Scott V. Harding

A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants

OBJECTIVES To test whether iron supplementation affects hematologic, biochemical, and developmental status in term breast-fed infants. STUDY DESIGN Term breast-fed infants (n=77) were randomly selected to receive either 7.5 mg per day of elemental iron as ferrous sulfate or placebo from 1 to 6 months of age. Investigators and families were unaware of group assignment. Complete blood count and ferritin, red cell superoxide dismutase, catalase, plasma ferric reducing antioxidant power, and zinc and copper levels were analyzed at 1, 3.5, 6, and 12 months of age. Bayley mental and psychomotor developmental indexes (MDI and PDI) and visual acuity (with the use of Teller acuity cards) were assessed from 12 to 18 months of age. Analysis performed by analysis of variance and t tests was by intention to treat. RESULTS Iron supplementation resulted in higher hemoglobin and mean corpuscular volume at 6 months of age and significantly higher visual acuity and PDI at 13 months of age (100+/-12 vs 93+/-9 [+/-SD]). Treatment and placebo groups did not differ in anthropometric indexes, compliance, biochemical status, or demographic characteristics. CONCLUSIONS Iron supplementation of breast-fed infants appears safe and might have beneficial hematologic and developmental effects for some infants.

Evidence of oxidative stress in full-term healthy infants.

We hypothesized that early infancy would be a time of oxidative stress due to the difficulty of adapting to ambient oxygen. Therefore, we measured levels of products of lipid peroxidation (F2-isoprostanes), antioxidant enzyme activity (catalase (CAT) and superoxide dismutase (SOD)), and ability to resist oxidative stress (ferric reducing ability of plasma (FRAP)) in full-term infants (38–42 wk) fed human milk from birth. Seventy-seven infants were followed at 1, 3.5, 6, and 12 mo of age. F2-isoprostanes in plasma declined significantly (p < 0.05) from 1 to 6 mo (160 ± 43; 90 ± 33; 41 ± 27 pg/mL (mean ± SD)). FRAP values (775 ± 196, 723 ± 133, 697 ± 126, 669 ± 145 μM) 1, 3.5, 6, and 12, respectively) declined (p = 0.06) from 1 to 3.5 mo and from 3.5 to 6 mo of age. RBC-SOD (2.7 ± 2, 3.2 ± 2.8, 2.1 ± 1.8, 2.5 ± 1.8 U, 1, 3.5, 6, 12 mo, respectively) declined from 3.5 to 6 mo. RBC-CAT (76 ± 23, 94 ± 28, 81 ± 22, 85 ± 31 U, 1, 3.5, 6, 12 mo, respectively) also declined between 3.5 and 6 mo, after a significant increase between 1 and 3.5 mo. These data suggest that the human infant is under oxidative stress early in infancy and further study may be warranted to assess the potential benefits of antioxidant supplementation for either the mother or the infant.

Guar gum and similar soluble fibers in the regulation of cholesterol metabolism: current understandings and future research priorities.

The hypocholesterolemic effects associated with soluble fiber consumption are clear from animal model and human clinical investigations. Moreover, the modulation of whole-body cholesterol metabolism in response to dietary fiber consumption, including intestinal cholesterol absorption and fecal sterol and bile acid loss, has been the subject of many published reports. However, our understanding of how dietary fibers regulate molecular events at the gene/protein level and alter cellular cholesterol metabolism is limited. The modern emphasis on molecular nutrition and rapid progress in ‘high-dimensional’ biological techniques will permit further explorations of the role of genetic polymorphisms in determining the variable interindividual responses to soluble fibers. Furthermore, with traditional molecular biology tools and the application of ‘omic’ technology, specific insight into how fibers modulate the expression of genes and proteins that regulate intestinal cholesterol absorption and alter hepatic sterol balance will be gained. Detailed knowledge of the molecular mechanisms by which soluble fibers reduce plasma cholesterol concentrations is paramount to developing novel fiber-based “cocktails” that target specific metabolic pathways to gain maximal cholesterol reductions.

