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Interactions of cosmic ray protons, atomic nuclei, and electrons in the interstellar medium in the inner part of the Milky Way produce a γ-ray flux from the Galactic Ridge. If the γ-ray emission is dominated by proton and nuclei interactions, a neutrino flux comparable to the γ-ray flux is expected from the same sky region.Data collected by the ANTARES neutrino telescope are used to constrain the neutrino flux from the Galactic Ridge in the 1-100 TeV energy range. Neutrino events reconstructed both as tracks and showers are considered in the analysis and the selection is optimized for the search of an excess in the region |l|

This letter presents a combined measurement of the energy spectra of atmospheric νe and νμ in the energy range between ∼100 GeV and ∼50 TeV with the ANTARES neutrino telescope. The analysis uses 3012 days of detector livetime in the period 2007–2017, and selects 1016 neutrinos interacting in (or close to) the instrumented volume of the detector, yielding shower-like events (mainly from νe+ν‾e charged current plus all neutrino neutral current interactions) and starting track events (mainly from νμ+ν‾μ charged current interactions). The contamination by atmospheric muons in the final sample is suppressed at the level of a few per mill by different steps in the selection analysis, including a Boosted Decision Tree classifier. The distribution of reconstructed events is unfolded in terms of electron and muon neutrino fluxes. The derived energy spectra are compared with previous measurements that, above 100 GeV, are limited to experiments in polar ice and, for νμ, to Super-Kamiokande.

Neutrino detectors participate in the indirect search for the fundamental constituents of dark matter (DM) in form of weakly interacting massive particles (WIMPs). In WIMP scenarios, candidate DM particles can pair-annihilate into Standard Model products, yielding considerable fluxes of high-energy neutrinos. A detector like ANTARES, located in the Northern Hemisphere, is able to perform a complementary search looking towards the Galactic Centre, where a high density of dark matter is thought to accumulate. Both this directional information and the spectral features of annihilating DM pairs are entered into an unbinned likelihood method to scan the data set in search for DM-like signals in ANTARES data. Results obtained upon unblinding 3170 days of data reconstructed with updated methods are presented, which provides a larger, and more accurate, data set than a previously published result using 2101 days. A non-observation of dark matter is converted into limits on the velocity-averaged cross section for WIMP pair annihilation.

We report a first measurement for ultrahigh energy cosmic rays of the correlation between the depth of shower maximum and the signal in the water Cherenkov stations of air-showers registered simultaneously by the fluorescence and the surface detectors of the Pierre Auger Observatory. Such a correlation measurement is a unique feature of a hybrid air-shower observatory with sensitivity to both the electromagnetic and muonic components. It allows an accurate determination of the spread of primary masses in the cosmic-ray flux. Up till now, constraints on the spread of primary masses have been dominated by systematic uncertainties. The present correlation measurement is not affected by systematics in the measurement of the depth of shower maximum or the signal in the water Cherenkov stations. The analysis relies on general characteristics of air showers and is thus robust also with respect to uncertainties in hadronic event generators. The observed correlation in the energy range around the ‘ankle’ at lg⁡(E/eV)=18.5–19.0 differs significantly from expectations for pure primary cosmic-ray compositions. A light composition made up of proton and helium only is equally inconsistent with observations. The data are explained well by a mixed composition including nuclei with mass A>4. Scenarios such as the proton dip model, with almost pure compositions, are thus disfavored as the sole explanation of the ultrahigh-energy cosmic-ray flux at Earth. Keywords: Pierre Auger Observatory, Cosmic rays, Mass composition, Ankle

