Journal of Nutrition current issue

[Recent Advances in Nutritional Sciences] Modulation of C-Reactive Protein, Tumor Necrosis Factor-{alpha}, and Adiponectin by Diet, Exercise, and Weight Loss

Puglisi, M. J., Fernandez, M. L. — 2008-11-20

Chronic disease has been strongly correlated with inflammation resulting from the body's release of inflammatory cytokines as a result of injury or infection. Specific interventions promoting weight loss, exercise, or intake of antioxidants have been used by several investigators in an effort to decrease inflammatory cytokines. C-reactive protein (CRP) is produced by the liver and its role in the development of inflammation has been well established. However, the strong association between CRP and risk for heart disease is a more recent discovery. During the inflammation process, the transcriptional activity of nuclear factor B leads to the increased production of inflammatory cytokines associated with atherosclerosis, including tumor necrosis factor- (TNF). Increased concentrations of TNF have been reported in obese patients; thus, weight loss is considered a key intervention to reduce the concentrations of this cytokine. In contrast to CRP and TNF, adiponectin increases during weight loss and insulin sensitivity. Additionally, lower concentrations of this cytokine have been reported in cardiovascular disease and type-2 diabetes. Recent epidemiological studies and clinical interventions have reported contradictory findings related to dietary or exercise interventions and the resulting alterations in plasma cytokines. Part of the discrepancies may be due to the population studied, the time of the treatment, and the lack of weight loss in some studies. Although it is clear from the literature that these cytokines play a major role in the development of chronic disease, the best strategy to favorably alter the inflammatory response is still debatable.

[Critical Review] Application of Systematic Review Methodology to the Field of Nutrition

Lichtenstein, A. H., Yetley, E. A., Lau, J. — 2008-11-20

Systematic reviews represent a rigorous and transparent approach to synthesizing scientific evidence that minimizes bias. They evolved within the medical community to support development of clinical and public health practice guidelines, set research agendas, and formulate scientific consensus statements. The use of systematic reviews for nutrition-related topics is more recent. Systematic reviews provide independently conducted comprehensive and objective assessments of available information addressing precise questions. This approach to summarizing available data is a useful tool for identifying the state of science including knowledge gaps and associated research needs, supporting development of science-based recommendations and guidelines, and serving as the foundation for updates as new data emerge. Our objective is to describe the steps for performing systematic reviews and highlight areas unique to the discipline of nutrition that are important to consider in data assessment. The steps involved in generating systematic reviews include identifying staffing and planning for outside expert input, forming a research team, developing an analytic framework, developing and refining research questions, defining eligibility criteria, identifying search terms, screening abstracts according to eligibility criteria, retrieving articles for evaluation, constructing evidence and summary tables, assessing methodological quality and applicability, and synthesizing results including performing meta-analysis, if appropriate. Unique and at times challenging, nutrition-related considerations include baseline nutrient exposure, nutrient status, bioequivalence of bioactive compounds, bioavailability, multiple and interrelated biological functions, undefined nature of some interventions, and uncertainties in intake assessment. Systematic reviews are a valuable and independent component of decision-making processes by groups responsible for developing science-based recommendations and policies.

[Commentary] AMPing Down Leucine Action in Skeletal Muscle

Anthony, T. G., Anthony, J. C. — 2008-11-20

[Biochemical, Molecular, and Genetic Mechanisms] Chlorogenic Acids from Green Coffee Extract are Highly Bioavailable in Humans

Farah, A., Monteiro, M., Donangelo, C. M., Lafay, S. — 2008-11-20

Chlorogenic acids (CGA) are cinnamic acid derivatives with biological effects mostly related to their antioxidant and antiinflammatory activities. Caffeoylquinic acids (CQA) and dicaffeoylquinic acids (diCQA) are the main CGA found in nature. Because green coffee is a major source of CGA, it has been used for production of nutraceuticals. However, data on the bioavailability of CGA from green coffee in humans are inexistent. The present study evaluated the pharmacokinetic profile and apparent bioavailability of CGA in plasma and urine of 10 healthy adults for 8 h after the consumption of a decaffeinated green coffee extract containing 170 mg of CGA. Three CQA, 3 diCQA, and caffeic, ferulic, isoferulic, and p-coumaric acids were identified in plasma by HPLC-Diode Array Detector-MS after treatment. Over 30% (33.1 ± 23.1%) of the ingested cinnamic acid moieties were recovered in plasma, including metabolites, with peak levels from 0.5 to 8 h after treatment. CGA and metabolites identified in urine after treatment were 4-CQA, 5-CQA, and sinapic, p-hydroxybenzoic, gallic, vanillic, dihydrocaffeic, caffeic, ferulic, isoferulic, and p-coumaric acids, totaling 5.5 ± 10.6% urinary recovery of the ingested cinnamic and quinic acid moiteties. This study shows that the major CGA compounds present in green coffee are highly absorbed and metabolized in humans.

[Biochemical, Molecular, and Genetic Mechanisms] Biotinylation of Histones Represses Transposable Elements in Human and Mouse Cells and Cell Lines and in Drosophila melanogaster

2008-11-20

Transposable elements such as long terminal repeats (LTR) constitute ~45% of the human genome; transposition events impair genome stability. Fifty-four promoter-active retrotransposons have been identified in humans. Epigenetic mechanisms are important for transcriptional repression of retrotransposons, preventing transposition events, and abnormal regulation of genes. Here, we demonstrate that the covalent binding of the vitamin biotin to lysine-12 in histone H4 (H4K12bio) and lysine-9 in histone H2A (H2AK9bio), mediated by holocarboxylase synthetase (HCS), is an epigenetic mechanism to repress retrotransposon transcription in human and mouse cell lines and in primary cells from a human supplementation study. Abundance of H4K12bio and H2AK9bio at intact retrotransposons and a solitary LTR depended on biotin supply and HCS activity and was inversely linked with the abundance of LTR transcripts. Knockdown of HCS in Drosophila melanogaster enhances retrotransposition in the germline. Importantly, we demonstrated that depletion of H4K12bio and H2AK9bio in biotin-deficient cells correlates with increased production of viral particles and transposition events and ultimately decreases chromosomal stability. Collectively, this study reveals a novel diet-dependent epigenetic mechanism that could affect cancer risk.

[Biochemical, Molecular, and Genetic Mechanisms] A 19-Base Pair Deletion Polymorphism in Dihydrofolate Reductase Is Associated with Increased Unmetabolized Folic Acid in Plasma and Decreased Red Blood Cell Folate

2008-11-20

Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. The functional impact of this polymorphism has not yet been demonstrated. The objective of this research was to determine the effects of the DHFR mutation with respect to folate status and assess influence of folic acid intake on these relations. The relationship between DHFR genotype and plasma concentrations of circulating folic acid, total folate, total homocysteine, and concentrations of RBC folate was determined in 1215 subjects from the Framingham Offspring Study. There was a significant interaction between DHFR genotype and folic acid intake with respect to the prevalence of high circulating unmetabolized folic acid (defined as >85th percentile). Folic acid intake of ≥500 µg/d increased the prevalence of high circulating unmetabolized folic acid in subjects with the deletion (del/del genotype (47.0%) compared with the wild type (WT)/del (21.4%) and wild type (WT)/WT genotypes (24.4%) (P for interaction = 0.03). Interaction between the DHFR polymorphism and folic acid intake was also seen with respect to RBC folate (P for interaction = 0.01). When folic acid intake was <250 µg/d, the del/del genotype was associated with significantly lower RBC folate (732.3 nmol/L) compared with the WT/WT genotype (844.4 nmol/L). Our results suggest the del/del polymorphism in DHFR is a functional polymorphism, because it limits assimilation of folic acid into cellular folate stores at high and low folic acid intakes.

