Wheat is the primary staple food for nearly one-third of the world's population. NaFeEDTA is the only iron (Fe) compound suitable for fortifying high extraction flours. We tested the hypothesis that NaFeEDTA-fortified, whole wheat flour reduces Fe deficiency (ID) and improves body Fe stores (BIS) and cognitive performance in Indian children. In a randomized, double-blind, controlled, school feeding trial, 6- to 15-y-old, Fe-depleted children (n = 401) were randomly assigned to either a daily wheat-based lunch meal fortified with 6 mg of Fe as NaFeEDTA or an otherwise identical unfortified control meal. Hemoglobin (Hb) and Fe status were measured at baseline, 3.5 mo, and 7 mo. Cognitive performance was evaluated at baseline and 7 mo in children (n = 170) at one of the study sites. After 7 mo, the prevalence of ID and ID anemia in the treatment group significantly decreased from 62 to 21% and 18 to 9%, respectively. There was a time x treatment interaction for Hb, serum ferritin, transferrin receptor, zinc protoporphyrin, and BIS (all P < 0.0001). Changes in BIS differed between the groups; it increased in the treatment group (0.04 ± 0.04 mmol/kg body weight) and decreased in the control group (-0.02 ± 0.04 mmol/kg body weight) (P < 0.0001). In sensory tests, NaFeEDTA-fortified flour could not be differentiated from unfortified flour. There were no significant differences in cognitive performance tests between the groups. NaFeEDTA-fortified wheat flour markedly improved BIS and reduced ID in Fe-depleted children. It may be recommended for wider use in national school feeding programs.

To investigate the inhibiting effects of multi-target anti-microRNA antisense oligonucleotide (MTg-AMOs) on proliferation and migration of human gastric cancer cells.

Angiopoietin-like protein 4 (Angptl4) is a circulating inhibitor of plasma triglyceride clearance via inhibition of lipoprotein lipase. The aim of the present study was to examine the regulation of Angptl4 by glucocorticoids and insulin in vivo in humans, since these factors regulate Angptl4 expression in vitro.

To assess the effects of an intra-articular (IA) lidocaine or bupivacaine injection on synovial fluid (SF) biomarkers of cartilage metabolism.

Studies suggested that microRNAs influence cellular activities in the uterus including cell differentiation and embryo implantation. In assisted reproduction cycles, luteal phase support, given to improve endometrial characteristics and to facilitate the implantation process, has been a standard practice. The effect of different types of luteal phase support using steroid hormones in relation to endometrial miRNA profiles during the peri-implantation period has not seen described. This study was designed to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles.

Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient?

The absorption of lysine is facilitated by leucine, but there is no information regarding the effect of crude protein, lysine and leucine levels on the expression of cationic amino acid transporters in pigs. Therefore, an experiment was conducted with 20 pigs (14.9 +/- 0.62 kg initial body weight) to evaluate the effect of two protein levels, and the content of lysine, threonine, methionine and leucine in low crude protein diets on the expression of b(0,+) and CAT-1 mRNA in jejunum, Longissimus dorsi and Semitendinosus muscles and serum concentration of amino acids. Treatments were as follows: (i) wheat-soybean meal diet, 20% crude protein (Control); (ii) wheat diet deficient in lysine, threonine and methionine (Basal diet); (iii) Basal diet plus 0.70% L-lysine, 0.27% L-threonine, 0.10% DL-methionine (Diet LTM); (iv) Diet LTM plus 0.80% L-leucine (Diet LTM + Leu). Despite the Basal diet, all diets were formulated to meet the requirements of lysine, threonine and methionine; Diet LTM + Leu supplied 60% excess of leucine. The addition of lysine, threonine and methionine in Diet LTM increased the expression of b(0,+) in jejunum and CAT-1 in the Semitendinosus and Longissiums muscles and decreased CAT-1 in jejunum; the serum concentration of lysine was also increased (p < 0.01). Further addition of L-leucine (Diet LTM + Leu) decreased the b(0,+) expression in jejunum and CAT-1 in the Longissimus dorsi muscle (p < 0.05), increased the serum concentration ofleucine and arginine and decreased the concentration of isoleucine (p < 0.05). Pigs fed the Control diet expressed less b(0,+) in jejunum, and CAT-1 in the Semitendinosus and Longissiums muscles expressed more CAT-1 in jejunum (p < 0.05) and had lower serum concentration ofisoleucine, leucine and valine (p < 0.05), but higher lysine concentrations (p < 0.01) than those fed Diet LTM. These results indicated that both, the level and the source of dietary amino acids, affect the expression of cationic amino acid transporters in pigs fed wheat-based diets.