Objective: To examine whether eating behavior and perceived stress predict the maintenance of self-reported dietary change and adherence to dietary instructions during an intervention., Design: A secondary analysis of the behavior maintenance stage (6-36 months) of the 3-year PREVIEW intervention (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World)., Participants: Adults (n = 1,311) with overweight and prediabetes at preintervention baseline., Variables Measured: Eating behavior (Three-Factor Eating Questionnaire), stress (Perceived Stress Scale), and dietary intake (4-day food records on 4 occasions) were reported., Analysis: Associations between predictors and dietary outcomes were examined with linear mixed-effects models for repeated measurements., Results: Eating behaviors and stress at 6 months did not predict the subsequent change in dietary outcomes, but higher cognitive restraint predicted lower energy intake, and both higher disinhibition and hunger predicted higher energy intake during the following behavior maintenance stage. In addition, higher disinhibition predicted higher saturated fat intake and lower fiber intake, and higher hunger predicted lower fiber intake. Stress was not associated with energy intake or dietary quality. Eating behaviors and stress were not consistently associated with adherence to dietary instructions., Conclusions and Implications: Higher cognitive restraint predicted lower energy intake (food quantity), but disinhibition and hunger were also associated with dietary quality., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(β-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(β-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(β-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to "reprogram" myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Josep M. Aran reports financial support was provided by Ministerio de Ciencia, Innovación y Universidades. Josep M. Aran reports financial support was provided by Departament de Recerca i Universitats de la Generalitat de Catalunya. Josep M. Aran reports financial support was provided by La Caixa Foundation. Josep M. Aran reports financial support was provided by The hna Foundation. Josep M. Aran has patent pending to IDIBELL. Inmaculada Serrano has patent pending to IDIBELL. Ana Luque has patent pending to IDIBELL., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Low-energy diet replacement is an effective tool to induce large and rapid weight loss and improve metabolic health, but in the long-term individuals often experience significant weight regain. Little is known about the role of animal-based foods in weight maintenance and metabolic health. We aimed to examine longitudinal associations of animal-based foods with weight maintenance and glycaemic and cardiometabolic risk factors. We also modelled replacement of processed meat with other high-protein foods., Methods: In this secondary analysis, longitudinal data were analysed from 688 adults (26-70 years) with overweight and prediabetes after 8-week low-energy diet-induced weight loss (≥8% of initial body weight) in a 3-year, multi-centre, diabetes prevention study (PREVIEW). Animal-based food consumption, including unprocessed red meat, processed red meat, poultry, dairy products, fish and seafood, and eggs, was repeatedly assessed using 4-day food records. Multi-adjusted linear mixed models and isoenergetic substitution models were used to examine the potential associations., Results: The available-case analysis showed that each 10-g increment in processed meat, but not total meat, unprocessed red meat, poultry, dairy products, or eggs, was positively associated with weight regain (0.17 kg⋅year -1 , 95% CI 0.10, 0.25, P < 0.001) and increments in waist circumference, HbA 1c , and triacylglycerols. The associations of processed meat with HbA 1c or triacylglycerols disappeared when adjusted for weight change. Fish and seafood consumption was inversely associated with triacylglycerols and triacylglycerol-glucose index, independent of weight change. Modelled replacement of processed meat with isoenergetic (250-300 kJ·day -1 or 60-72 kcal·day -1 ) dairy, poultry, fish and seafood, grains, or nuts was associated with -0.59 (95% CI -0.77, -0.41), -0.66 (95% CI -0.93, -0.40), -0.58 (95% CI -0.88, -0.27), and -0.69 (95% CI -0.96, -0.41) kg·year -1 of weight regain, respectively (all P < 0.001) and significant improvements in HbA 1c , and triacylglycerols., Conclusions: Higher intake of processed meat, but not total or unprocessed red meat, poultry, dairy products, or eggs may be associated with greater weight regain and more adverse glycaemic and cardiometabolic risk factors. Replacing processed meat with a wide variety of high-protein foods, including unprocessed red meat, poultry, dairy products, fish, eggs, grains, and nuts, could improve weight maintenance and metabolic health after rapid weight loss. This study was registered as ClinicalTrials.gov, NCT01777893., Competing Interests: Conflicts of interest AR has received honorariums from the International Sweeteners Association and Unilever. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. IAM was a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition. He was also a member of the Nestle Research Scientific Advisory Board, and of the Novozymes Scientific Advisory Board. He withdrew from all of these roles in 2020 and on August 1 2020 became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. The rest of the authors declare that they have no potential conflicts of interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: The association of quantity and quality of carbohydrate sources with appetite during long-term weight-loss maintenance (WLM) after intentional weight loss (WL) is unclear. We aimed to investigate longitudinal associations of quantity and quality of carbohydrate sources with changes in subjective appetite sensations during WLM., Methods: This secondary analysis evaluated longitudinal data from the 3-year WLM phase of the PREVIEW study, a 2 × 2 factorial (diet-physical activity arms), multi-center, randomized trial. 1279 individuals with overweight or obesity and prediabetes (25-70 years; BMI≥25 kg m -2 ) were included. Individuals were merged into 1 group to assess longitudinal associations of yearly changes in appetite sensations. Quantity and quality of carbohydrate sources including total carbohydrate, glycemic index (GI), glycemic load (GL), and total dietary fiber were assessed via 4-day food diaries at 4 timepoints (26, 52, 104, and 156 weeks) during WLM. Visual analog scales were used to assess appetite sensations in the previous week., Results: During WLM, participants consumed on average 160.6 (25th, 75th percentiles 131.1, 195.8) g·day -1 of total carbohydrate, with GI 53.8 (48.7, 58.8) and GL 85.3 (67.2, 108.9) g day -1 , and 22.3 (17.6, 27.3) g·day -1 of dietary fiber. In the available-case analysis, multivariable-adjusted linear mixed models with repeated measures showed that each 30-g increment in total carbohydrate was associated with increases in hunger (1.36 mm year -1 , 95% CI 0.77, 1.95, P < 0.001), desire to eat (1.10 mm year -1 , 0.59, 1.60, P < 0.001), desire to eat something sweet (0.99 mm year -1 , 0.30, 1.68, P = 0.005), and weight regain (0.20%·year -1 , 0.03, 0.36, P = 0.022). Increasing GI was associated with weight regain, but not associated with increases in appetite sensations. Each 20-unit increment in GL was associated with increases in hunger (0.92 mm year -1 , 0.33, 1.51, P = 0.002), desire to eat (1.12 mm year -1 , 0.62, 1.62, P < 0.001), desire to eat something sweet (1.13 mm year -1 , 0.44, 1.81, P < 0.001), and weight regain (0.35%·year -1 , 0.18, 0.52, P < 0.001). Surprisingly, dietary fiber was also associated with increases in desire to eat, after adjustment for carbohydrate or GL., Conclusions: In participants with moderate carbohydrate and dietary fiber intake, and low to moderate GI, we found that higher total carbohydrate, GL, and total fiber, but not GI, were associated with increases in subjective desire to eat or hunger over 3 years. This study was registered as ClinicalTrials.gov, NCT01777893., Competing Interests: Conflicts of interest AR has received honorariums from the International Sweeteners Association and Unilever. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. TML is advisor for “Sense” diet programme. TL is employed by NetUnion sarl, who contributed to the data collection process in the absence of commercial or financial conflict of interest with the study analysis. The rest of the authors declare that they have no potential conflicts of interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Observed associations of high-protein diets with changes in insulin resistance are inconclusive., Objectives: We aimed to assess associations of changes in both reported and estimated protein (PRep; PEst) and energy intake (EIRep; EIEst) with changes in HOMA-IR, glycated hemoglobin (HbA1c), and BMI (in kg/m2), in 1822 decreasing to 833 adults (week 156) with overweight and prediabetes, during the 3-y PREVIEW (PREVention of diabetes through lifestyle intervention and population studies In Europe and around the World) study on weight-loss maintenance. Eating behavior and measurement errors (MEs) of dietary intake were assessed. Thus, observational post hoc analyses were applied., Methods: Associations of changes in EIEst, EIRep, PEst, and PRep with changes in HOMA-IR, HbA1c, and BMI were determined by linear mixed-model analysis in 2 arms [high-protein-low-glycemic-index (GI) diet and moderate-protein-moderate-GI diet] of the PREVIEW study. EIEst was