[Biochemical, Molecular, and Genetic Mechanisms] Redox Regulation of Protein Tyrosine Phosphatase 1B by Manipulation of Dietary Selenium Affects the Triglyceride Concentration in Rat Liver

2008-11-20

Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme in the counter-regulation of insulin signaling and in the stimulation of fatty acid synthesis. Selenium (Se), via the activities of glutathione peroxidase (GPx) and thioredoxin reductase (TrxR), is involved in the removal of H₂O₂ and organic peroxides, which are critical compounds in the modulation of PTP1B activity via glutathionylation. Our study with growing rats investigated how the manipulation of dietary Se concentration influences the regulation of PTP1B and lipogenic effects mediated by PTP1B. Weanling albino rats were divided into 3 groups of 10. The negative control group (NC) was fed a Se-deficient diet for 8 wk. Rats in groups Se75 and Se150 received diets supplemented with 75 or 150 µg Se/kg. Se supplementation of the rats strongly influenced expression and activity of the selenoenzymes cytosolic GPx, plasma GPx, phospholipidhydroperoxide GPx, and cytosolic TrxR, and liver PTP1B. Liver PTP1B activity was significantly higher in groups Se75 and Se150 than in the NC group and this was attributed to a lowered inhibition of the enzyme by glutathionylation. The increased liver PTP1B activity in groups Se75 and Se150 resulted in 1.1- and 1.4-fold higher liver triglyceride concentrations than in the NC rats. The upregulation of the sterol regulatory element binding protein-1c and of fatty acid synthase, 2 PTP1B targets, provided a possible explanation for the lipogenic effect of PTP1B due to the manipulation of dietary Se. We therefore conclude that redox-regulated proteins, such as PTP1B, represent important interfaces between dietary antioxidants such as Se and the regulation of metabolic processes.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] 9-Cis Retinoic Acid Reduces 1{alpha},25-Dihydroxycholecalciferol-Induced Renal Calcification by Altering Vitamin K-Dependent {gamma}-Carboxylation of Matrix {gamma}-Carboxyglutamic Acid Protein in A/J Male Mice

Fu, X., Wang, X.-D., Mernitz, H., Wallin, R., Shea, M. K., Booth, S. L. — 2008-11-20

Matrix -carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. We previously reported that 9-cis retinoic acid (RA) mitigates 1,25-dihydroxycholecalciferol [1,25(OH)₂D3]-induced renal calcification in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer A/J male mouse model. This raised the question if the mechanism(s) underlying this calcification involves vitamin K. We assessed expression and vitamin K dependent -carboxylation of MGP and vitamin K concentrations [phylloquinone (PK), as well as its conversion product, menaquinone-4 (MK-4)] in tissues obtained from NNK-injected A/J male mice fed 1,25(OH)₂D3 (2.5 µg/kg diet; D group) ± RA (15 mg/kg diet) for 20 wk. Renal calcification was only observed in the D group (2/10; 20% of the group). Renal MGP mRNA and uncarboxylated MGP (ucMGP) increased in response to D (P < 0.05) but not in response to RA or RA + D. In contrast, -carboxylated MGP increased to 2.2-fold of the control in response to D+RA (P < 0.05) but not in response to RA or D alone. Although all diets contained equal amounts of PK, the kidney MK-4 concentration was higher in the D group (P < 0.05) and lower in the RA group (P < 0.05) compared with the RA+D or control groups. Renal PK concentrations were lower in the RA and RA+D groups than in the control and D groups (P < 0.05). These data suggest that 9-cis RA mitigated 1,25(OH)₂D3-induced renal calcification by modifying the 1,25(OH)₂D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)₂D3 alter vitamin K concentrations warrant further investigation.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] Ultra High Temperature Treatment, but Not Pasteurization, Affects the Postprandial Kinetics of Milk Proteins in Humans

2008-11-20

Although the chemical and physical modifications to milk proteins induced by technological treatments have been characterized extensively, their nutritional consequences have rarely been assessed in humans. We measured the effect of 2 technological treatments on the postprandial utilization of milk nitrogen (N), pasteurization (PAST) and ultra high temperature (UHT), compared with microfiltration (MF), using a sensitive method based on the use of milk proteins intrinsically labeled with ¹⁵N. Twenty-five subjects were studied after a 1-wk standardization of their diet. On the day of the investigation, they ingested a single test meal corresponding to 500 mL of either MF, PAST, or UHT defatted milk. Serum amino acid (AA) levels as well as the transfer of ¹⁵N into serum protein and AA, body urea, and urinary urea were determined throughout the 8-h postprandial period. The kinetics of dietary N transfer to serum AA, proteins, and urea did not differ between the MF and PAST groups. The transfer of dietary N to serum AA and protein and to body urea was significantly higher in UHT than in either the PAST or MF group. Postprandial deamination losses from dietary AA represented 25.9 ± 3.3% of ingested N in the UHT group, 18.5 ± 3.0% in the MF group, and 18.6 ± 3.7% in the PAST group (P < 0.0001). The higher anabolic use of dietary N in plasma proteins after UHT ingestion strongly suggests that these differences are due to modifications to digestive kinetics and the further metabolism of dietary proteins subsequent to this particular treatment of milk.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] Structurally Different Wheat-Derived Arabinoxylooligosaccharides Have Different Prebiotic and Fermentation Properties in Rats

2008-11-20

To evaluate the prebiotic potential and intestinal fermentation products of wheat bran-derived arabinoxylooligosaccharides (AXOS) in relation to their structure, 5 preparations with structurally different AXOS were included (~4% wt:wt) in rat diets that mimicked the average Western human diet composition. Xylooligosaccharides (XOS), fructooligosaccharides (FOS), and inulin were used as references. The observed effects mainly depended on the average degree of polymerization (avDP) of the AXOS preparations. The AXOS and XOS preparations with a low avDP (≤3) resulted in increased colonic acetate and butyrate production and boosted bifidobacteria concentrations in the cecum, but did not significantly lower the concentrations of branched SCFA, which are considered to be markers of protein fermentation by intestinal microbiota. In contrast, an AXOS preparation with a higher avDP (61) effectively suppressed branched SCFA concentrations and thus tipped the balance away from protein fermentation. However, it neither increased colonic butyrate concentrations nor stimulated cecal bifidobacteria development. Two AXOS preparations with a similar avDP (12 and 15) but different average degrees of arabinose substitution (avDAS) (0.69 and 0.27) affected the measured intestinal characteristics similarly, suggesting that the influence of the avDAS was apparently limited and possibly overshadowed by that of the avDP. Among those tested, an AXOS preparation with an avDP of 5 and an avDAS of 0.27 exhibited the best combination of desirable effects on gut health characteristics. Compared with this optimal AXOS preparation, FOS and inulin resulted in similar bifidogenic effects with increased production of colonic acetate (inulin) but not of butyrate. These new insights into the structure-activity relation of AXOS open up new perspectives for the production and application of AXOS preparations with optimized prebiotic and fermentation properties.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] Maternal Dietary L-Carnitine Supplementation Influences Fetal Carnitine Status and Stimulates Carnitine Palmitoyltransferase and Pyruvate Dehydrogenase Complex Activities in Swine