Previous positron emission tomography (PET) studies employing competition paradigms have shown either no change or substantial declines in striatal [(11)C]-raclopride binding after challenge with psychotogenic doses of the N-methyl-D-aspartate antagonist ketamine. We sought to probe the relationship between the severity of ketamine-induced psychotic symptoms and altered dopamine D(2/3) receptor availability throughout brain using the high affinity ligand [(18)F]-fallypride (FP). PET recordings were obtained in a group of 10 healthy, young male volunteers, in a placebo condition, and in the course of an infusion with ketamine at a psychotomimetic dose. Administration of the Positive and Negative Syndrome Scale and the Thought and Language Index in both conditions revealed a substantial emergence of mainly negative symptoms of schizophrenia, persisting until the end of the 3 h PET recordings. The baseline FP binding in cortex, caudate nucleus and other brain regions was highly predictive of the individual severity of psychotic symptoms in the ketamine condition. However, there was no evidence of ketamine-evoked reductions in FP binding. In the context of earlier findings, we speculate that high baseline D(2/3)-receptor availability may impart benefits with regard to cognitive flexibility, but increases the risk of maladaptive information processing in the face of environmental stresses and challenges.

Estradiol (E(2)) promotes and maintains the female phenotype characterized by subcutaneous fat accumulation. There is evidence to suggest that this effect is due to increased anti-lipolytic α2A-adrenergic receptors, but whether this requires long-term exposure to E(2) or is an immediate effect is not clear.

A study was performed to characterize the effects of dexamethasone (DEX) and insulin administration on gene expression of glucose transporters (GLUT) in chicken (Gallus gallus domesticus) skeletal muscles and in cultured embryonic myoblasts. Three groups of 1-wk-old male chickens were randomly subjected to one of the following treatments for 7 d: DEX (a subcutaneous injection of 1 mg/kg BW, twice daily at 0800 h and 2000 h), controls (injected with saline), and pair-fed controls (restricted to the same feed intake as for the DEX treatment). Expressions of GLUT-1, GLUT-3, GLUT-8, and 18S rRNA mRNA were determined by quantitative reverse transcription PCR in the pectoralis major (PM) and biceps femoris (BF) muscles. Using chicken embryonic myoblasts (CEM), the interaction between DEX (200 nM) and insulin (100 nM) administration was evaluated on GLUT gene and GLUT-1 protein expressions and 2-deoxy-D-[1, 2-(3)H]-glucose (2-DG) uptake. Myoblasts were incubated with serum-free medium for 3 h in the presence or absence of insulin (0, 0.02, 0.1, 0.5, and 2.5 μM). Although GLUT-1 is not considered an insulin-responsive GLUT in mammals, this study shows that insulin stimulated 2-DG uptake and GLUT-1 mRNA and protein expression in CEM (P < 0.0001), suggesting that both are regulated in chicken skeletal muscle. Dexamethasone inhibited insulin-stimulated glucose uptake in CEM (P < 0.0001), likely accounting for insulin resistance in skeletal muscles. The results of the present study indicate that the altered GLUT-1 gene and protein expression may contribute to the insulin resistance induced by DEX treatment in chicken muscles.

We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25(POS) myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25(POS) patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25(NEG) cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITD(POS) AML was restricted to CD25(POS) patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25(POS) status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25(POS) status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.

Sulphur-induced polioencephalomalacia (sPEM), a neurological disorder affecting ruminants, is frequently associated with the consumption of high-sulphur (S) water and subsequent poor performance. Currently, there is no economical method for S removal from surface water sources, and alternative water sources are typically neither readily available nor cost-effective. Determination of genes differentially expressed in response to high-S water consumption may provide a better understanding of the physiology corresponding to high dietary S and ultimately lead to the development of treatment and prevention strategies. The objective of this study was to determine changes in gene expression in the liver, an organ important for S metabolism, of fibre-fed steers consuming high-S water. For this study, liver tissues were collected on the final day of a trial from yearling steers randomly assigned to low-S water control (566 mg/kg SO4 ; n = 24), high-S water (3651 mg/kg SO4 ; n = 24) or high-S water plus clinoptilolite supplemented at either 2.5% (n = 24) or 5.0% (n = 24) of diet dry matter (DM). Microarray analyses on randomly selected healthy low-S control (n = 4) and high-S (n = 4; no clinoptilolite) steers using the Affymetrix GeneChip Bovine Genome Array revealed 488 genes upregulated (p < 0.05) and 154 genes downregulated (p < 0.05) in response to the high- vs. low-S water consumption. Real-time RT-PCR confirmed the upregulation (p < 0.10) of seven genes involved in inflammatory response and immune functions. Changes in such genes suggest that ruminant animals administered high-S water may be undergoing an inflammation or immune response, even if signs of sPEM or compromised health are not readily observed. Further study of these, and other affected genes, may deliver new insights into the physiology underlying the response to high dietary S, ultimately leading to the development of treatments for high S-affected ruminant livestock.