derived from energy requirement: total energy expenditure = basal metabolic rate × physical activity level; PEst from urinary nitrogen, and urea. MEs were calculated as [(EIEst - EIRep)/EIEst] × 100% and [(PRep - PEst)/PEst] × 100%. Eating behavior was determined using the Three Factor Eating Questionnaire, examining cognitive dietary restraint, disinhibition, and hunger., Results: Increases in PEst and PRep and decreases in EIEst and EIRep were associated with decreases in BMI, but not independently with decreases in HOMA-IR. Increases in PEst and PRep were associated with decreases in HbA1c. PRep and EIRep showed larger changes and stronger associations than PEst and EIEst. Mean ± SD MEs of EIRep and PRep were 38% ± 9% and 14% ± 4%, respectively; ME changes in EIRep and En% PRep were positively associated with changes in BMI and cognitive dietary restraint and inversely with disinhibition and hunger., Conclusions: During weight-loss maintenance in adults with prediabetes, increase in protein intake and decrease in energy intake were not associated with decrease in HOMA-IR beyond associations with decrease in BMI. Increases in PEst and PRep were associated with decrease in HbA1c.This trial was registered at clinicaltrials.gov as NCT01777893., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: There has been limited evidence about whether genotype-tailored advice provides extra benefits in reducing obesity-related traits compared with the benefits of conventional one-size-fits-all advice. Objective: We determined whether the disclosure of information on fat-mass and obesity-associated ( FTO ) genotype risk had a greater effect on a reduction of obesity-related traits in risk carriers than in nonrisk carriers across different levels of personalized nutrition. Design: A total of 683 participants (women: 51%; age range: 18-73 y) from the Food4Me randomized controlled trial were included in this analysis. Participants were randomly assigned to 4 intervention arms as follows: level 0, control group; level 1, dietary group; level 2, phenotype group; and level 3, genetic group. FTO (single nucleotide polymorphism rs9939609) was genotyped at baseline in all participants, but only subjects who were randomly assigned to level 3 were informed about their genotypes. Level 3 participants were stratified into risk carriers (AA/AT) and nonrisk carriers (TT) of the FTO gene for analyses. Height, weight, and waist circumference (WC) were self-measured and reported at baseline and months 3 and 6. Results: Changes in adiposity markers were greater in participants who were informed that they carried the FTO risk allele (level 3 AT/AA carriers) than in the nonpersonalized group (level 0) but not in the other personalized groups (level 1 and 2). Mean reductions in weight and WC at month 6 were greater for FTO risk carriers than for noncarriers in the level 3 group [-2.28 kg (95% CI: -3.06, -1.48 kg) compared with -1.99 kg (-2.19, -0.19 kg), respectively ( P = 0.037); and -4.34 cm (-5.63, -3.08 cm) compared with -1.99 cm (-4.04, -0.05 cm), respectively, ( P = 0.048)]. Conclusions: There are greater body weight and WC reductions in risk carriers than in nonrisk carriers of the FTO gene. This trial was registered at clinicaltrials.gov as NCT01530139., (© 2017 American Society for Nutrition.)

Background: The apolipoprotein E (APOE) risk allele (ɛ4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether ɛ4 carriers would benefit from gene-based personalized nutrition (PN)., Objectives: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1-2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E4-) on dietary change after gene-based PN (level 3)., Design: Individuals (n = 1466) recruited into the Food4Me pan-European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and ω-3 (n-3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models., Results: Significantly higher TC concentrations were observed in E4+ participants than in E4- (P < 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E4-), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean ± SD: E4+, -0.72% ± 0.35% compared with -1.95% ± 0.45%, P = 0.035; E4-, -0.31% ± 0.20% compared with -1.68% ± 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E4- participants (-1.68% ± 0.35% compared with -2.56% ± 0.27%, P = 0.025)., Conclusions: The APOE ɛ4 allele was associated with higher TC. Although gene-based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE "risk" and "nonrisk" groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN. This trial was registered at clinicaltrials.gov as NCT01530139., (© 2016 American Society for Nutrition.)