Xi, L., Brown, K., Woodworth, J., Shim, K., Johnson, B., Odle, J. — 2008-11-20

Effects of increasing maternal l-carnitine on carnitine status and energy metabolism in the fetus were evaluated by feeding pregnant swine a corn-soybean–based diet containing either 0 or 50 mg/kg added l-carnitine (n = 10/treatment) during the first 70 d of gestation. Carnitine, carnitine palmitoyltransferase (CPT), and pyruvate dehydrogenase complex (PDHC) activities were analyzed in tissues collected from fetuses on d 55 and 70. Maternal l-carnitine supplementation increased both fetal free and long-chain carnitine concentrations by 45% in liver and free carnitine by 31% in heart tissues but did not affect kidney tissue. Elevations in free and acylcarnitines increased with gestational age from 55 to 70 d in liver but not in heart and kidney. The increased carnitine concentrations resulted in a 45% increase in PDHC activity in heart and liver on d 70 of gestation but did not affect kidney and liver on d 55 of gestation. The increases in carnitine concentrations were accompanied by a 70% increase in hepatic CPT activity in 70-d-old fetuses, but activities in heart and kidney were unaffected. The Michaelis constant (K_m) of CPT for carnitine in fetal tissues was not influenced by carnitine supplementation (P > 0.1). Notably, the concentrations of carnitine measured on d 70 were only 25–40% of the K_m values in liver, 60–70% in heart, and 30–40% in kidney (P < 0.001). We conclude that carnitine ingestion during pregnancy increases fetal carnitine concentrations and stimulates heart PDHC and liver CPT activity without altering carnitine K_m.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] Dietary Reference Intakes for Zinc May Require Adjustment for Phytate Intake Based upon Model Predictions

Hambidge, K. M., Miller, L. V., Westcott, J. E., Krebs, N. F. — 2008-11-20

The quantity of total dietary zinc (Zn) and phytate are the principal determinants of the quantity of absorbed Zn. Recent estimates of Dietary Reference Intakes (DRI) for Zn by the Institute of Medicine (IOM) were based on data from low-phytate or phytate-free diets. The objective of this project was to estimate the effects of increasing quantities of dietary phytate on these DRI. We used a trivariate model of the quantity of Zn absorbed as a function of dietary Zn and phytate with updated parameters to estimate the phytate effect on the Estimated Average Requirement (EAR) and Recommended Daily Allowance for Zn for both men and women. The EAR predicted from the model at 0 phytate was very close to the EAR of the IOM. The addition of 1000 mg phytate doubled the EAR and adding 2000 mg phytate tripled the EAR. The model also predicted that the EAR for men and women could not be attained with phytate:Zn molar ratios > 11:1 and 15:1, respectively. The phytate effect on upper limits (UL) was predicted by first estimating the quantity of absorbed Zn corresponding to the UL of 40 mg for phytate-free diets, which is 6.4 mg Zn/d. Extrapolation of the model suggested, for example, that with 900 mg/d phytate, 100 mg dietary Zn is required to attain 6.4 mg absorbed Zn/d. Experimental studies with higher Zn intakes are required to test these predictions.

[Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions] Lycopene Biodistribution Is Altered in 15,15'-Carotenoid Monooxygenase Knockout Mice

2008-11-20

15,15'-carotenoid monooxygenase (CMO I) is generally recognized as the central carotenoid cleavage enzyme responsible for converting provitamin A carotenoids to vitamin A, while having little affinity for nonprovitamin A carotenoids, such as lycopene. To investigate the role of CMO I in carotenoid metabolism, ~90-d-old C57BL/6 x 129/SvJ [CMO I wild-type (WT)] and B6;129S6-Bcmo1tm1Dnp [CMO I knockout (KO)] mice were fed a high-fat, moderate vitamin A, cholesterol-containing diet supplemented with 150 mg/kg diet of β-carotene, lycopene, or placebo beadlets for 60 d (n = 12–14). CMO I KO mice fed lycopene (Lyc-KO) exhibited significant decreases in hepatic, spleen, and thymus lycopene concentrations and significant increases in prostate, seminal vesicles, testes, and brain lycopene concentrations compared with WT mice fed lycopene (Lyc-WT). Furthermore, in the serum and all tissues analyzed, excluding the testes, there was a significant increase in the percent lycopene cis isomers in Lyc-KO mice compared with Lyc-WT mice. CMO I KO mice fed β-carotene (βC-KO) had significantly lower hepatic vitamin A concentrations (17% of WT mice fed β-carotene [βC-WT]). Concordantly, βC-KO mice had higher serum and tissue β-carotene concentrations than βC-WT mice. In addition, phenotypically CMO I KO mice had significantly higher final body weights and CMO I KO female mice had significantly lower uterus weights than CMO I WT mice. In conclusion, CMO I KO mice fed low levels of vitamin A have altered lycopene biodistribution and isomer patterns and do not cleave β-carotene to vitamin A at appreciable levels.

[Nutrition and Disease] Dietary Folate, Methionine, Riboflavin, and Vitamin B-6 and Risk of Sporadic Colorectal Cancer

2008-11-20

Adequate intake of folate, methionine, riboflavin, and vitamin B-6 may prevent aberrant DNA methylation and thereby protect against colorectal cancer (CRC). However, previous epidemiological studies investigating associations between dietary intakes of these nutrients and CRC have been inconsistent. We investigated the associations between intakes of folate, methionine, riboflavin, and vitamin B-6 and CRC risk, accounting for the sublocalization of the tumor. Within the Netherlands Cohort Study on diet and cancer (n = 120,852), 2349 cases and 4168 subcohort members were available for data analyses from a follow-up period of 13.3 y after baseline. Gender-specific adjusted incidence rate ratios (RR) were calculated over quintiles of dietary intake in case-cohort analyses. Folate intake was not associated with CRC risk in either men or women. However, methionine was associated with decreased risk of proximal colon cancer among men (RR = 0.57 for highest vs. lowest quintile of intake; P-trend = 0.03) and rectal cancer among women (highest vs. lowest quintile; RR = 0.45; P-trend = 0.05). Riboflavin tended to be associated with decreased proximal colon cancer risk among women (RR = 0.61; P-trend = 0.07). Conversely, there was a strong positive association between vitamin B-6 and rectal cancer among women (RR = 3.57; P-trend = 0.01). Our findings suggest that relatively high methionine intake may protect against proximal colon cancer in men and rectal cancer in women but that folate may not have a protective effect. This is the 2nd prospective cohort study in which vitamin B-6 intake was associated with increased risk of rectal tumors in women, which might suggest that this vitamin enhances rectal cancer in women.

