- 3.6 mg/kg in the electrolytic iron group, and from 1.3 +/- 3.2 to 3.2 +/- 4.3 mg/kg in the hydrogen-reduced iron group (P < 0.01 for all 3 groups) but did not change significantly in the control group. CONCLUSIONS: Ferrous sulfate, electrolytic iron, and hydrogen-reduced iron, fortified into wheat-based snacks, significantly improved iron status. On the basis of the change in body iron stores during the 35-wk study, the relative efficacy of the electrolytic and hydrogen-reduced iron compared with ferrous sulfate was 77% and 49%, respectively.