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.

The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes.

To evaluate the impact of enzyme-inducing antiepileptic drugs (EI-AEDs) on serum antiretroviral (ARV) levels in patients with HIV.

Gene expression analysis of healthy postmenopausal women in a prospective clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy (HT) with natural versus synthetic estrogens. Two 28-day cycles of daily estradiol (E2) gel 1.5 mg and oral micronized progesterone (P) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation (Ki-67 MIB-1 positive cells) at the cell level nor at the mRNA level (MKI-67 gene). A borderline significant beneficial reduction in anti-apoptotic protein bcl-2, favouring apoptosis, was also seen followed by a slight numeric decrease of its mRNA. By contrast, two 28-day cycles of daily oral conjugated equine estrogens (CEE) 0.625 mg and oral medroxyprogesterone acetate (MPA) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level, and significantly enhanced mammographic breast density, an important risk factor for breast cancer. In addition, CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional, synthetic therapy.

The long-lived glycoprotein hormone, human chorionic gonadotropin (hCG), downregulates testosterone (T) biosynthesis in vitro and in vivo in animals and humans. The degree to which short-lived pulses of pituitary luteinizing hormone (LH) do so, particularly at physiological concentrations, is not known. We test the hypothesis that continuous LH infusion compared with bolus injections of LH every 1 h or every 2 h overnight downregulates T secretory responses to a subsequent fixed template of three consecutive intravenous pulses of a physiological amount of recombinant human (rh) LH (triple stimulus). Nineteen healthy men ages 18-49 yr each underwent four separate randomly ordered overnight gonadotropin-releasing hormone-receptor antagonist treatments with superimposed intravenous infusions of saline or rhLH (1-h pulses, 2-h pulses, or continuously). Each 12-h infusion protocol was followed by the triple rhLH-pulse stimulus the next morning. During the triple stimulus, basal (nonpulsatile) as well as total (basal plus pulsatile) T secretion was higher after overnight 2- and 1-h rhLH pulses than after continuous rhLH or saline delivery. Approximate entropy, a probabilistic measure of feedforward-induced irregularity of T concentration time series, was higher after 1-h rhLH pulses than after continuous rhLH. Analytical estimation of pulsatile rhLH-T dose-response measures revealed higher T secretory sensitivity and greater rhLH potency (lower EC₅₀) after exposure to 1-h than 2-h rhLH pulses. Collectively, these data indicate that in vivo dynamics of LH-stimulated T secretion under standardized conditions in men depend on the prior time mode of LH delivery in the bloodstream.

Vitamin E modulates the immune response, in part by reducing inflammation. The bacterial component lipopolysaccharide (LPS) can induce an inflammatory response in chickens. The objective of this study was to evaluate immunomodulatory effects of dietary type and level of vitamin E on response of broilers to LPS. One-day-old broiler males (n=96) were placed in a vitamin E-type (synthetic, natural) × vitamin E level (22, 220 IU/kg)×LPS (LPS, saline) block design. At 22 d, LPS (or saline) was injected subcutaneously. Spleens were harvested for RNA isolation at 3 and 24 h postinjection. Relative levels of RNA expression were measured for the immune-related genes: avian β defensin 10 (AvBD10), interleukin 6 (IL6), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), interleukin 10 and transforming growth factor- β1 (TGF-β1). Avian β defensin 10 and iNOS are innate antimicrobial proteins. Interleukin 6 and IFN-γ are pro-inflammatory cytokines, whereas interleukin 10 and transforming growth factor-β1 are anti-inflammatory cytokines. There were significantly higher splenic levels of IL6, IFN-γ, iNOS, and IL10 RNA expression at 3 h postinjection in chickens receiving LPS than in chickens 24 h post-LPS injection or saline-injected birds at either time. These data suggest that LPS induced an immune response that was regulated by both pro- and anti-inflammatory cytokines. Birds fed natural-type (versus synthetic) vitamin E had a significantly lower LPS-induced inflammatory response, as indicated by lower IL6 RNA expression levels, suggesting a protective effect from natural-type vitamin E when a chicken encounters a bacterial component.