[Nutrition and Disease] 3,3'-Diindolylmethane and Genistein Decrease the Adverse Effects of Estrogen in LNCaP and PC-3 Prostate Cancer Cells

Smith, S., Sepkovic, D., Bradlow, H. L., Auborn, K. J. — 2008-11-20

Evidence suggests that 17β-estradiol (E2) contributes to the risk of prostate cancer (PCa), whereas the phytochemicals genistein from soy and 3,3'-diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, decrease the risk of PCa. This study examined the potential of these phytochemicals to reduce the adverse effects of E2 on PCa. In LNCaP PCa cells (E2 sensitive), DIM decreased E2-induced proliferation. Genistein increased proliferation at low concentrations and decreased proliferation at higher concentrations; DIM abolished the increased proliferation by genistein. The E2 stimulation in LNCaP cells was consistent with dependence on the androgen receptor, as evidenced by the inhibition of E2-induced proliferation with the antiandrogen casodex, E2 stimulation of an androgen response element luciferase reporter, and E2 stimulation of prostate-specific antigen (PSA) protein expression. Both genistein and DIM abrogated the E2 stimulation of PSA. Genistein and DIM altered major E2 metabolism pathways in LNCaP and PC-3 (E2 insensitive) PCa cells by increasing the expression of the 2-hydoxylation enzyme cytochrome P450 1A1 (CYP1A1) and the O-methylating enzyme catechol-o-methyltransferase (COMT) as determined by real-time RT-PCR. The increase in COMT mRNA occurred only when the combination of DIM and genistein (15 µmol/L) was used. Quantitation by MS indicated increased 2-hydroxyestrogen and decreased 16-hydroxyestrone, a result that should result in less estrogenicity and increased amounts of the anticancer metabolite 2-methoxyestrone. We conclude that DIM and genistein decrease the effects of E2 that have the potential to promote PCa.

[Nutrition and Disease] Dietary Cod Protein Reduces Plasma C-Reactive Protein in Insulin-Resistant Men and Women

2008-11-20

Chronic low-grade inflammation has been associated with insulin resistance and type 2 diabetes. Recently, we showed that cod protein (CP) improved insulin sensitivity in insulin-resistant subjects. In this study, we investigated the effects of dietary CP compared with those of other animal proteins on plasma concentrations of inflammatory markers, lipids, and lipoproteins in insulin-resistant subjects. Nineteen Caucasian men and women aged 40–65 y, overweight or obese (BMI > 25 kg/m²), and insulin resistant, rotated in a crossover design and consumed a CP diet and a similar diet containing lean beef, pork, veal, eggs, milk, and milk products (BPVEM) for 4 wk each. Diets differed only in protein source and thus provided equivalent amounts of dietary fibers, monounsaturated fat, PUFA [including (n-3) fatty acids], and SFA. Blood samples were collected before and after each experimental diet. Notably, the CP diet decreased high-sensitivity C-reactive protein (hsCRP; P = 0.021), whereas the BPVEM diet tended to increase it (P = 0.063), leading to a significant difference between diets (P = 0.041). Changes in plasma interleukin-6, tumor necrosis factor-, and adiponectin concentrations did not differ between diets. Plasma total cholesterol (P = 0.0007), LDL cholesterol (P = 0.014), and apolipoprotein B (P = 0.005) were reduced only by the BPVEM diet. Thus, changes in total cholesterol differed between diets (P = 0.040), whereas changes in LDL cholesterol (P = 0.052) and apolipoprotein B (P = 0.075) tended to differ. Changes in all other lipids and lipoproteins did not differ between diets. Therefore, these results show that CP can lower hsCRP, a marker of inflammation associated with insulin resistance and type 2 diabetes.

[Nutrition and Disease] Supplementing Suckling Rats with Whey Protein Concentrate Modulates the Immune Response and Ameliorates Rat Rotavirus-Induced Diarrhea

2008-11-20

Group A rotaviruses (RV) are the most common causative agents of acute gastroenteritis in children <2 y. The present study was designed to establish the effect of a bovine whey protein concentrate (WPC) in a RV infection model in suckling rats. From d 3 of life, suckling Lewis rats received daily supplements of WPC, WPC plus lactoferrin (LF), standard infant formula (SIF), or water (RV-infected group and an untreated, uninfected reference group). On d 8 of life, heterologous simian RV SA-11 was inoculated orally in the WPC-RV, WPC+LF-RV, SIF-RV, and RV groups. WPC and WPC+LF reduced diarrhea incidence from ~90% in RV group to ~60% in WPC-RV and WPC+LF-RV groups (P < 0.05), whereas the area under the curve (AUC) of severity along time diminished from ~10 AUC in the RV group to ~6 AUC in both supplemented groups (P < 0.05). Serum levels of anti-RV antibodies, splenocyte proliferation, and interferon- secretion after specific stimulation were significantly lower in the WPC-RV and WPC+LF-RV groups than in the SIF-RV and RV groups. In the intraepithelial intestinal compartment, RV infection increased the proportion of typical mucosal T cells (IE-T CD8+); however, this modification was controlled by WPC and WPC+LF supplementation. In general, for most of the parameters studied, the SIF-RV and RV groups did not differ. In summary, daily supplementation with WPC or WPC+LF in early life considerably reduces the severity of RV-induced acute gastroenteritis and modulates the immune response against the pathogen.

[Nutrition and Disease] Fasting and Postprandial Remnant-Like Particle Cholesterol Concentrations in Obese Participants Are Associated with Plasma Triglycerides, Insulin Resistance, and Body Fat Distribution

2008-11-20

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (–2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20–25 vs. 40–45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMA_IR (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R² (adj. R²) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R² = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMA_IR, and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMA_IR and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet.

[Nutritional Epidemiology] Studies of Twins Indicate That Genetics Influence Dietary Intake

Hasselbalch, A. L., Heitmann, B. L., Kyvik, K. O., Sorensen, T. I. A. — 2008-11-20

Habitual dietary intake is a complex behavior that may have both biological and nonbiological bases. We estimated the contribution of genetic and environmental influences on dietary intake in a large population-based sample of healthy twins. Data originated from a cross-sectional study of 600 male and female healthy twin pairs with self-reported food consumption frequency using a validated questionnaire with 247 foods and recipes. Estimates of relative proportion of additive genetic, nonadditive genetic, shared environmental, and unshared environmental effects on various aspects of dietary intake were obtained by quantitative genetic modeling of twin data based on linear structural equations. The analyses demonstrated genetic influence on total energy, macronutrient energy, and dietary fiber intakes, the glycemic index and the glycemic load of the foods consumed, and the dietary energy density, with significant heritability estimates ranging from 0.25 (0.11–0.38) to 0.47 (0.31–0.60) in men and 0.32 (0.12–0.48) to 0.49 (0.35–0.61) in women. When analyzing dietary intake as the intake of energy from 20 food groups, the genetic and environmental influences differed among food groups and between gender. For some food groups (fruit for both genders, poultry and eggs for men), no genetic influence was found, whereas nonadditive genetic effects were demonstrated for other food groups (juices and eggs for women). A number of food groups had shared environmental influences (potatoes, vegetables, fruits, poultry, fish, margarine, and candy). These results provide evidence for both genetic and shared environmental effects on dietary intake. Although the remaining nonshared environmental effects include measurement errors, there appears to be considerable potential for individually modifiable effects.