Dietary oils and FADS1-FADS2 genetic variants modulate [13C]α-linolenic acid metabolism and plasma fatty acid composition

BACKGROUND Desaturation of dietary α-linolenic acid (ALA) to omega-3 (n-3) long-chain fatty acids (FAs) is mediated through FA desaturases (FADS1-FADS2) and may be influenced by dietary FA composition. OBJECTIVE We investigated the effects of diets enriched in flaxseed oil (FXCO) or high-oleic acid canola oil (HOCO) compared with a Western diet (WD) and FADS1-FADS2 single nucleotide polymorphisms (SNPs) on plasma FAs and [U-(13)C]ALA metabolism. DESIGN In a randomized crossover design, 36 hyperlipidemic subjects consumed 3 isoenergetic diets enriched in FXCO (20.6 g ALA/d), HOCO (2.4 g ALA/d), or WD (1.3 g ALA/d) for 4 wk. On day 27, blood was sampled 0, 24, and 48 h after the subjects (n = 26) consumed 45 mg [U-(13)C]ALA. The subjects were genotyped for 4 FADS SNPs. RESULTS FXCO increased (P < 0.001) plasma ALA, EPA, and docosapentaenoic acid (DPA), with no change in DHA compared with the HOCO or WD diets. At 24 and 48 h, [U-(13)C]ALA recovered as plasma [(13)C]EPA and [(13)C]DPA were lower (P < 0.001) after the FXCO diet than after the HOCO and WD diets. No change in [(13)C]DHA was observed between diets. Minor allele homozygotes of rs174545, rs174583, rs174561, and rs174537 had lower (P < 0.05) plasma EPA, arachidonic acid (AA), EPA/ALA, and AA/linoleic acid compositions and lower (P < 0.05) plasma [(13)C]EPA enrichment at 24 and 48 h in comparison with carriers of the major allele after all diets. SNPs were not associated with plasma composition of DHA or [(13)C]DHA enrichment. CONCLUSION An increase in ALA intake resulting in increased plasma EPA composition may be cardioprotective, especially in minor allele homozygotes. This trial was registered at www.clinicaltrials.gov as NCT00927199.

Consumption of plant sterols reduces plasma and hepatic triglycerides and modulates the expression of lipid regulatory genes and de novo lipogenesis in C57BL/6J mice.

To investigate emerging clinical data suggesting a triglyceride (TAG)-lowering response to plant sterol (PS) therapy, we characterized changes in TAG metabolism in 16 C57BL/6J mice fed a basal control diet (CON) or the CON diet supplemented with 2% PS for 6 wk. PS consumption reduced (p<0.05) plasma (-28%) and hepatic (-30%) TAG concentrations compared with CON mice. PS consumption increased (p<0.05) hepatic lipogenic gene expression (sterol-regulatory-element-binding protein 1c, 2.4-fold of CON; fatty acid synthase, 6.5-fold of CON) and de novo lipogenesis (4.51+/-0.72 versus 2.82+/-0.61%/day) compared with CON. PS consumption increased (p<0.05) fecal palmitate and stearate excretion and reduced body weight gain compared with CON mice. Although no change in the transcription of intestinal fatty acid absorptive genes was observed, peroxisome proliferator-activated receptor alpha mRNA was reduced (p<0.05, 2.0-fold of CON) in the PS-fed mice. In conclusion, PS-fed C57BL/6J mice showed pronounced reductions in plasma and hepatic TAG concentrations despite increases in hepatic lipogenic gene expression and de novo lipogenesis. Interference with intestinal fatty acid/TAG metabolism as suggested by increased fecal fatty acid loss and reduced weight gain may be associated with the TAG-lowering response to PS consumption.

High basal fractional cholesterol synthesis is associated with nonresponse of plasma LDL cholesterol to plant sterol therapy

