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Effects of menopausal hormone therapy on erythrocyte n-3 and n-6 PUFA concentrations in the Women's Health Initiative randomized trial.
Harris, WS, Tintle, NL, Manson, JE, Metherel, AH, Robinson, JG
The American journal of clinical nutrition. 2021;(6):1700-1706
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Abstract
BACKGROUND The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (ɷ-3) PUFA concentrations are unknown. OBJECTIVE We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations. METHODS Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n = 560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n = 610). RBC n-3 and n-6 (ɷ-6) PUFAs were quantified. RESULTS Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged. CONCLUSIONS HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory.
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Docosahexaenoic Acid (DHA) Bioavailability in Humans after Oral Intake of DHA-Containing Triacylglycerol or the Structured Phospholipid AceDoPC®.
Hachem, M, Nacir, H, Picq, M, Belkouch, M, Bernoud-Hubac, N, Windust, A, Meiller, L, Sauvinet, V, Feugier, N, Lambert-Porcheron, S, et al
Nutrients. 2020;(1)
Abstract
AceDoPC® is a structured glycerophospholipid that targets the brain with docosahexaenoic acid (DHA) and is neuroprotective in the experimental ischemic stroke. AceDoPC® is a stabilized form of the physiological 2-DHA-LysoPC with an acetyl group at the sn1 position; preventing the migration of DHA from the sn2 to sn1 position. In this study we aimed to know the bioavailability of 13C-labeled DHA after oral intake of a single dose of 13C-AceDoPC®, in comparison with 13C-DHA in triglycerides (TAG), using gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) to assess the 13C enrichment of DHA-containing lipids. 13C-DHA enrichment in plasma phospholipids was significantly higher after intake of AceDoPC® compared with TAG-DHA, peaking after 24 h in both cases. In red cells, 13C-DHA enrichment in choline phospholipids was comparable from both sources of DHA, with a maximum after 72 h, whereas the 13C-DHA enrichment in ethanolamine phospholipids was higher from AceDoPC® compared to TAG-DHA, and continued to increase after 144 h. Overall, our study indicates that DHA from AceDoPC® is more efficient than from TAG-DHA for a sustained accumulation in red cell ethanolamine phospholipids, which has been associated with increased brain accretion.
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A new antigen SUMI carried on glycophorin A encoded by the GYPA*M with c.91A>C (p.Thr31Pro) belongs to the MNS blood group system.
Ito, S, Kaito, S, Miyazaki, T, Kikuchi, G, Isa, K, Tsuneyama, H, Kurita, R, Ogasawara, K, Uchikawa, M, Satake, M
Transfusion. 2020;(6):1287-1293
Abstract
BACKGROUND MNS is one of the highly polymorphic blood groups comprising many antigens generated by genomic recombination among the GYPA, GYPB, and GYPE genes as well as by single-nucleotide changes. We report a patient with red blood cell (RBC) antibody against an unknown low-frequency antigen, tentatively named SUMI, and investigated its carrier molecule and causal gene. STUDY DESIGN AND METHODS Standard serologic tests, including enzyme tests, were performed. Monoclonal anti-SUMI-producing cells (HIRO-305) were established by transformation and hybridization methods using lymphocytes from a donor having anti-SUMI. SUMI+ RBCs were examined by immunocomplex capture fluorescence analysis (ICFA) using HIRO-305 and murine monoclonal antibodies against RBC membrane proteins carrying blood group antigens. Genomic DNA was extracted from whole blood, and the GYPA gene was analyzed by polymerase chain reactions and Sanger sequencing. RESULTS Serologic screening revealed that 23 of the 541,522 individuals (0.0042%) were SUMI+, whereas 1351 of the 10,392 individuals (13.0%) had alloanti-SUMI. SUMI antigen was sensitive to ficin, trypsin, pronase, and neuraminidase, but resistant to α-chymotrypsin and sulfydryl-reducing agents. ICFA revealed that the SUMI antigen was carried on glycophorin A (GPA). According to Sanger sequencing and cloning, the SUMI+ individuals had a GYPA*M allele with c.91A>C (p.Thr31Pro), which may abolish the O-glycan attachment site. CONCLUSIONS The new low-frequency antigen SUMI is carried on GPA encoded by the GYPA*M allele with c.91A>C (p.Thr31Pro). Neuraminidase sensitivity suggests that glycophorin around Pro31 are involved in the SUMI determinant.