[Nutritional Epidemiology] Soy Protein Intake Has Sex-Specific Effects on the Risk of Metabolic Syndrome in Middle-Aged and Elderly Chinese

2008-11-20

Soy protein intake has been postulated to improve lipid profiles, glucose homeostasis, and blood pressure. However, data linking soy protein intake and metabolic syndrome (MetS) are limited. We evaluated the association between soy protein intake and the risk of MetS and its components among middle-aged and elderly Chinese. A cross-sectional study was conducted among 2811 Chinese men and women aged 50–70 y, who were free of diagnosed cardiovascular diseases and cancers. Dietary data, including soy protein intake, was collected using a 74-item FFQ. MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. We used multivariate logistical regression models to quantify these associations. The median level of soy protein intake was 7.82 g/d (7.64 g/d in men and 8.02 g/d in women). Overall, the association of soy protein intake and the risk of MetS differed between men and women (P for interaction = 0.008). In men, the adjusted odds ratio comparing the extreme quartiles was 1.64 (95% CI: 0.95–2.81; P-trend = 0.077), whereas for women, it was 0.66 (95% CI: 0.42–1.03; P-trend = 0.138). Soy protein intake was positively associated with hyperglycemia (P-trend = 0.005) in men, whereas it was inversely associated with elevated blood pressure (P-trend = 0.049). It was not associated with any component in women. In conclusion, habitual soy protein intake may have sex-dependent effects on risk of MetS in middle-aged and elderly Chinese.

[Nutritional Epidemiology] Frequency and Type of Seafood Consumed Influence Plasma (n-3) Fatty Acid Concentrations

2008-11-20

Few studies have adequately considered the type of seafood and background dietary factors when evaluating diet-biomarker and diet-disease associations. The objective of this paper is to evaluate the relationship between different seafood meals and long-chain (n-3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] biomarkers in the Multi-Ethnic Study of Atherosclerosis (MESA) with white, Chinese-American, black, and Hispanic participants. Dietary intake from a FFQ and plasma phospholipid fatty acids were assessed in 900 MESA participants who were not taking fish oil supplements. When simultaneously adjusting for all seafood groups, concentrations of EPA and DHA in plasma phospholipids were positively correlated with nonfried fish consumption in all 4 ethnic groups (r = 0.24–0.46; P < 0.01) but not with nonfried shellfish, fried fish, or fish in mixed dishes. The magnitude of this correlation was attenuated by up to 67% when type of seafood was not taken into account. After further adjusting for demographic characteristics and other dietary characteristics in multivariate regression models, the association of nonfried fish consumption remained significant (P-trend < 0.001). Data were suggestive of a plateau effect at a nonfried fish intake of about twice weekly. The association of nonfried fish consumption was not modified by intake of (n-6) PUFA or -linolenic acid. This study highlights the importance of cooking methods (nonfried vs. fried fish), types of seafood (fish vs. shellfish), and the overall seafood consumption when assessing health effects of long-chain (n-3) fatty acids of seafood consumption.

[Nutritional Epidemiology] Birthplace Is Associated with More Adverse Dietary Profiles for US-Born Than for Foreign-Born Latino Adults

Duffey, K. J., Gordon-Larsen, P., Ayala, G. X., Popkin, B. M. — 2008-11-20

Our objective was to examine the association between ethnicity and birthplace and the percent of energy from selected food groups among Hispanics, the largest growing segment of the US population. We used data from NHANES 1999–2004, collected from Mexican (n = 3375) and other Hispanic (n = 622) adults (18 y and older), classified as foreign born (FB) or US born (USB). Using University of North Carolina's food-grouping system, we created 24 nutrient- and behavioral-based food groups. We examined percent consuming and per-consumer estimates using logistic and linear regression models, respectively. Predicted mean energy was estimated using marginal effect models. All models were controlled for gender, age, income, and education and were weighted to account for sampling design. FB Hispanics obtained more energy from food groups such as legumes, fruits, and low-fat/high-fiber breads, with differences accounted for by a greater percent consuming these foods rather than higher energy intake among consumers. Conversely, FB Hispanics consumed a lower percentage of energy from foods such as non-Mexican fast food and snacks and desserts. Speaking Spanish also was associated with greater consumption of legumes, rice, fruits, soups, and potatoes. Variation in diet may in part account for the difference in nutrition-related adverse health outcomes observed among USB Hispanics, particularly Mexicans. Targeted dietary interventions are needed to reduce health disparities associated with dietary intake.

[Nutritional Epidemiology] Excessive Body Iron Stores Are Not Associated with Risk of Coronary Heart Disease in Women

Sun, Q., Ma, J., Rifai, N., Franco, O. H., Rexrode, K. M., Hu, F. B. — 2008-11-20

The positive association between body iron stores and risk of coronary heart disease (CHD) initially observed among a Finnish male population has not been corroborated by studies conducted in other populations. The soluble transferrin receptor (sTfR):ferritin ratio has been suggested to be a better index than ferritin to measure body iron stores. Because sTfR is sensitive to iron deficiency, this ratio can distinguish individuals with similar ferritin levels with respect to their iron status. To evaluate this novel index in relation to CHD risk, we prospectively identified and confirmed 242 incident CHD cases and randomly selected 483 controls matched for age, smoking, and fasting status among women that provided blood samples in the Nurses' Health Study during 9 y of follow-up. In both crude and multivariate analyses, neither the sTfR:ferritin ratio nor ferritin was significantly associated with an elevated risk of CHD. After multivariate adjustment for established and potential CHD risk factors, compared with women in the lowest quartile of the sTfR:ferritin ratio, women in the 2nd to 4th quartiles had relative risks (RR) (95% CI) of 1.39 (0.82, 2.36), 1.12 (0.66, 1.91), and 1.13 (0.65, 1.97; P-trend = 0.61), respectively. The multivariate RR (95% CI) for ferritin were 1.05 (0.62, 1.77), 1.19 (0.69, 2.03), and 1.05 (0.60, 1.85; P-trend = 0.90) across quartiles. Our data do not support the hypothesis that excessive body iron stores are associated with risk of CHD.

[Community and International Nutrition] Adiposity and Pathogen Exposure Predict C-Reactive Protein in Filipino Women

McDade, T. W., Rutherford, J. N., Adair, L., Kuzawa, C. — 2008-11-20

Obesity and infectious agents are both sources of inflammatory stimuli that result in increased production of C-reactive protein (CRP). Rates of overweight and obesity are increasing globally, but for many populations, gains in body fat are set against a backdrop of high levels of pathogen exposure. Our primary objective was to evaluate the extent to which adiposity and pathogenicity contribute to a double burden of inflammation in a population currently undergoing the nutrition transition. Measures of adiposity, pathogen exposure, and infectious disease symptoms were evaluated as predictors of high-sensitivity CRP concentration in plasma samples from 1875 women participating in the Cebu Longitudinal Health and Nutrition Survey in the Philippines. Proxy measures of pathogen exposure included household crowding and cleanliness, quality of water source, mode of waste disposal, and fecal exposure. A series of maximum likelihood logistic regression models were used to predict a plasma CRP concentration > 3 mg/L. Waist circumference was the strongest anthropometric predictor of elevated CRP [odds ratio (OR) = 2.29; 95% CI = 2.00, 2.62; P < 0.001]. Presence of infectious disease symptoms (OR = 2.51; 95% CI = 1.84, 3.44; P < 0.001) and level of pathogen exposure (OR = 1.56; 95% CI = 1.15, 2.12; P < 0.01) were also associated with elevated CRP. These associations were independent of socioeconomic status and other health behaviors. Overweight/obesity and infectious exposures are associated with elevated CRP in the Philippines; it is likely that other populations undergoing the nutrition transition are experiencing comparable double burdens of inflammatory stimuli. These results underscore the need for additional research on the contributions of pathogenicity, adiposity, and inflammation to global epidemics of cardiovascular and metabolic diseases.