Background: Little is known about the efficacy of personalized nutrition (PN) interventions for improving consumption of a Mediterranean diet (MedDiet)., Objective: The objective was to evaluate the effect of a PN intervention on dietary changes associated with the MedDiet., Design: Participants (n = 1607) were recruited into a 6-mo, Internet-based, PN randomized controlled trial (Food4Me) designed to evaluate the effect of PN on dietary change. Participants were randomly assigned to receive conventional dietary advice [control; level 0 (L0)] or PN advice on the basis of current diet [level 1 (L1)], diet and phenotype [level 2 (L2)], or diet, phenotype, and genotype [level 3 (L3)]. Dietary intakes from food-frequency questionnaires at baseline and at 6 mo were converted to a MedDiet score. Linear regression compared participant characteristics between high (>5) and low (≤5) MedDiet scores. Differences in MedDiet scores between treatment arms at month 6 were evaluated by using contrast analyses., Results: At baseline, high MedDiet scorers had a 0.5 lower body mass index (in kg/m(2); P = 0.007) and a 0.03 higher physical activity level (P = 0.003) than did low scorers. MedDiet scores at month 6 were greater in individuals randomly assigned to receive PN (L1, L2, and L3) than in controls (PN compared with controls: 5.20 ± 0.05 and 5.48 ± 0.07, respectively; P = 0.002). There was no significant difference in MedDiet scores at month 6 between PN advice on the basis of L1 compared with L2 and L3. However, differences in MedDiet scores at month 6 were greater in L3 than in L2 (L3 compared with L2: 5.63 ± 0.10 and 5.38 ± 0.10, respectively; P = 0.029)., Conclusions: Higher MedDiet scores at baseline were associated with healthier lifestyles and lower adiposity. After the intervention, MedDiet scores were greater in individuals randomly assigned to receive PN than in controls, with the addition of DNA-based dietary advice resulting in the largest differences in MedDiet scores. Although differences were significant, their clinical relevance is modest. This trial was registered at clinicaltrials.gov as NCT01530139., (© 2016 American Society for Nutrition.)

Background: Accurate dietary assessment is key to understanding nutrition-related outcomes and is essential for estimating dietary change in nutrition-based interventions., Objective: The objective of this study was to assess the pan-European reproducibility of the Food4Me food-frequency questionnaire (FFQ) in assessing the habitual diet of adults., Methods: Participants from the Food4Me study, a 6-mo, Internet-based, randomized controlled trial of personalized nutrition conducted in the United Kingdom, Ireland, Spain, Netherlands, Germany, Greece, and Poland, were included. Screening and baseline data (both collected before commencement of the intervention) were used in the present analyses, and participants were included only if they completed FFQs at screening and at baseline within a 1-mo timeframe before the commencement of the intervention. Sociodemographic (e.g., sex and country) and lifestyle [e.g., body mass index (BMI, in kg/m(2)) and physical activity] characteristics were collected. Linear regression, correlation coefficients, concordance (percentage) in quartile classification, and Bland-Altman plots for daily intakes were used to assess reproducibility., Results: In total, 567 participants (59% female), with a mean ± SD age of 38.7 ± 13.4 y and BMI of 25.4 ± 4.8, completed both FFQs within 1 mo (mean ± SD: 19.2 ± 6.2 d). Exact plus adjacent classification of total energy intake in participants was highest in Ireland (94%) and lowest in Poland (81%). Spearman correlation coefficients (ρ) in total energy intake between FFQs ranged from 0.50 for obese participants to 0.68 and 0.60 in normal-weight and overweight participants, respectively. Bland-Altman plots showed a mean difference between FFQs of 210 kcal/d, with the agreement deteriorating as energy intakes increased. There was little variation in reproducibility of total energy intakes between sex and age groups., Conclusions: The online Food4Me FFQ was shown to be reproducible across 7 European countries when administered within a 1-mo period to a large number of participants. The results support the utility of the online Food4Me FFQ as a reproducible tool across multiple European populations. This trial was registered at clinicaltrials.gov as NCT01530139., (© 2016 American Society for Nutrition.)