BACKGROUND The cholesterol-lowering effectiveness of plant sterol (PS) therapy is hindered by wide-ranging variability in LDL-cholesterol responsiveness across individuals. To capitalize on the LDL-cholesterol-lowering potential of PS in the clinical setting, it is paramount to characterize the metabolic factors that underlie this heterogeneity of responsiveness. OBJECTIVE The objective was to investigate the relation between cholesterol synthesis and plasma LDL-cholesterol reductions in response to PS consumption. DESIGN We evaluated previously conducted clinical PS interventions incorporating stable-isotope measures of cholesterol synthesis and conducted feeding studies in animal models of response (Syrian Golden hamsters) and nonresponse (C57BL/6J mice) to PS consumption. RESULTS From our clinical study population (n = 113), we identified 47 nonresponders (3.73 +/- 1.10% change in LDL cholesterol) and 66 responders (-15.16 +/- 1.04% change in LDL cholesterol) to PS therapy. The basal cholesterol fractional synthesis rate (FSR) as measured by direct deuterium incorporation was 23% higher (P = 0.003) in the nonresponder subgroup than in responders to PS therapy. The basal cholesterol FSR correlated (r = 0.22, P = 0.02) with the percentage change in LDL cholesterol after PS intervention. In support of our clinical observations, nonresponding mice showed a 77% higher (P = 0.001) basal cholesterol FSR than that of responding hamsters. Compared with control mice, PS-fed mice showed an increase in hepatic nuclear sterol regulatory element binding protein 2 abundance (1.3-fold of control, P = 0.04) and beta-hydroxy-beta-methylglutaryl coenzyme A reductase-mRNA expression (2.4-fold of control, P = 0.00). CONCLUSION The results suggest that subjects with high basal cholesterol synthesis are less responsive to PS treatment than are subjects with low basal cholesterol synthesis.

Hypocholesterolemic and Anti-Obesity Effects of Saponins from Platycodon grandiflorum in Hamsters Fed Atherogenic Diets

Platycodins, a group of saponin glycosides from Platycodon grandiflorum, are believed to possess anti-obesity and cholesterol-lowering properties. The aim of the present study was to investigate whether dietary platycodins affect plasma, hepatic, or fecal cholesterol concentrations, as well as cholesterol absorption and fractional synthesis rates in a dose-dependent manner. Golden Syrian hamsters (n= 45) were fed atherogenic (0.25% cholesterol) diets enriched with platycodins in the forms of either aqueous extracts (containing 0.3% to 0.5% of platycodins of diet mass) or crude saponins fractions (containing 0.9% to 1.0% of platycodins of diet mass) for 28 d. [3, 4](-13)C-cholesterol and (2)H2O tracers were administered on days 26 and 28 to assess cholesterol absorption and biosynthesis, respectively. After platycodin intervention, total cholesterol concentrations in plasma and liver were reduced (P < 0.05) by 13% to 28% and 41% to 79%, respectively, whereas cholesterol concentrations in feces were increased (P < 0.05) up to 2.5-fold compared to controls. Platycodin feeding increased (P < 0.001) cholesterol absorption up to 60%, but not cholesterol synthesis. These results suggest that platycodin-enriched diets can lower circulating and whole body cholesterol contents, and thus reduce the risk of cardiovascular diseases through mechanisms independent from cholesterol absorption or synthesis.

Low and moderate-fat plant sterol fortified soymilk in modulation of plasma lipids and cholesterol kinetics in subjects with normal to high cholesterol concentrations: report on two randomized crossover studies

BackgroundAlthough consumption of various plant sterol (PS)-enriched beverages is effective in lowering plasma cholesterol, the lipid-lowering potential of PS in a soymilk format has not been investigated thoroughly. Therefore, to evaluate the efficacy of PS-enriched soy beverages on plasma lipids and cholesterol kinetics, we conducted two separate 28 d dietary controlled cross-over studies. In study 1, the cholesterol-lowering efficacy of a low-fat (2 g/serving) PS enriched soy beverage was examined in 33 normal cholesterolemic subjects in comparison with 1% dairy milk. In study 2, we investigated the efficacy of a moderate-fat (3.5 g/serving) PS-enriched soy beverage on plasma cholesterol concentrations and cholesterol kinetic responses in 23 hypercholesterolemic subjects compared with 1% dairy milk. Both the low and moderate-fat PS-enriched soymilk varieties provided 1.95 g PS/d. Endpoint plasma variables were analyzed by repeated-measures ANOVA using baseline values as covariates for plasma lipid measurements.ResultsIn comparison with the 1% dairy milk control, the low-fat soy beverage reduced (P < 0.05) total and LDL-cholesterol by 10 and 13%, respectively. Consumption of the moderate-fat PS-enriched soy beverage reduced (P < 0.05) plasma total and LDL-cholesterol by 12 and 15% respectively. Fasting triglycerides were reduced by 9.4% following consumption of the moderate-fat soy beverage in comparison with the 1% dairy milk. Both low and moderate-fat PS-enriched soy varieties reduced (P < 0.05) LDL:HDL and TC:HDL ratios compared with the 1% dairy milk control. Consumption of the moderate-fat PS-enriched soymilk reduced (P < 0.05) cholesterol absorption by 27%, but did not alter cholesterol synthesis in comparison with 1% dairy milk.ConclusionWe conclude that, compared to 1% dairy milk, consumption of low and moderate-fat PS-enriched soy beverages represents an effective dietary strategy to reduce circulating lipid concentrations in normal to hypercholesterolemic individuals by reducing intestinal cholesterol absorption.Trial registration (clinicaltrials.gov)NCT00923403 (Study 1), NCT00924391 (Study 2).