[Community and International Nutrition] Dietary Diversity Is a Good Predictor of the Micronutrient Density of the Diet of 6- to 23-Month-Old Children in Madagascar

Moursi, M. M., Arimond, M., Dewey, K. G., Treche, S., Ruel, M. T., Delpeuch, F. — 2008-11-20

This study was conducted in the context of a multicountry validation of indicators of diet quality and had the following objectives: 1) to determine how well dietary diversity scores (DDS) predict diet quality of children aged 6–23 mo in urban Madagascar; and 2) to assess whether the prediction was improved by changing the food groups included and by imposing a minimum amount restriction. Correlation and regression were used to describe the relationship between 4 diversity scores (2 based on 8 and 7 food groups, the latter excluding fats and oils, and 2 that imposed a 10-g minimum restriction on food groups) and the mean micronutrient density adequacy (MMDA) of the diet. MMDA, the dietary quality score used, was calculated as the mean individual micronutrient density adequacy for 9 or 10 "problem" nutrients (depending on age and breast-feeding status), each capped at 100%. We used sensitivity and specificity analysis to determine how well DDS predicted MMDA below or above selected cut-offs. All scores were positively correlated with MMDA. When the fats and oils group was omitted, correlations were 10–16% higher for breast-fed children and 19–28% higher for non-breast–fed children. Correlations were only slightly improved with the 10-g minimum. With the 7-food group score, a score of ≤2 best predicted low dietary quality (MMDA <50%), with 64% sensitivity, 82% specificity, and 22% misclassification. Imposing a 10-g minimum increased misclassification (30%). These results support the growing evidence of the usefulness of dietary diversity to predict dietary quality, and among infants and young children more specifically.

[Community and International Nutrition] Energy Intake from Beverages Is Increasing among Mexican Adolescents and Adults

2008-11-20

Little is understood about the patterns and trends in adolescent and adult beverage intake in Mexico or most other countries. Here, we used nationally representative dietary intake, income, and food expenditure surveys, which included 416 adolescents (aged 12–18 y) and 2180 adults (aged ≥19 y) from the 1999 Mexican Nutrition Survey and 7464 adolescents and 21,113 adults from the 2006 Mexican Health and Nutrition Survey. We measured the volume and energy per day contributed by all beverages consumed by the sample subjects. In 2006, Mexican adolescents and adults obtained 20.1 and 22.3%, respectively, of their energy intake from energy-containing beverages. Whole milk, carbonated and noncarbonated sugar-sweetened beverages, fruit juice with various sugar and water combinations added, and alcohol represented the 4 major categories of beverage intake. The trends from the dietary intake surveys showed very large increases in the intake of energy-containing beverages among adolescents and adults between 1999 and 2006. Income elasticities showed a high likelihood that intakes will increase as Mexican incomes continue to rise. Whereas the own-price elasticities for whole milk and sodas were both modest, intakes of these were increasing and higher than those for all other food groups. Energy intake trends and current levels of beverage intakes in Mexico are the highest recorded in a nationally representative survey and present major challenges for public health authorities.

[Community and International Nutrition] Zinc Modifies the Association between Nasopharyngeal Streptococcus pneumoniae Carriage and Risk of Acute Lower Respiratory Infection among Young Children in Rural Nepal

2008-11-20

Nasopharyngeal (NP) carriage is necessary for Streptococcus pneumoniae (Spn) transmission and invasive infection. This study evaluated the effect of zinc prophylaxis on the association between NP colonization with Spn and acute lower respiratory infection (ALRI) in children aged 1–35 mo living in a rural district in southern Nepal. We compared carriage prevalence of Spn in 550 ALRI cases with that of healthy age- and season-matched controls. This study, conducted from December 2003 to July 2005, was nested in a community-randomized trial designed to evaluate the effect of zinc on morbidity and mortality in 1- to 36-mo-old children. They were randomized to receive either 10-mg tablets of zinc or placebo daily until discharge. Approximately 75% of cases and controls were Spn carriers. There was an interaction between zinc and Spn carriage (P = 0.091). Spn carriage increased the risk of ALRI in the placebo group [adjusted matched odds ratio (AMOR) = 2.57; P = 0.025] but not in the zinc group (AMOR = 0.95; P = 0.890). Among the subset of symptomatic cases and their controls, the odds of ALRI for Spn carriers in the placebo group was 30 times greater (AMOR = 78.09; P = 0.006) than in the zinc group (AMOR = 2.77; P = 0.288). These findings suggest that zinc prophylaxis may protect children against ALRI associated with carriage of Spn and that the effect may differ by infectious etiology.

[Community and International Nutrition] Dietary Supplementation of Rural Gambian Women during Pregnancy Does Not Affect Body Composition in Offspring at 11-17 Years of Age

Hawkesworth, S., Prentice, A. M., Fulford, A. J. C., Moore, S. E. — 2008-11-20

Fetal nutrition is thought to be an important determinant of later disease risk, although evidence from randomized-controlled trials in humans is lacking. We followed children born during a protein-energy supplementation trial to investigate to what extent this maternal supplement, which improved birth weight, influenced offspring body composition in adolescence. Subjects were 1270 Gambian children (659 boys, 611 girls) aged 11–17 y whose mothers had participated in the original cluster-randomized trial and had received the supplement during pregnancy (intervention) or postpartum (control). Basic anthropometry was measured using standard techniques and fatness was assessed by bioelectrical impedance analysis and population-specific prediction equations. For boys, mean body fat was 12.6% for both intervention and control groups. Mean trunk fat was 11.9% in the intervention group and 12.0% in the control. Intervention girls had a mean body fat of 19.5% and trunk fat of 15.2%; for control girls, it was 19.3 and 14.8%, respectively. BMI, body fat, trunk fat, fat mass index, and fat-free mass index did not differ for either sex when analyzed with generalized estimating equations adjusted for age, maternal height, maternal parity, location, season of birth, and menarche in females. Neither infant-attained size nor the onset of menarche were affected by maternal supplementation. These findings suggest that protein-energy supplements to pregnant women, compared with lactating women, do not affect offspring body composition during adolescence.

[Community and International Nutrition] Hypovitaminosis D Is Common among Pulmonary Tuberculosis Patients in Tanzania but Is Not Explained by the Acute Phase Response

2008-11-20

Vitamin D is essential to immune function, but little is known about the vitamin D status in equatorial populations. A cross-sectional study was conducted among pulmonary tuberculosis (PTB) patients in Mwanza, Tanzania to identify the predictors of their vitamin D status. Data on sociodemography, season, and intake of food, alcohol, tobacco, and soil were collected, anthropometric measurements taken, and serum ₁-antichymotrypsin (ACT), ferritin and soluble transferrin receptor (sTfR), and serum 25-hydroxy-(ergocalciferol+cholecalciferol) [25(OH)D] determined. Of the 655 patients studied, 79.7% (508/637) were culture-positive (PTB+) and 47.2% HIV infected. Mean serum ACT, an acute phase reactant, was 0.73 ± 0.25 g/L with 69.2% >0.6 g/L. Mean serum 25(OH)D was 86.6 ± 32.9 nmol/L, with 41.2% <75 nmol/L. Serum 25(OH)D was highest during the harvest season, May to July, compared with the remaining year. Single subjects had lower [10.4 (95% CI 4.0; 16.9) nmol/L] serum 25(OH)D concentrations than married subjects and PTB+ patients had concentrations lower [8.2 (95% CI 1.5; 14.9) nmol/L] than PTB– patients. Serum 25(OH)D increased with consumption of a large freshwater fish but not of small dried fish or other foods. BMI and serum TfR were positive predictors of serum 25(OH)D, whereas neither elevated serum ACT nor HIV were predictors. In conclusion, serum 25(OH)D is a valid measure of vitamin D status during the acute phase response. The lower concentrations in PTB+ patients may reflect lower sun exposure or increased utilization. The health consequences of hypovitaminosis D in low-income equatorial populations, at risk for both infectious and chronic diseases, should be studied.

