Effect of Lifestyle Intervention in the Concentration of Adipoquines and Branched Chain Amino Acids in Subjects with High Risk of Developing Type 2 Diabetes: Feel4Diabetes Study

Introduction: The global prevalence of type 2 diabetes (T2D) is increasing rapidly, especially in low- and middle-income countries and has a high number of associated comorbidities. Plasmatic concentrations of branched chain amino acids (BCAA) and retinol-binding protein 4 (RBP4) have been shown to be elevated in T2D subjects in cross-sectional studies. However, the effect of lifestyle community-based interventions on BCAA and RBP4 concentrations has not yet been analyzed. Material and methods: The Feel4Diabetes study is a school and community-based intervention that identified 360 European families with a high risk of developing T2D according to the FINDRISC questionnaire. Families were randomized in control and intervention groups were followed-up from 2016 to 2018. In the Spanish families, the concentration of BCAA and RBP4 was determined in 266 subjects (115 control and 151 intervention group) that attended the three time-point assessments by colorimetric and ELISA reaction, respectively. Results: Baseline BCAA levels showed positive correlations with the FINDRISC score and glucose impairment (baseline glucose, insulin, and glycated hemoglobin), body mass index, and body weight. The participants receiving the community-based intervention showed a significant decrease in glycated hemoglobin and BCAA levels compared to the control group (p = 0.011 and p < 0.001, respectively). However, baseline RBP4 did not show significant correlations with anthropometric and glycemic parameters, and no significant change was observed in anthropometric parameters and RBP4 concentrations throughout the follow-up. Conclusion: A community-based intervention on lifestyle led to a significant reduction in BCAA levels regardless of weight loss. These findings suggest that this interventional approach could be promising in T2D prevention

Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions

Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Background: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption. Objectives: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD. Methods: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries. Results: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P &lt; 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P &lt; 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P &lt; 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P &lt; 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78). Conclusions: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD

A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders

Effectiveness of rotavirus vaccination in Spain

With the aim of determining rotavirus vaccine effectiveness (RVVE) in Spain, from Oct-2008/Jun-2009, 467 consecutive children below 2 years old with acute gastroenteritis (AGE) were recruited using a pediatric research network (ReGALIP-www.regalip.org) that includes primary, emergency and hospital care settings. Of 467 enrolled children, 32.3% were rotavirus positive and 35.0% had received at least one dose of any rotavirus vaccine. RRVE to prevent any episode of rotavirus AGE was 91.5% (95% CI: 83.7%-95.6%). RVVE to prevent hospitalization by rotavirus AGE was 95.6% (85.6-98.6%). No differences in RVVE were found regarding the vaccine used. Rotavirus vaccines have showed an outstanding effectiveness in Spain

Measuring Incineration Plants' Performance using Combined Data Envelopment Analysis, Goal Programming and Mixed Integer Linear Programming

Incineration plants produce heat and power from waste, reduce waste disposal to landfills, and discharge harmful emissions and bottom ash. The objective of the incineration plant is to maximize desirable outputs (heat and power) and minimize undesirable outputs (emissions and bottom ash). Therefore, studying the overall impact of incineration plants in a region so as to maximize the benefits and minimize the environmental impact is significant. Majority of prior works focus on plant specific decision making issues including performance analysis. This study proposes a hybrid Data Envelopment Analysis (DEA), Goal Programming (GP) and Mixed Integer Linear Programming (MILP) model to assess the performance of incineration plants, in a specific region, to enhance overall power production, consumption of waste and reduction of emissions. This model not only helps the plant operators to evaluate the effectiveness of incineration but also facilitates the policy makers to plan for overall waste management of the region through decision-making on adding and closing plants on the basis of their efficiency. Majority of prior studies on incineration plants emphasize on how to improve their performance on heat and power production and neglect the waste management aspects. Additionally, optimizing benefits and minimizing negative outputs through fixing targets in order to make decision on shutting down the suboptimal plants has not been modeled in prior research. This research combines both the aspects and addresses the overall performance enhancement of incineration plants within a region from both policy makers and plant operators’ perspectives. The proposed combined DEA, GP and MILP model enables to optimize incineration plants performance within a region by deriving efficiency of each plant and identifying plants to close down on the basis of their performance. The proposed model has been applied to a group of 22 incineration plants in the UK using secondary data in order to demonstrate the effectiveness of the model.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain

Introduction: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufcient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of fnancial support and limited research infrastructure in our hospitals. Methods: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difculties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. Results: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. Conclusions: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30