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High Variability in Erythrocyte, Plasma and Whole Blood EPA and DHA Levels in Response to Supplementation.
Sparkes, C, Sinclair, AJ, Gibson, RA, Else, PL, Meyer, BJ
Nutrients. 2020;(4)
Abstract
(1) Aim: the aim of this secondary analysis was to report the variability in response to n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation in erythrocytes, plasma and whole blood of a previously published dose response study. (2) Methods: a randomized, double-blind, placebo-controlled trial of parallel design was conducted, whereby pre-menopausal women were randomly assigned to consume 0, 0.35, 0.7 or 1 g/day of supplemental eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). Fasted blood samples were taken at baseline and after eight weeks intervention. Erythrocyte, plasma and whole blood fatty acids were extracted using the method of Lepage and Roy and analysed using gas chromatography. (3) Results: There were significant increases in EPA plus DHA levels in the 0.7 g and 1 g dose groups, with the highest increase with the 1 g dose notably: in erythrocytes (from 5.69% to 7.59%), plasma (from 2.94% to 5.48%) and in whole blood (from 3.81% to 6.03%). There was high variability in response to the supplement in erythrocytes, plasma and whole blood across the different doses. (4) Conclusion: there is high individual variability in n-3 LCPUFA levels in response to n-3 LCPUFA supplementation, which should be taken into account in clinical trials using n-3 LCPUFA supplements.
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Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation.
Chen, MY, Rose, CE, Qi, YP, Williams, JL, Yeung, LF, Berry, RJ, Hao, L, Cannon, MJ, Crider, KS
The American journal of clinical nutrition. 2019;(5):1452-1461
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Abstract
BACKGROUND For women of reproductive age, a population-level red blood cell (RBC) folate concentration below the threshold 906 nmol/L or 400 ng/mL indicates folate insufficiency and suboptimal neural tube defect (NTD) prevention. A corresponding population plasma/serum folate concentration threshold for optimal NTD prevention has not been established. OBJECTIVE The aim of this study was to examine the association between plasma and RBC folate concentrations and estimated a population plasma folate insufficiency threshold (pf-IT) corresponding to the RBC folate insufficiency threshold (RBCf-IT) of 906 nmol/L. METHODS We analyzed data on women of reproductive age (n = 1673) who participated in a population-based, randomized folic acid supplementation trial in northern China. Of these women, 565 women with anemia and/or vitamin B-12 deficiency were ineligible for folic acid intervention (nonintervention group); the other 1108 received folic acid supplementation for 6 mo (intervention group). We developed a Bayesian linear model to estimate the pf-IT corresponding to RBCf-IT by time from supplementation initiation, folic acid dosage, methyltetrahydrofolate reductase (MTHFR) genotype, body mass index (BMI), vitamin B-12 status, or anemia status. RESULTS Using plasma and RBC folate concentrations of the intervention group, the estimated median pf-IT was 25.5 nmol/L (95% credible interval: 24.6, 26.4). The median pf-ITs were similar between the baseline and postsupplementation samples (25.7 compared with 25.2 nmol/L) but differed moderately (±3-4 nmol/L) by MTHFR genotype and BMI. Using the full population-based baseline sample (intervention and nonintervention), the median pf-IT was higher for women with vitamin B-12 deficiency (34.6 nmol/L) and marginal deficiency (29.8 nmol/L) compared with the sufficient group (25.6 nmol/L). CONCLUSIONS The relation between RBC and plasma folate concentrations was modified by BMI and genotype and substantially by low plasma vitamin B-12. This suggests that the threshold of 25.5 nmol/L for optimal NTD prevention may be appropriate in populations with similar characteristics, but it should not be used in vitamin B-12 insufficient populations. This trial was registered at clinicaltrials.gov as NCT00207558.