[Nutritional Immunology] Combined Glutamine and Arginine Decrease Proinflammatory Cytokine Production by Biopsies from Crohn's Patients in Association with Changes in Nuclear Factor-{kappa}B and p38 Mitogen-Activated Protein Kinase Pathways

2008-11-20

Glutamine (Gln) and arginine (Arg) are conditionally essential amino acids with immunomodulatory properties. The aim of the study was to assess the effects of Gln and Arg alone or in combination on cytokine release by cultured colonic biopsies from patients with active Crohn's disease (CD). Ten consecutive patients [mean (range) age 26 (18–39) y] with active colonic CD (mean CD activity index: 383.7 ± 129.8) were prospectively included in the study. Eight colonic biopsies were obtained via a colonoscopy and incubated during 18 h with low (physiological) or high (pharmacological) doses of Arg (0.1 or 2 mmol/L designated as Arg^low or Arg^high, respectively) and Gln (0.6 or 10 mmol/L designated as Gln^low or Gln^high, respectively). The concentrations of cytokines [interleukin (IL)-4, IL-10, IL-8, IL-6, tumor necrosis factor- (TNF), IL-1β, interferon-) were assessed by ELISA, and nitric oxide (NO) production was evaluated by Griess assay. Nuclear factor (NF)-B p65 subunit, inhibitor of NFB-, and p38 mitogen-activated protein kinase (MAPK) were assessed by immunoblotting. Arg^high/Gln^high decreased the production of TNF, IL-1β, IL-8, and IL-6 (each P < 0.01). Arg^low/Gln^high decreased IL-6 and IL-8 production (both P < 0.01), whereas Arg^high/Gln^low did not affect cytokine and NO production. Arg^low/Gln^high and Arg^high/Gln^high decreased NF-B p65 subunit expression, whereas p38 MAPK was decreased only by Arg^high/Gln^high. Combined pharmacological doses of Arg and Gln decreased TNF and the main proinflammatory cytokines release in active colonic CD biopsies via NF-B and p38 MAPK pathways. These results could be the basis of prospective studies evaluating the effects of enteral supply of combined Arg and Gln during active CD.

[Ingestive Behavior and Neurosciences] Dopamine D2 Receptor Expression Is Altered by Changes in Cellular Iron Levels in PC12 Cells and Rat Brain Tissue

Unger, E. L., Wiesinger, J. A., Hao, L., Beard, J. L. — 2008-11-20

Iron deficiency anemia in early life alters the development and functioning of the dopamine neurotransmitter system, but data regarding the specific effects of brain iron loss on dopamine D₂ receptor regulation are lacking. Cell culture and animal models were employed in this study to determine whether D₂ receptor expression is altered when cellular iron levels are depleted. Endogenous D₂ receptor-expressing PC12 cells exposed to increasing concentrations of the iron chelator desferrioxamine (25–100 µmol/L) exhibited dose-dependent decreases in total D₂ receptor protein concentrations (20–65%), but there were minimal effects on D₂ receptor mRNA levels. When iron-deficient cells were repleted with ferric ammonium citrate for 24 h, D₂ receptor protein densities were similar to control. Dietary iron deficiency for 6 wk in weanling rats also reduced regional iron concentrations by nearly 50% in the ventral midbrain and caudate but did not affect D₂ receptor mRNA levels in the ventral midbrain. Iron deficiency significantly reduced membrane D₂ receptor protein levels by >70% in caudate, whereas cytosolic concentrations showed only 25% losses. D₂ receptor protein densities and regional iron concentrations were restored within 2 wk of dietary iron repletion. These results support the concept that D₂ receptor gene expression is not significantly changed by iron deficiency, whereas dopamine receptor trafficking is affected and is likely related to known dopamine system alterations in iron deficiency.

[Ingestive Behavior and Neurosciences] Early-Life Iron Deficiency Anemia Alters Neurotrophic Factor Expression and Hippocampal Neuron Differentiation in Male Rats

Tran, P. V., Carlson, E. S., Fretham, S. J. B., Georgieff, M. K. — 2008-11-20

Fetal-neonatal iron deficiency alters hippocampal neuronal morphology, reduces its volume, and is associated with acute and long-term learning impairments. However, neither the effects of early-life iron deficiency anemia on growth, differentiation, and survival of hippocampal neurons nor regulation of the neurotrophic factors that mediate these processes has been investigated. We compared hippocampal expression of neurotrophic factors in male rats made iron deficient (ID) from gestational d 2 to postnatal d (P) 7 to iron-sufficient controls at P7, 15, and 30 with quantitative RT-PCR, Western analysis, and immunohistology. Iron deficiency downregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus without compensatory upregulation of its specific receptor, tyrosine-receptor kinase B. Consistent with low overall BDNF activity, we found lower expression of early-growth response gene-1 and -2, transcriptional targets of BDNF signaling. Doublecortin expression, a marker of differentiating neurons, was reduced during peak iron deficiency, suggesting impaired neuronal differentiation in the ID hippocampus. In contrast, iron deficiency upregulated hippocampal nerve growth factor, epidermal growth factor, and glial-derived neurotrophic factor accompanied by an increase in neurotrophic receptor p75 expression. Our findings suggest that fetal-neonatal iron deficiency lowers BDNF function and impairs neuronal differentiation in the hippocampus.

[Ingestive Behavior and Neurosciences] Cognitive Impairment in Folate-Deficient Rats Corresponds to Depleted Brain Phosphatidylcholine and Is Prevented by Dietary Methionine without Lowering Plasma Homocysteine

2008-11-20

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

[Symposium: Dietary PUFA and the Aging Brain--Food for Thought] Docosahexaenoic Acid and the Aging Brain

Lukiw, W. J., Bazan, N. G. — 2008-11-20

The dietary essential PUFA docosahexaenoic acid [DHA; 22:6(n-3)] is a critical contributor to cell structure and function in the nervous system, and deficits in DHA abundance are associated with cognitive decline during aging and in neurodegenerative disease. Recent studies underscore the importance of DHA-derived neuroprotectin D1 (NPD1) in the homeostatic regulation of brain cell survival and repair involving neurotrophic, antiapoptotic and antiinflammatory signaling. Emerging evidence suggests that NPD1 synthesis is activated by growth factors and neurotrophins. Evolving research indicates that NPD1 has important determinant and regulatory interactions with the molecular-genetic mechanisms affecting β-amyloid precursor protein (βAPP) and amyloid beta (Aβ) peptide neurobiology. Deficits in DHA or its peroxidation appear to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in Alzheimer disease (AD), a common and progressive age-related neurological disorder unique to structures and processes of the human brain. This article briefly reviews our current understanding of the interactions of DHA and NPD1 on βAPP processing and Aβ peptide signaling and how this contributes to oxidative and pathogenic processes characteristic of aging and AD pathology.