Background & Aims: The aim of this study is to further clarify the role of plasma 25(OH)D concentration after a weight-lowering nutritional intervention on body composition, blood pressure and inflammatory biomarkers in overweight/obese middle-aged subjects., Methods: This longitudinal research encompassed a total of 50 subjects [57.26 (5.24) year], who were under a 15% energy restricted diet for 4 weeks. Anthropometric and body composition variables, blood routine, inflammatory markers as well as 25(OH)D were analysed., Results: Circulating 25(OH)D levels [12.13(±17.61%)] increased while anthropometric, body composition, routine blood markers as well as the concentration of TNF-α, C-reactive protein and Lp-PLA2 were significantly reduced after the intervention. Multiple linear regression analyses evidenced that Δ25(OH)D increase was linked to the decrease in weight, adiposity, SBP and IL-6 levels. Moreover, a relationship was found between Δ25(OH)D, Δfat mass (r = -0.405; p = 0.007), ΔSBP (r = -0.355; p = 0.021) and ΔIL-6 (r = -0.386; p = 0.014). On the other hand, a higher increase in 25(OH)D was accompanied by reductions in weight, BMI, SBP, IL-6 and an increase in bone mineral concentration (p < 0.05). Interestingly, higher levels of 25(OH)D at the endpoint, showed a significantly higher decrease in weight, BMI and total fat mass., Conclusions: The increase in plasma 25(OH)D level is linked with the decrease in SBP and adiposity in middle-aged subjects after a weight-loss intervention. Therefore, 25(OH)D assessment is a potential marker to be accounted in metabolic measures related to blood pressure, adiposity and inflammation in obesity management., Trial Registration: www.clinicaltrials.gov (NCT01596309)., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background and Aims: Cocoa flavanols are recognised by their favourable antioxidant and vascular effects. This study investigates the influence on health of the daily consumption of ready-to-eat meals supplemented with cocoa extract within a hypocaloric diet, on middle-aged overweight/obese subjects., Methods and Results: Fifty healthy male and female middle-aged volunteers [57.26 ± 5.24 years and body mass index (BMI) 30.59 ± 2.33 kg/m(2)] were recruited to participate in a 4 week randomised, parallel and double-blind study. After following 3 days on a low-polyphenol diet, 25 volunteers received meals supplemented with 1.4 g of cocoa extract (645.3 mg of polyphenols) and the other 25 participants received control meals, within a 15% energy restriction diet. On the 4th week of intervention individuals in both dietary groups improved (p < 0.05) anthropometric, body composition, blood pressure and blood biochemical measurements. Oxidised LDL cholesterol (oxLDL), showed a higher reduction (p = 0.030) in the cocoa group. Moreover, myeloperoxidase (MPO) levels decreased only in the cocoa supplemented group (p = 0.007). Intercellular Adhesion Molecule-1 (sICAM-1) decreased significantly in both groups, while Vascular Cell Adhesion Molecule-1 (sVCAM-1) did not present differences after the 4 weeks of intervention. Interestingly, cocoa intake showed a different effect by gender, presenting more beneficial effects in men., Conclusions: The consumption of cocoa extract as part of ready-to-eat meals and within a hypocaloric diet improved oxidative status (oxLDL) in middle-aged subjects, being most remarkable in males., Registration Number: Registered at www.clinicaltrials.gov (NCT01596309)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cellular microRNAs (miRNAs) are an important class of small, non-coding RNAs that bind to host mRNAs based on sequence complementarity and regulate protein expression. They play important roles in controlling key cellular processes including cellular inception, differentiation and death. While several viruses have been shown to encode for viral miRNAs, controversy persists over the expression of a functional miRNA encoded in the human immunodeficiency virus type 1 (HIV-1) genome. However, it has been reported that HIV-1 infectivity is influenced by cellular miRNAs. Either through directly targeting the viral genome or by targeting host cellular proteins required for successful virus replication, multiple cellular miRNAs seem to modulate HIV-1 infection and replication. Perhaps as a survival strategy, HIV-1 may modulate proteins in the miRNA biogenesis pathway