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Evaluation of plasma and erythrocyte fatty acids C15:0, t-C16:1n-7 and C17:0 as biomarkers of dairy fat consumption in adolescents.
Slim, M, Ha, C, Vanstone, CA, Morin, SN, Rahme, E, Weiler, HA
Prostaglandins, leukotrienes, and essential fatty acids. 2019;:24-29
Abstract
INTRODUCTION Pentadecanoic (C15:0), heptadecanoic (C17:0) and trans-palmitoleic (t-C16:1n-7) fatty acids (FAs) are often used as biomarkers for dairy fat in adults. This study aimed to investigate the relationship between dairy product intake and these FAs in adolescents. MATERIAL AND METHODS Healthy adolescents were randomized to one of three groups (Group 1: control; Group 2: consume 3 dairy servings/day; and Group 3: consume ≥ 4 servings/d). C15:0, C17:0 and t-C16:1n-7 were quantified using gas chromatography. Dietary intakes were assessed by 24 h diet recalls. RESULTS No difference was observed in FAs at baseline or 6 months (mo), however, at 12 mo, erythrocyte C15:0 increased in group 3 (+0.37 µg/ml, p = 0.01). Dairy intake increased in both intervention groups (Group 2: +1.4 servings/d; Group 3: +2.4 servings/d, p < 0.0001) and positively correlated with erythrocyte C15:0 at 12 mo. CONCLUSION Erythrocyte FAs appear to be associated with increasing dairy intakes during adolescence.
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The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.
Freitas-Simoes, TM, Cofán, M, Blasco, MA, Soberón, N, Foronda, M, Corella, D, Asensio, EM, Serra-Mir, M, Roth, I, Calvo, C, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(2):958-961
Abstract
BACKGROUND & AIMS Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.
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Response of Red Blood Cell Folate to Supplementation in Nonpregnant Women is Predictable: A Proposal for Personalized Supplementation.
Obeid, R, Schön, C, Wilhelm, M, Shrestha, RP, Pilz, S, Pietrzik, K
Molecular nutrition & food research. 2018;(4)
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SCOPE We modeled red blood cell (RBC)-folate response to supplementation and developed personalized folate supplementation concepts. METHODS AND RESULTS The changes of RBC-folate were modeled in a time- (4 or 8 weeks) and dose- (400 or 800 μg d-1 folate) dependent manner. Post-supplementation RBC-folate levels were predicted from folate-loading capacities (= measured RBC-folate - [baseline RBC-folate × RBC-survival]). The prediction equations were validated in 119 participants. The median increase of RBC-folate was higher in the 800 μg d-1 than in the 400 μg d-1 group (275 vs 169 nmol L-1 after 4 weeks, and 551 vs 346 nmol L-1 after 8 weeks). Medians (interquartile range) of RBC-folate loading were (4 weeks: 299 (160) vs 409 (237) nmol L-1 ) and (8 weeks: 630 (134) versus 795 (187) nmol L-1 ) in the 400 and 800 μg d-1 group, respectively. The individual measured and predicted RBC-folate values (after 4 weeks/400 μg d-1 = 25 + 1.27 × baseline RBC-folate) and (after 4 weeks/800 μg d-1 = 65 + 1.41 × baseline RBC-folate) did not differ significantly. The measured and predicted concentrations showed high agreement in the validation cohort. CONCLUSIONS The models can guide nutritional recommendations in women when baseline RBC-folate concentrations are measured and the time to pregnancy between 4 and 8 weeks.
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A Study of the Pharmacokinetic Properties and the In Vivo Kinetics of Erythrocytes Loaded With Dexamethasone Sodium Phosphate in Healthy Volunteers.