[Symposium: Dietary PUFA and the Aging Brain--Food for Thought] Arachidonic Acid and the Brain

Rapoport, S. I. — 2008-11-20

Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A₂ (PLA₂) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA₂ or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA₂ were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA₂ and COX-1 expression, whereas AA-selective cPLA₂, sPLA₂, and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.

[Symposium: Dietary PUFA and the Aging Brain--Food for Thought] (n-6) and (n-3) Polyunsaturated Fatty Acids and the Aging Brain: Food for Thought

Whelan, J. — 2008-11-20

Over the last decade, the role of dietary PUFA in growth, development, and cognitive function in the infant has been a topic at numerous national and international meetings. Only recently has the role of PUFA been more seriously examined as they relate to the aging brain. In fact, a search of the literature reveals very few randomized control trials exploring this research area. However, the literature reveals growing mechanistic evidence that cognitive function of the aging brain can be preserved, or loss of function can be diminished with docosahexaenoic acid, a long-chain (n-3) PUFA. Furthermore, no symposia have taken a serious look at the impact of (n-6) PUFA on the brain, in particular arachidonic acid (AA), the most highly concentrated (n-6) PUFA in the brain. This symposium explores the role of AA metabolism in the brain as it relates to neurological mood disorders. To that end, this symposium was designed to highlight the potential effects of dietary PUFA on the adult brain, an important issue given the growing elderly population in this country and the growing problems with neurological disorders (dementia, Alzheimer disease, Parkinson disease, bipolar disorders, etc.).

[Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries--The Critical Role of Research to Guide Policy and Programs] Iron Deficiency in Young Children in Low-Income Countries and New Approaches for Its Prevention

Lutter, C. K. — 2008-11-20

Anemia resulting from severe iron deficiency (ID) is the most prevalent and widespread nutrition-related health problem in infants and young children in low-income countries and has proven very resistant to prevention through public health interventions. Accumulative evidence from animal and human studies suggests that such deficiencies are associated with large adverse effects on child cognitive and motor development. Therefore, effective interventions to improve iron status will have large health benefits. Action to reduce young child ID would benefit from overarching policy and programmatic guidance that informs decision makers about what to do, when to do it, and how to do it. The impetus for new approaches to prevent ID in young children reflects growing recognition of the need to intervene early and often and for better vehicles to deliver iron. Prevention of ID requires strong delivery systems that enhance consumer demand and promote compliance. When this occurs, the prevalence of anemia is greatly reduced.

[Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries--The Critical Role of Research to Guide Policy and Programs] Setting the Stage for Child Health and Development: Prevention of Iron Deficiency in Early Infancy

Chaparro, C. M. — 2008-11-20

Iron deficiency is estimated to be the most common nutritional deficiency worldwide and is particularly persistent among infants and children. The high prevalence of anemia in 6- to 9-mo-old children raises the concern that birth iron stores in some infants are inadequate to sustain growth and development through the first 6 mo of life, and postnatal factors are contributing to early depletion of iron stores and development of anemia. At the same time, there are concerns about negative effects of excess iron in infants. Maternal iron status, infant birth weight and gestational age, as well as the timing of umbilical cord clamping at birth all contribute to the establishment of adequate total body iron at birth. Postnatally, feeding practices and growth rate are factors that will affect how quickly birth iron is depleted during the first 6 mo of life. Under conditions in which maternal iron status, birth weight, gestational age, and umbilical cord clamping time are optimal, and exclusive breast-feeding is practiced, infants should have adequate iron stores for the first 6–8 mo of life. Under suboptimal conditions, infants may not reach this goal and may need to be targeted for iron supplementation before 6 mo of age.

[Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries--The Critical Role of Research to Guide Policy and Programs] Why Iron Deficiency Is Important in Infant Development

Beard, J. L. — 2008-11-20

Infants who experience iron deficiency during the first 6–12 mo of life are likely to experience persistent effects of the deficiency that alter functioning in adulthood. A lack of sufficient iron intake may significantly delay the development of the central nervous system as a result of alterations in morphology, neurochemistry, and bioenergetics. Depending on the stage of development at the time of iron deficiency, there may be an opportunity to reverse adverse effects, but the success of repletion efforts appear to be time dependent. Publications in the past several years describe the emerging picture of the consequences of iron deficiency in both human and animal studies. The mechanisms for iron accumulation in the brain and perhaps redistribution are being understood. The data in human infants are consistent with altered myelination of white matter, changes in monoamine metabolism in striatum, and functioning of the hippocampus. Rodent studies also show effects of iron deficiency during gestation and lactation that persist into adulthood despite restoration of iron status at weaning. These studies indicate that gestation and early lactation are likely critical periods when iron deficiency will result in long-lasting damage.

[Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries--The Critical Role of Research to Guide Policy and Programs] Iron Metabolism, Malaria, and Other Infections: What Is All the Fuss About?

Prentice, A. M. — 2008-11-20

This article briefly describes how iron lies at the center of a host-pathogen battle for nutrients and why there are many theoretical reasons to suspect that administration of supplemental iron might predispose to infection. This is supported by in vitro and small animal studies, but meta-analysis of human epidemiological and intervention studies has found little evidence for most disease outcomes. Supplemental iron does appear to increase susceptibility to malaria as measured by a variety of malariometric indices. However, even in malarious areas, iron appears beneficial in iron-deficient subjects. The concerns about iron supplementation programs for children seem to be confined to Sub-Saharan Africa and to areas of high malaria endemicity, where it will be necessary to adopt a cautious approach to supplementation based either on screening out iron-replete children or combining iron administration with effective disease-control strategies.

[Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries--The Critical Role of Research to Guide Policy and Programs] Research Needed to Strengthen Science and Programs for the Control of Iron Deficiency and Its Consequences in Young Children

Stoltzfus, R. J. — 2008-11-20

The purpose of this article is to highlight critical research needs for the effective prevention and control of iron deficiency and its consequences in children living in low-income countries. Four types of research are highlighted: The first involves scaling up interventions that we know are effective, namely iron supplementation of pregnant women, delayed cord clamping at delivery, immediate and exclusive breast-feeding, and continued exclusive breast-feeding for ~6 mo. The second entails evaluation research of alternative interventions that are likely to work, to find the most cost-effective strategies for a given social, economic, and epidemiological context. This research is especially needed to expand the implementation of appropriate complementary feeding interventions. In this area, research needs to be designed to provide causal evidence, to measure cost-effectiveness, and to measure potential effect modifiers. The third is efficacy research to discover promising practices where we lack proven interventions. Examples include how to detect infants younger than 6 mo who are at high risk of iron deficiency, efficacious and safe interventions for those young high-risk infants, and best protocols for the treatment of severe anemia. The fourth includes basic research to elucidate physiological processes and mechanisms underlying the risks and benefits of supplemental iron for children exposed to infectious diseases, especially malaria. Strategic research in all 4 areas will ensure that interventions to control pediatric iron deficiency are integrated into national programs and global initiatives to make pregnancy safer, reduce newborn deaths, and promote child development, health, and survival.

[Announcements] Announcements

2008-11-20

[Retractions] RETRACTED: The Maturation of the Fetal and Neonatal Immune System.

2008-11-20