to subvert miRNA-induced antiviral effects. Global expression profiles of cellular miRNAs have also identified alterations of specific miRNAs post-HIV-1 infection both in vitro and in vivo (in various infected patient cohorts), suggesting potential roles for miRNAs in pathogenesis and disease progression. However, little attention has been devoted in understanding the roles played by these miRNAs at a cellular level. In this manuscript, we review past and current findings pertaining to the field of miRNA and HIV-1 interplay. In addition, we suggest strategies to exploit miRNAs therapeutically for curbing HIV-1 infectivity, replication and latency since they hold an untapped potential that deserves further investigation., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effects of amantadine (1-5 microM) and interferon alpha (IFNalpha)-2a alone (1000 IU/ml) and combined, have been studied in cultured peripheral blood mononuclear cells (PBMC) from 15 chronic hepatitis C patients and ten healthy donors. Amantadine itself did not affect cell viability and had minor effects on the response to mitogens by PBMC. Four patients (27%), but no donors, had hepatitis C virus (HCV) core and NS3-specific proliferative responses. Amantadine suppressed these responses in all cases and its antiproliferative effect was greater than that of IFNalpha (Mann-Whitney's U-test: P < 0.05 in both cases). All PBMC cultures from patients, but none from donors, were HCV RNA positive. Amantadine alone or combined with IFNalpha dose-dependently reduced HCV RNA content in individual PBMC (Wilcoxon's signed rank test: 1 microM, P < 0.05; 2 microM, P < 0.02; and 5 microM, P = 0.16) with respect to untreated cultures. In addition, 7, 13 and 20% of PBMC cultures became HCV RNA negative with 2 microM amantadine alone, IFNalpha alone and their combination, respectively. Finally, in contrast to IFNalpha, amantadine did not modify expression of 2',5'-oligoadenylate synthetase activity or the spontaneous or mitogen-stimulated IFNgamma and interleukin 10 production. In conclusion, these effects in PBMC from HCV patients suggest that the amantadine/IFNalpha combination might be considered a therapeutic option for treating chronic hepatitis C patients.

At present, routine screening for hepatitis C virus (HCV) infection is based on the detection of antiviral antibodies. Underdiagnosis of HCV infection by using HCV antibody tests, however, still occurs. Additional diagnostic means are provided by the polymerase chain reaction (PCR). The measurement of aminotransferase (ASAT and ALAT) has served as an auxiliary, less specific test. The present research aimed to design practical and low cost strategies to diminish underdiagnosis of HCV infection in dialysis patients. With this purpose in mind, we examined whether aminotransferases values in HCV antibody-negative patients could be related to undiagnosed HCV infection, by using HCV RNA testing by PCR as the gold standard. In 112 hemodialysis patients, we found 78 negative and 34 positive for HCV antibodies. A major finding was that 222 (28.2%) out of the 78 HCV antibodies-negative patients had positive HCV RNA by PCR. In repeated samples taken at six months follow-up from 19 out of these 22 patients, only one of them was positive for anti-HCV antibodies; moreover, a positive HCV RNA by PCR was confirmed in 13 (68.5%) of them. Within the HCV antibody-negative group, the mean values of ASAT, ALAT and gammaglutamiltransferase were higher (P < 0.001, P < 0.001 and P < 0.02, respectively) in the HCV PCR-positive versus the HCV PCR-negative patients. No significant differences were found in the liver enzyme values between the HCV antibody-negative, HCV RNA positive and the HCV antibody positive, HCV RNA positive individuals. Histological samples from two HCV RNA positive, HCV antibody-negative patients disclosed the presence of a mild liver disease. In conclusion, the present study demonstrates the critical importance of HCV RNA determination by PCR in hemodialysis patients who have no detectable circulating antibodies against the HCV. Furthermore, in conditions in which PCR technology is not readily available, we have established that the existence of a moderate increase of aminotransferases is a helpful clue to detect patients with absent HCV antibodies, and might represent an useful, low cost tool for HCV screening in dialysis patients.

