Reduced availability of voltage-gated sodium channels by depolarization or blockade by tetrodotoxin boosts burst firing and catecholamine release in mouse chromaffin cells

KEY POINTS: Mouse chromaffin cells (MCCs) of the adrenal medulla possess fast-inactivating Nav channels whose availability alters spontaneous action potential firing patterns and the Ca2+ -dependent secretion of catecholamines. Here, we report MCCs expressing large densities of neuronal fast-inactivating Nav1.3 and Nav1.7 channels that carry little or no subthreshold pacemaker currents and can be slowly inactivated by 50% upon slight membrane depolarization. Reducing Nav1.3/Nav1.7 availability by tetrodotoxin or by sustained depolarization near rest leads to a switch from tonic to burst-firing patterns that give rise to elevated Ca2+ -influx and increased catecholamine release. Spontaneous burst firing is also evident in a small percentage of control MCCs. Our results establish that burst firing comprises an intrinsic firing mode of MCCs that boosts their output. This occurs particularly when Nav channel availability is reduced by sustained splanchnic nerve stimulation or prolonged cell depolarizations induced by acidosis, hyperkalaemia and increased muscarine levels. ABSTRACT: Action potential (AP) firing in mouse chromaffin cells (MCCs) is mainly sustained by Cav1.3 L-type channels that drive BK and SK currents and regulate the pacemaking cycle. As secretory units, CCs optimally recruit Ca2+ channels when stimulated, a process potentially dependent on the modulation of the AP waveform. Our previous work has shown that a critical determinant of AP shape is voltage-gated sodium channel (Nav) channel availability. Here, we studied the contribution of Nav channels to firing patterns and AP shapes at rest (-50 mV) and upon stimulation (-40 mV). Using quantitative RT-PCR and immunoblotting, we show that MCCs mainly express tetrodotoxin (TTX)-sensitive, fast-inactivating Nav1.3 and Nav1.7 channels that carry little or no Na+ current during slow ramp depolarizations. Time constants and the percentage of recovery from fast inactivation and slow entry into closed-state inactivation are similar to that of brain Nav1.3 and Nav1.7 channels. The fraction of available Nav channels is reduced by half after 10 mV depolarization from -50 to -40 mV. This leads to low amplitude spikes and a reduction in repolarizing K+ currents inverting the net current from outward to inward during the after-hyperpolarization. When Nav channel availability is reduced by up to 20% of total, either by TTX block or steady depolarization, a switch from tonic to burst firing is observed. The spontaneous occurrence of high frequency bursts is rare under control conditions (14% of cells) but leads to major Ca2+ -entry and increased catecholamine release. Thus, Nav1.3/Nav1.7 channel availability sets the AP shape, burst-firing initiation and regulates catecholamine secretion in MCCs. Nav channel inactivation becomes important during periods of high activity, mimicking stress responses

GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation

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

Surveillance de la vaccination COVID-19 dans les maisons de repos et maisons de repos et de soins belges. Résultats jusqu’au 24 mars 2021.

Les résidents et le personnel des maisons de repos et maisons de repos et de soins (MR/MRS) constituent le premier groupe prioritaire de la stratégie Belge de vaccination contre la COVID-19. La campagne de vaccination de ce groupe s’est déroulée du 28 Décembre 2020 au 24 Mars 2021. Au terme de celle-ci, sur base d’une surveillance à laquelle &gt; 85 % des MR/MRS belges ont participé, la couverture vaccinale atteinte chez les résidents des MR/MRS était très élevée dans l’ensemble de ces établissements, avec une moyenne nationale de 89,4 %. Les premiers signaux de l’impact bénéfique de cette vaccination massive sur l’épidémie du COVID-19 apparaissent, avec une diminution du nombre de clusters de cas confirmés en MR/MRS mais également du nombre d’hospitalisations et de décès parmi les résidents des MR/MRS belges. Les couvertures vaccinales atteintes chez les membres du personnel de MR/MRS sont par contre plus faibles. Elles étaient comprises entre 47 % et 65 % dans les MR/MRS dépendantes de Bruxelles, de la Communauté germanophone et de la Wallonie, et atteignaient 86,5 % dans les MR/MRS dépendantes de la Flandre à la date du 24 mars 2021. Des données collectées en Flandre et à Bruxelles montrent que la principale raison de non vaccination tant chez les membres du personnel que chez les résidents est un refus sans raison médicale. Ces résultats indiquent une hésitation vaccinale significative à examiner plus précisément dans le futur afin de comprendre les motivations exactes de ce refus. Après le 24 mars, le processus de vaccination se poursuit encore dans les MR/MRS mais à un niveau plus spécifique afin de garantir la vaccination des nouveaux résidents entrant en MR/MRS ainsi que la vaccination des membres du personnel qui la demanderaient après un premier&nbsp;refus.</p

The management of physical health for patients with psychotic disorders in primary care

Introduction Primary care can contribute to a qualitative and effective process of (somatic) care for patients with psychosis. The use of antipsychotics e.g. needs a conscientious follow up. The aim of this project was to explore how the guidelines concerning the follow up of cardiovascular and metabolic side effects of antipsychotic drugs are used in Flanders, how this process can be improved, how the somatic care for patients with psychosis is handled in general practice and what role psychiatrists, pharmacists and GPs play in this process. Methods 1. A mixed method was used combining personal interviews and postal questionnaires of general practitioners, community and hospital pharmacists and psychiatrists. 2. The NHS Lester UK adaptation guideline 2014 was adapted to the Flemish situation. Results In total 57 health care professionals were involved: 29 were interviewed (9 GPs, 7 psychiatrists, 11 pharmacists and 2 nurses) and 28 GPs answered the postal questionnaire. The adapted guideline is manageable in Flanders. The follow up of cardiometabolic parameters is a GPs task, supported by the psychiatrist and pharmacist and using evidence based guidelines. The knowledge and use of guidelines in all disciplines are very poor and suboptimal. Shared electronic medical records and structured interdisciplinary consultation are favourable. Discussion 1. The care for somatic problems in patients with psychosis is a GP task, to be supported by psychiatrists, pharmacists, evidence based guidelines, shared electronic data files and interdisciplinary concertation. 2. Guidelines are not well used, implemented and followed 3. The NHS Lester UK adaptation guideline 2014 was adapted to the Flemish situationstatus: publishe

COVID-19 Clusters in Belgian Nursing Homes: Impact of Facility Characteristics and Vaccination on Cluster Occurrence, Duration and Severity

COVID-19 severely affected nursing home residents from March 2020 onwards in Belgium. This study aimed to model the impact of vaccination and facility characteristics on cluster occurrence, duration and severity in this setting. Possible clusters were identified between June 2020 and January 2022, based on the Belgian COVID-19 surveillance in nursing homes. Median attack rates (AR) among residents and staff, case hospitalization rates (CHR) and case fatality rates (CFR) were calculated. A negative binomial model was used to identify the association between nursing home characteristics and the number of cases, hospital admissions and deaths and the duration of the cluster. A total of 2,239 clusters were detected in more than 80% of nursing homes. Most of these (62%) occurred before the start of COVID-19 vaccination (end of December 2020). After vaccination, the number of clusters, the AR among residents and staff, the CHR and the CFR dropped. Previous cluster(s) and vaccination decreased the number of cases, hospital admissions and deaths among residents. Previous cluster experience and having started vaccination were protective factors. We recommend continued implementation of targeted interventions such as vaccination, large-scale screening and immediate implementation of additional infection prevention and control&nbsp;measures.</p