Phase angle by electrical bioimpedance is a predictive factor of hospitalisation, falls and mortality in patients with cirrhosis

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements

The influence of genetic and environmental factors among MDMA users in cognitive performance

Abstract This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Comple

A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking

The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entryexit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. To deal with such complex system, we additionally formulate a multiscale asymptotic method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state, with ER driving transitions between these states. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation- refractory (stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validates the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer. © 2019 Folguera-Blasco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Zona Franca: Men-Par, S.A.

13 x 13 c

Plasticity in secondary sexual characteristics in male freshwater blennies (Salaria fluviatilis)

Alternative reproductive tactics (ARTs) driven by environmental factors are common among fish. However, the flexibility of fish to adopt distinct tactics in response to the characteristics of their environment has received little attention. The aim of the present work was to study phenotypic plasticity in the adoption of dominant behaviour ("bourgeois tactic") by male freshwater blennies (Salaria fluviatilis (Asso, 1801)). For this purpose, two simultaneous experiments in aquaria were performed to examine the effect of social cues and nest abundance on the acquisition of secondary sexual characteristics (SSCs). Experiments were conducted with small (individuals without SSCs), medium-sized (1-year-old individuals), and large older dominant males (more than 2 years old), all collected in the wild. In experiment 1, the three sizes of males were combined to compare the development of SSCs depending on intrasexual context. In experiment 2, the effect of nest abundance (two nests vs. six nests) was tested for each size of male. Medium-sized males showed phenotypic plasticity in response to the environmental conditions simulated in the two experiments. The absence of larger dominant males was found to be the main factor enhancing SSCs and the onset of parental behaviour. Nest shortage also influenced the degree of cephalic crest development among medium-sized males. This knowledge helps to understand how the population of freshwater blennies still persists when it is reduced to young individuals during the summer droughts in Mediterranean streams

Tumor cell-intrinsic immunometabolism and precision nutrition in cancer immunotherapy

One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune systems ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular-and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

In silico clinical trials for anti-aging therapies

Therapeutic strategies targeting the hallmarks of aging can be broadly grouped into four categories, namely systemic (blood) factors, metabolic manipulation (diet regimens and dietary restriction mimetics), suppression of cellular senescence (senolytics), and cellular reprogramming, which likely have common characteristics and mechanisms of action. In evaluating the potential synergism of combining such strategies, however, we should consider the possibility of constraining trade-off phenotypes such as impairment in wound healing and immune response, tissue dysfunction and tumorigenesis. Moreover, we are rapidly learning that the benefit/risk ratio of aging-targeted interventions largely depends on intra- and inter-individual variations of susceptibility to the healthspan-, resilience-, and/or lifespan-promoting effects of the interventions. Here, we exemplify how computationally-generated proxies of the efficacy of a given lifespan/healthspan-promoting approach can predict the impact of baseline epigenetic heterogeneity on the positive outcomes of ketogenic diet and mTOR inhibition as single or combined anti-aging strategies. We therefore propose that stochastic biomathematical modeling and computational simulation platforms should be developed as in silico strategies to accelerate the performance of clinical trials targeting human aging, and to provide personalized approaches and robust biomarkers of healthy aging at the individual-to-population levels. © Menendez et al

CSR and Deregulation : Social Responsibility and Competitive Advantage

Bakgrund: Den statliga utredningen En framtida spelreglering presenterades under december 2008. Ett förslag i utredningen är att delar av monopolet på den svenska spelmarknaden i framtiden kan komma att konkurrensutsättas. Syfte: Denna studie syftar till att undersöka hur det sociala ansvarstagandet påverkas och i vilken omfattning CSR kan utgöra en konkurrensfördel på en avreglerad marknad. Genomförande: Vi har använt oss av en kvalitativ undersökningsmetod där Svenska Spel, Ladbrokes och Betssons CSR - arbete studeras. Utöver sekundärdata har det empiriska materialet kompletterats genom intervjuer med varje företag. Resultat: En avreglerad marknad behöver inte innebära att företagens sociala ansvarstagande minskar i samhället. Att integrera CSR i företagsstrategin är ett viktigt led i att nå acceptans bland intressenterna på marknaden. För ett lyckat CSR – arbete menar vi att företagens interna resurser måste användas med hänsyn till flertalet faktorer i den omgivande miljön.Background: During the end of 2008 the Swedish government published a submission for comment regarding the future legislation of the Swedish gambling industry. The investigation suggests that new entrants may be allowed to enter the Swedish market. Aim: The purpose of this thesis is to determine if and how the social responsibility is affected when a market is deregulated, and if CSR is a possible tool for creating competitive advantage. Completion: The study is based on a qualitative method and examines the gambling companies Svenska Spel, Ladbrokes and Betsson. We conducted questionnaire studies among the examined gambling companies to enhance the secondary data. Findings: Our findings suggest that there is a good possibility for social responsibility to maintain a strong position in a deregulated market. CSR integration with the corporate strategy is an important step concerning acceptance among the company’s stakeholders