In this study, 42 hepatitis C virus (HCV)-infected patients included in different treatment protocols were assessed by semiquantitative Amplicor assay to evaluate the changes in HCV-RNA titer during antiviral therapy. Amplicor detected change to negative HCV-RNA at the end of treatment in four biochemically responding patients; a decrease in HCV-RNA titer from base line was observed in 2/6 complete responder patients, in 7/11 responders with relapse, and in 6/21 nonresponder patients. Furthermore, Amplicor also detected an increase in HCV-RNA titer from the end of treatment to the follow-up samples in 3/6 complete responder patients, in 7/11 responders with relapse, and in 3/6 nonresponder patients in whom HCV-RNA titer at the end of treatment was lower than in the basal sample. None of the nonresponder patients showed a change to negative HCV-RNA either at the end of treatment or at follow-up. When comparing the detection of HCV-RNA by this semiquantitative method and by nested-PCR, we found a concordance in 113/118 polymerase chain reaction (PCR) results (96%), including three negative results by both methods. With respect to the noncorrelated results, negative PCR samples were found to be positive by Amplicor assay in three cases (correspondent to final samples of treatment); by contrast, two positive PCR samples were found to be negative by Amplicor assay (correspondent to final and follow-up samples of different patients).

To investigate the replicative hepatitis C virus status and its relation to liver damage, serum, peripheral blood mononuclear cells and liver-paired samples from 45 untreated hepatitis C virus infected patients (38 with chronic hepatitis, three with minimal changes, and four with normal liver) were studied by nested polymerase chain reaction, using primers from the 5' untranslated region. Positive HCV-RNA strand was detected in serum (69%), peripheral blood mononuclear cells (100%) and liver samples (100%). The presence of negative HCV-RNA strand was confirmed using specificity controls assays and was only detected in liver and peripheral blood mononuclear cells samples, (95% and 82%, respectively). No correlation between the presence of negative HCV-RNA strand in peripheral blood mononuclear cells and positive HCV-RNA strand in serum was found, whereas serum HCV-RNA was not detected in patients without negative HCV-RNA strand in the liver. Both positive and negative HCV-RNA strands were found in liver and peripheral blood mononuclear cells of four patients with normal liver histology, and three with minimal changes. Furthermore, the presence of HCV-RNA in serum did not correlate with the alanine aminotransferase values and the histological activity index. These data confirm the existence of replicative intermediates in the liver, not only from patients with histologically proven chronic hepatitis, but also from those with normal liver, suggesting the existence of hepatitis C virus in true healthy carriers.

Hepatitis C virus (HCV) RNA is the most reliable marker of HCV infection. However, because of HCV genome heterogeneity and the procedures used to isolate the viral genome and to perform the amplification steps, results do not accurately reflect the actual rate of HCV infection. In this study, several isolation procedures and sets of primers to perform PCR were compared for the detection of HCV-RNA in serum and peripheral blood mononuclear cells (PBMC) of patients with HCV infection. It was found that the extraction with guanidinium isothiocyanate prior to cDNA synthesis followed by PCR amplification of the 5'-UTR region gave the best results in serum and PBMC. The presence of the viral genome in PBMC is a frequent event during HCV infection and this has important consequences for the understanding of the viral pathogenesis.