Coker, SA, Szczepiorkowski, ZM, Siegel, AH, Ferrari, A, Mambrini, G, Anand, R, Hartman, RD, Benatti, L, Dumont, LJ
Transfusion medicine reviews. 2018;(2):102-110
Abstract
The objectives of this 2-phase study were to elucidate pharmacokinetics (PK), in vivo 24-hour recovery, and red blood cell (RBC) survival properties of RBC-encapsulated dexamethasone sodium phosphate (DSP) prepared using the EryDex System (EDS). The 24-hour RBC recovery and T50 survival phase studied subjects were randomized to receive autologous RBCs loaded with either 15-20 mg DSP (Group 1A) or sham saline (Group 2A). Loaded RBCs were radiolabeled with 51-Cr, and the labeled RBCs were followed over time in vivo. The PK phase evaluated dose levels of 2.5-5 mg (Group 1B) and 15-20 mg (Group 2B) DSP encapsulated in RBCs infused into healthy randomized subjects. The mean ± SD 24-hour RBC recovery was 77.9% ± 3.3% and 72.7% ± 10.5% for Groups 1A and 2A, respectively. The mean ± SD RBC life span was 84.3 ± 8.3 days in Group 1A and 88.9 ± 6.2 days in Group 2A. The PK phase actual DSP loading doses (mean ± SEM) were 4.2 ± 0.27 mg and 16.9 ± 0.90 mg in Groups 1B and 2B, respectively. Release of dexamethasone from RBCs in vivo peaked at 1 hour, and a sustained release of dexamethasone could be detected until 35 days after the single intravenous infusion in Group 2B. The mean RBC in vivo recovery for DSP-loaded processed cells compares similarly to the 24-hour recovery of regulated RBC products intended for transfusion. There was a minimal but acceptable adverse impact on the survival of EDS-processed RBCs. DSP-loaded autologous RBCs, prepared using the EDS, delivered a sustained dose of dexamethasone in vivo.
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The effectiveness of daily supplementation with 400 or 800 µg/day folate in reaching protective red blood folate concentrations in non-pregnant women: a randomized trial.
Obeid, R, Schön, C, Wilhelm, M, Pietrzik, K, Pilz, S
European journal of nutrition. 2018;(5):1771-1780
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PURPOSE Folate required to achieve desirable red blood cell (RBC) folate concentrations within 4-8 weeks pre-pregnancy is not known. We studied the effect of supplementation with 400 or 800 µg/day folate in achieving RBC-folate ≥906 nmol/L. METHODS Non-pregnant women were randomized to receive multinutrient supplements containing 400 µg/day (n = 100) or 800 µg/day (n = 101) folate [folic acid and (6S)-5-CH3-H4folate-Ca (1:1)]. The changes of folate biomarkers were studied after 4 and 8 weeks in the 198 women who returned at least for visit 2. RESULTS At baseline, 12 of the 198 participants (6.1%) had RBC-folate <340 nmol/L, but 88% had levels <906 nmol/L. The RBC-folate concentrations increased significantly in the 800 µg/day (mean ± SD = 652 ± 295 at baseline; 928 ± 330 at 4 weeks; and 1218 ± 435 nmol/L at 8 weeks) compared with the 400 µg/day [632 ± 285 at baseline (p = 0.578); 805 ± 363 at 4 weeks (p < 0.001); 1021 ± 414 nmol/L at 8 weeks (p < 0.001)]. The changes of RBC-folate were greater in the 800 µg/day than in the 400 µg/day at any time (changes after 8 weeks: 566 ± 260 vs. 389 ± 229 nmol/L; p < 0.001). Significantly more women in the 800 µg group achieved desirable RBC-folate concentrations at 4 weeks (45.5 vs. 31.3%; p = 0.041) or 8 weeks (83.8 vs. 54.5%; p < 0.001) compared with the 400 µg group. RBC-folate levels below the population median (590 nmol/L) were associated with a reduced response to supplements. CONCLUSIONS 88% of the women had insufficient RBC-folate to prevent birth defects, while 6.1% had deficiency. Women with low RBC-folate were unlikely to achieve desirable levels within 4-8 weeks, unless they receive 800 µg/day. The current supplementation recommendations are not sufficient in countries not applying fortification. TRIALS REGISTER The trial was registered at The German Clinical Trials Register: DRKS-ID: DRKS00009770.