Hepatic Nuclear Sterol Regulatory Binding Element Protein 2 Abundance Is Decreased and That of ABCG5 Increased in Male Hamsters Fed Plant Sterols

The effect of dietary plant sterols on cholesterol homeostasis has been well characterized in the intestine, but how plant sterols affect lipid metabolism in other lipid-rich tissues is not known. Changes in hepatic cholesterol homeostasis in response to high dietary intakes of plant sterols were determined in male golden Syrian hamsters fed hypercholesterolemia-inducing diets with and without 2% plant sterols (wt:wt; Reducol, Forbes Meditech) for 28 d. Plasma and hepatic cholesterol concentrations, cholesterol biosynthesis and absorption, and changes in the expression of sterol response element binding protein 2 (SREBP2) and liver X receptor-beta (LXRbeta) and their target genes were measured. Plant sterol feeding reduced plasma total cholesterol, non-HDL cholesterol, and HDL cholesterol concentrations 43% (P < 0.0001), 60% (P < 0.0001), and 21% (P = 0.001), respectively, compared with controls. Furthermore, there was a 93% reduction (P < 0.0001) in hepatic total cholesterol and >6-fold (P = 0.029) and >2-fold (P < 0.0001) increases in hepatic beta-sitosterol and campesterol concentrations, respectively, in plant sterol-fed hamsters compared with controls. Plant sterol feeding also increased fractional cholesterol synthesis >2-fold (P < 0.03) and decreased cholesterol absorption 83% (P < 0.0001) compared with controls. Plant sterol feeding increased hepatic protein expression of cytosolic (inactive) SREBP2, decreased nuclear (active) SREBP2, and tended to increase LXRbeta (P = 0.06) and ATP binding cassette transporter G5, indicating a differential modulation of the expression of proteins central to cholesterol metabolism. In conclusion, high-dose plant sterol feeding of hamsters changes hepatic protein abundance in favor of cholesterol excretion despite lower hepatic cholesterol concentrations and higher cholesterol fractional synthesis.

The effects of partial sleep deprivation on energy balance: A systematic review and meta-analysis

Background/Objectives:It is unknown whether short sleep duration causatively contributes to weight gain. Studies investigating effects of partial sleep deprivation (PSD) on energy balance components report conflicting findings. Our objective was to conduct a systematic review and meta-analysis of human intervention studies assessing the effects of PSD on energy intake (EI) and energy expenditure (EE).Subjects/Methods:EMBASE, Medline, Cochrane CENTRAL, Web of Science and Scopus were searched. Differences in EI and total EE following PSD compared with a control condition were generated using the inverse variance method with random-effects models. Secondary outcomes included macronutrient distribution and resting metabolic rate. Heterogeneity was quantified with the I2-statistic.Results:Seventeen studies (n=496) were eligible for inclusion in the systematic review, and 11 studies (n=172) provided sufficient data to be included in meta-analyses. EI was significantly increased by 385 kcal (95% confidence interval: 252, 517; P<0.00001) following PSD compared with the control condition. We found no significant change in total EE or resting metabolic rate as a result of PSD. The observed increase in EI was accompanied by significantly higher fat and lower protein intakes, but no effect on carbohydrate intake.Conclusions:The pooled effects of the studies with extractable data indicated that PSD resulted in increased EI with no effect on EE, leading to a net positive energy balance, which in the long term may contribute to weight gain.