Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence

It has previously been shown that the inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol-dependent rats during protracted abstinence and naive controls using in situ hybridization and western blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca2+/calmodulin-dependent protein kinase parallel to alpha (CaMKII alpha)-expressing neurons. Our results show that Cacna1c mRNA concentration was increased in the amygdala and hippocampus of alcohol-dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein concentration and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA), and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. The inhibition of central LTCCs via i. c. v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new antirelapse medications

Antimicrobial use in European acute care hospitals: results from the second point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use, 2016 to 2017

Antimicrobial agents used to treat infections are life-saving. Overuse may result in more frequent adverse effects and emergence of multidrug-resistant microorganisms. In 2016-17, we performed the second point-prevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals. We included 1,209 hospitals and 310,755 patients in 28 of 31 European Union/European Economic Area (EU/EEA) countries. The weighted prevalence of antimicrobial use in the EU/EEA was 30.5% (95% CI: 29.2-31.9%). The most common indication for prescribing antimicrobials was treatment of a community-acquired infection, followed by treatment of HAI and surgical prophylaxis. Over half (54.2%) of antimicrobials for surgical prophylaxis were prescribed for more than 1 day. The most common infections treated by antimicrobials were respiratory tract infections and the most commonly prescribed antimicrobial agents were penicillins with beta-lactamase inhibitors. There was wide variation of patients on antimicrobials, in the selection of antimicrobial agents and in antimicrobial stewardship resources and activities across the participating countries. The results of the PPS provide detailed information on antimicrobial use in European acute care hospitals, enable comparisons between countries and hospitals, and highlight key areas for national and European action that will support efforts towards prudent use of antimicrobials

Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases

We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment

Multi-agent modeling and analysis of EV users’ travel willingness based on an integrated causal/statistical/behavioral model

An electric vehicle (EV) centred ecosystem has not yet been formed, the existing limited statistic data are far from enough for the analysis of EV users’ travel and charge behaviors, which however tends to be affected by many certain and uncertain factors. An experimental economics (EE) based simulation method can be used to analyze the behaviors of key participants in a system. However, it is restricted by the system size, experimental site and the number of qualified human participants. Therefore, this method is hard to be adopted for the behavioral analysis of a large number of human participants. In this paper, a new method combining a questionnaire statistics and the EE-based simulation is proposed. The causal relationship is considered in the design of the questionnaires and data extraction, then a multi-agent modeling integration method is introduced in the EE-based simulation, which enables the integration of causal/statistical/behavioral models into the multi-agent framework to reflect the EV users’ travel willingness statistically. The generated multi-agents are used to replace human participants in the EE-based simulation in order to evaluate EV users’ travel demands in different scenarios, and compare the differences of simulated or measured travel behaviors between potential EV users and internal combustion engine (ICE) vehicle users

Understanding collaborative interactions in relation to research impact in social sciences and humanities:A meta-ethnography

The number and type of collaborations between researchers and stakeholders has increased significantly. This responds to the demand from policymakers, funders, and citizens that researchers should help to tackle important social issues (e.g. climate change, healthy aging). However, there is little knowledge about how collaboration processes are experienced, how we can theoretically conceptualize them, and how in this way we can develop efficient collaboration methods that contribute to solving urgent societal problems. In this meta-ethnography, we gathered relevant knowledge from carefully selected qualitative studies. A title/abstract analysis of 3422 articles from Web of Science and ProQuest led to the interpretative analysis of qualitative data from eight publications. The results of this study show that despite the need for a better understanding of complex collaborative interactions, the differences (or asymmetry) between organizations to which various partners belong hinder efficient collaboration. Bridging figures (brokers) can play an essential role if they succeed in drawing diverse stakeholders out of their organizational context into a new dimension that allows creativity and mutual understanding, but that also allows conflict and distortion. In ideal circumstances, this leads to a quasi-automatic transfer of knowledge between partners that takes place naturally and in both directions (knowledge diffusion)

Generalization of pain-related fear based on conceptual knowledge

Increasing evidence suggests that pain-related fear is key to the transition from acute to chronic pain. Previous research has shown that perceptual similarity with a pain-associated movement fosters the generalization of fear to novel movements. Perceptual generalization of pain-related fear is adaptive as it enables individuals to extrapolate the threat value of one movement to another without the necessity to learn anew. However, excessive spreading of fear to safe movements may become maladaptive and may lead to sustained anxiety, dysfunctional avoidance behaviors, and severe disability. A hallmark of human cognition is the ability to extract conceptual knowledge from a learning episode as well. Although this conceptual pathway may be important to understand fear generalization in chronic pain, research on this topic is lacking. We investigated acquisition and generalization of concept-based pain-related fear. During acquisition, unique exemplars of one action category (CS+; e.g., opening boxes) were followed by pain, whereas exemplars of another action category (CS-; e.g., closing boxes) were not. Subsequently, spreading of pain-related fear to novel exemplars of both action categories was tested. Participants learned to expect the pain to occur and reported more pain-related fear to the exemplars of the CS+ category compared with those of the CS- category. During generalization, fear and expectancy generalized to novel exemplars of the CS+ category, but not to the CS- category. This pattern was not corroborated in the eyeblink startle measures. This is the first study that demonstrates that pain-related fear can be acquired and generalized based on conceptual knowledge.. Published by Elsevier Ltd

