The cerebellum is sensitive to ethanol (EtOH) consumption. Chronic EtOH consumption impairs motor learning by modulating the cerebellar circuitry synaptic transmission and long-term plasticity. Under in vitro conditions, acute EtOH inhibits both parallel fiber (PF) and climbing fiber (CF) long-term depression (LTD). However, thus far it has not been investigated how chronic EtOH consumption affects sensory stimulation-evoked LTD at the molecular layer interneurons (MLIs) to the Purkinje cell (PC) synapses (MLI-PC LTD) in the cerebellar cortex of living animals. In this study, we investigated the effect of chronic EtOH consumption on facial stimulation-evoked MLI-PC LTD, using an electrophysiological technique as well as pharmacological methods, in urethane-anesthetized mice. Our results showed that facial stimulation induced MLI–PC LTD in the control mice, but it could not be induced in mice with chronic EtOH consumption (0.8 g/kg; 28 days). Blocking the cannabinoid type 1 (CB1) receptor activity with AM-251, prevented MLI-PC LTD in the control mice, but revealed a nitric oxide (NO)-dependent long-term potentiation (LTP) of MLI–PC synaptic transmission (MLI-PC LTP) in the EtOH consumption mice. Notably, with the application of a NO donor, S-nitroso-N-Acetyl-D, L-penicillamine (SNAP) alone prevented the induction of MLI–PC LTD, but a mixture of SNAP and AM-251 revealed an MLI-PC LTP in control mice. In contrast, inhibiting NO synthase (NOS) revealed the facial stimulation-induced MLI-PC LTD in EtOH consumption mice. These results indicate that long-term EtOH consumption can impair the sensory stimulation-induced MLI–PC LTD via the activation of a NO signaling pathway in the cerebellar cortex in vivo in mice. Our results suggest that the chronic EtOH exposure causes a deficit in the cerebellar motor learning function and may be involved in the impaired MLI–PC GABAergic synaptic plasticity.

Background:Atrial fibrillation (AF) is the most common type of heart arrhythmia, but the impact of long-term, high-intensity endurance exercise on the risk of AF remains uncertain.Methods:PubMed, EMBASE, and Cochrane library databases were searched till Nov 2017 to retrieve the articles. The included studies were summarized, pooled odds ratio (OR) and its 95% confidence interval (CI) were calculated. Both fixed and random effects models were used to combine the data. Stratified and logistic meta-regression analyses were performed to explore the sources of heterogeneity across studies.Results:Nine studies including 2308 athletes and 6593 controls were eligible. Our results showed that the risk of AF was significantly higher in athletes than in general population (OR = 2.34, 95% CI = 1.04–5.28, Pheterogeneity<.001, I2 = 92.3%). Subgroup analysis based on gender and mean age demonstrated a significantly increased risk in men (OR = 4.03, 95% CI = 1.73–9.42, Pheterogeneity<.001, I2 = 82.7%) and participants with mean age <60 (OR = 3.24, 95% CI = 1.23–8.55, Pheterogeneity<.001, I2 = 84.3%). Furthermore, subgroup analysis based on type of athletes demonstrated a significantly increased risk of AF in participants with single type of sport (OR = 3.97, 95% CI = 1.16–13.62, Pheterogeneity = .018, I2 = 70.4%). Results remained unchanged after performing sensitivity analysis. Meta-regression showed that gender, age, type of study, sample size, and sports mode were unrelated to heterogeneity.Conclusion:Our study confirmed that the risk of AF was significantly higher in athletes than in general population, especially among men and participants aged <60.

Sensory information is transferred to the cerebellar cortex via the mossy fiber–granule cell (MF–GC) pathway, which participates in motor coordination and motor learning. We previously reported that chronic ethanol exposure from adolescence facilitated the sensory-evoked molecular layer interneuron–Purkinje cell synaptic transmission in adult mice in vivo. Herein, we investigated the effect of chronic ethanol exposure from adolescence on facial stimulation-evoked MF–GC synaptic transmission in the adult mouse cerebellar cortex using electrophysiological recording techniques and pharmacological methods. Chronic ethanol exposure from adolescence induced an enhancement of facial stimulation-evoked MF–GC synaptic transmission in the cerebellar cortex of adult mice. The application of an N-methyl-D-aspartate receptor (NMDAR) antagonist, D-APV (250 μM), induced stronger depression of facial stimulation-evoked MF–GC synaptic transmission in chronic ethanol-exposed mice compared with that in control mice. Chronic ethanol exposure-induced facilitation of facial stimulation evoked by MF–GC synaptic transmission was abolished by a selective GluN2A antagonist, PEAQX (10 μM), but was unaffected by the application of a selective GluN2B antagonist, TCN-237 (10 μM), or a type 1 metabotropic glutamate receptor blocker, JNJ16259685 (10 μM). These results indicate that chronic ethanol exposure from adolescence enhances facial stimulation-evoked MF–GC synaptic transmission via GluN2A, which suggests that chronic ethanol exposure from adolescence impairs the high-fidelity transmission capability of sensory information in the cerebellar cortex by enhancing the NMDAR-mediated components of MF–GC synaptic transmission in adult mice in vivo.

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Background and purposeData on the efficacy and safety of alteplase for acute ischaemic stroke (AIS) administered 3–4.5 hours after the onset of stroke symptoms in Chinese patients is limited. We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective, multicentre, single-arm trial in China.Materials and methodsEligible AIS patients were given 0.9 mg/kg alteplase intravenously. The primary efficacy endpoint was a favourable outcome at 3 months, defined as a score of 0 or 1 on the modified Rankin Scale. Thresholds for the primary efficacy endpoint were determined to be 40% based on the literature review. The primary safety endpoint was symptomatic intracranial haemorrhage (sICH) according to the European Cooperative Acute Stroke Study III (ECASS III) trial definition. Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching (PSM) method.ResultsA total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study. The median time from onset of symptoms to needle was 3 hours 54 min. The percentage of patients with a favourable outcome was 63.3% (95% CI 54.4 to 71.4), significantly higher than the predefined threshold (p<0.0001). Three patients (2.5%, 95% CI 0.5 to 7.1) had sICH, including two fatal sICH. Six patients died within 3 months after treatment. The post hoc PSM analysis showed a numerically higher rate of the primary efficacy endpoint in this study (63.3%) than the matched placebo arm (56.7%) in the ECASS III trial.ConclusionsIntravenous alteplase with a standard dose administered between 3 and 4.5 hours after onset of symptoms is effective and safe for Chinese AIS patients.Trial registration numberNCT02930837