Stability Effects Associated With the Introduction of a Partial and a Complete Ca2+-binding Site Into Human Lysozyme

Two mutants of human lysozyme were synthesized. Mutant A92D, in which Ala92 was substituted by Asp, contains a partial Ca2+-binding site and mutant M4, in which Ala83, Gln86, Asn88 and Ala92 were replaced by Lys, Asp, Asp and Asp respectively, contains the complete Ca2+-binding site of bovine alpha-lactalbumin. The Ca2+-binding constants of wild type human lysozyme and of mutants A92D and M4, measured at 25-degrees-C and pH 7.5, were 2(+/- 1) x 10(2) M-1, 8(+/- 2) x 10(3) M-1 and 9(+/- 0.5) X 10(6) M-1 respectively. Information gathered from microcalorimetric and CD spectroscopic measurements indicates that the conformational changes of the M4 mutant lysozyme, induced by Ca2+ binding, are smaller than those observed for bovine alpha-lactalbumin and for the Ca2+-binding equine lysozyme. At pH 4.5, the thermostability of both the apo and Ca2+ forms of the A92D human was decreased in comparison with that of native human lysozyme. In particular, within the apo form of this mutant an alpha-helix-containing sequence was destabilized. In contrast, at the same pH the thermostability of the apo and Ca2+ forms of the M4 mutant lysozyme was increased. The epsilon-ammonium group of the Lys83 side chain is assumed to be responsible for the stabilization of the apo form of this mutant

Antibiotic use and resistance in Belgium: the impact of two decades of multi-faceted campaigning.

: To present an overview of almost two decades of multi-faceted campaigning by the Belgian Antibiotic Policy Coordination Committee (BAPCOC) and partners, and its impact on public and prescribers’ awareness, outpatient antibiotic use, its cost and antimicrobial resistance in Belgium.: Awareness of both public and prescribers was assessed through pre- and post-campaign interviews and surveys. Outpatient antibiotic use was evaluated using national reimbursement data expressed in number of defined daily doses and packages (a good proxy for treatments) per 1000 inhabitants per day (DID and PID, respectively) from July 1997 to June 2018. Its cost was studied using the same data expressed in number of euros per 1000 inhabitants per day. Antimicrobial resistance was evaluated between 1986 and 2017 using national data on the proportion of Streptococcus pneumoniae isolates not susceptible to penicillins, macrolides and tetracyclines.: Antibiotic awareness improved significantly, with general practitioners preferred by 87.5% of respondents as source of information. The Belgian outpatient antibiotic use has decreased by 12.8% in DID and by 42.8% in PID in the 2017-2018 winter compared to the winter before the start of its public awareness campaigns (1999-2000). This evolution coincided with decreasing costs for antibiotics and decreasing antimicrobial resistance. Despite multi-faceted campaigning, outpatient antibiotic use and use of broad-spectrum antibiotics, especially fluoroquinolones and amoxicillin with clavulanic acid, are still high in Belgium.: Almost two decades of multi-faceted campaigning coincide with improvements in antibiotic awareness among the public and prescribers, outpatient antibiotic use and resistance. Nevertheless, additional efforts are needed to reach the targets set in BAPCOC’s national action plan 2014-2019. Therefore, a new national action plan was developed for 2020-2024 using a One Health&nbsp;approach.</p

Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: Emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking

AbstractVoltage-gated Ca2+ channels (VGCCs) are voltage sensors that convert membrane depolarizations into Ca2+ signals. In the chromaffin cells of the adrenal medulla, the Ca2+ signals driven by VGCCs regulate catecholamine secretion, vesicle retrievals, action potential shape and firing frequency. Among the VGCC-types expressed in these cells (N-, L-, P/Q-, R- and T-types), the two L-type isoforms, Cav1.2 and Cav1.3, control key activities due to their particular activation–inactivation gating and high-density of expression in rodents and humans. The two isoforms are also effectively modulated by G protein-coupled receptor pathways delimited in membrane micro-domains and by the cAMP/PKA and NO/cGMP/PKG phosphorylation pathways which induce prominent Ca2+ current changes if opposingly regulated. The two L-type isoforms shape the action potential and directly participate to vesicle exocytosis and endocytosis. The low-threshold of activation and slow rate of inactivation of Cav1.3 confer to this channel the unique property of carrying sufficient inward current at subthreshold potentials able to activate BK and SK channels which set the resting potential, the action potential shape, the cell firing mode and the degree of spike frequency adaptation during spontaneous firing or sustained depolarizations. These properties help chromaffin cells to optimally adapt when switching from normal to stress-mimicking conditions. Here, we will review past and recent findings on cAMP- and cGMP-mediated modulations of Cav1.2 and Cav1.3 and the role that these channels play in the control of chromaffin cell firing. This article is part of a Special Issue entitled: Calcium channels