Autophagy, which targets cellular constituents for degradation, is normally inhibited in metabolically replete cells by the metabolic checkpoint kinase mTOR. Although autophagic degradation of invasive bacteria has emerged as a critical host defense mechanism, the signals that induce autophagy upon bacterial infection remain unclear. We find that infection of epithelial cells with Shigella and Salmonella triggers acute intracellular amino acid (AA) starvation due to host membrane damage. Pathogen-induced AA starvation caused downregulation of mTOR activity, resulting in the induction of autophagy. In Salmonella-infected cells, membrane integrity and cytosolic AA levels rapidly normalized, favoring mTOR reactivation at the surface of the Salmonella-containing vacuole and bacterial escape from autophagy. In addition, bacteria-induced AA starvation activated the GCN2 kinase, eukaryotic initiation factor 2α, and the transcription factor ATF3-dependent integrated stress response and transcriptional reprogramming. Thus, AA starvation induced by bacterial pathogens is sensed by the host to trigger protective innate immune and stress responses.

Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced autophagic flux and phosphatidylinositol 3-phosphate (PI3P) levels, causing pre-autophagosomal structure stalling and preventing efficient targeting of cytosolic bacteria. In co-infection experiments, wild-type Listeria protected PlcA/B-deficient bacteria from autophagy-mediated clearance. Thus, our results uncover a critical role for Listeria phospholipases C in the inhibition of autophagic flux, favouring bacterial escape from host autophagic defense.

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Background:Tic disorders (TD) are common neuropsychiatric disorders among children and adolescents. Still, there is great uncertainty regarding their epidemiology in China. We aim to depict the prevalence of TD for children in China and explore the influence of sex, age, geographic distribution, and diagnostic criteria on the prevalence rates.Methods:We searched PubMed, EMBASE, four Chinese electronic databases, and relevant lists. Two reviewers independently selected trials, assessed trial quality, and extracted the data.Results:We included 13 studies investigating 269,571 participants. The sample size ranged from 563 to 216,005 participants. The age of participants ranged from 3 to 16 years. The meta-analysis of the prevalence of TD was 6.1% [95% CI: 0.036–0.100, I2 = 49.7%]. The prevalence of transient tic disorder (TTD), chronic tic disorder (CTD), and Tourette syndrome (TS) was 1.7% [95% CI = 0.009–0.031, I2 = 49%], 1.2% [95% CI = 0.007–0.022, I2 = 48.3%], and 0.3% [95% CI = 0.001–0.008, I2 = 49.5%], respectively. The prevalence of TD in boys [5.1%, 95% CI = 0.026–0.098, I2 = 49.3%] was higher than that in girls [2.4%, 95% CI = 0.009–0.065, I2 = 49.4%]. The prevalence of TD in urban area [2.6%, 95% CI = 0.019–0.034, I2 = 35.5%] was higher than that in rural area [2.2%, 95% CI = 0.016–0.030, I2 = 33.9%]. The prevalence of TD in central China [10.7%, 95% CI = 0.043–0.242, I2 = 49.2%] was higher than that in North China [7.8%, 95% CI = 0.007–0.522, I2 = 49.9%] and East China [4.4%, 95% CI = 0.015–0.120, I2 = 49.8%].Conclusion:TD is a common disease in China, with prevalence differing based on sex, age, and region.

Objective: Myoclonus was considered as one conundrum in etomidate induction, which led to multiple risks during clinical anesthesia. The present study was conducted to compare the efficacy of pretreatment with remifentanil to different pharmacological approaches on reducing etomidate-induced myoclonus. Methods: We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure from the inception to October 2018. Randomized controlled trials comparing remifentanil versus other pharmacological approaches in reducing etomidate-induced myoclonus were eligible to be analyzed. Results: Overall, 13 trials with 1,392 patients met with the inclusion criteria. 1) Pretreatment with remifentanil could reduce the incidence of etomidate-induced myoclonus compared to placebo and fentanyl; few differences were found between the use of remifentanil and the use of midazolam: (incidence of myoclonus: 5.56% with remifentanil vs 71.65% with saline, RR=0.08, with 95% CI [0.05, 0.12], P <0.0001; 3.80% with remifentanil vs 13.33% with fentanyl, RR with 95% 0.31 [0.11, 0.86], P =0.02; 46.00% with remifentanil vs 55.45% with midazolam, RR=0.82, with 95% CI [0.64, 1.06], P =0.13). 2) Compared with placebo, pretreatment with remifentanil could reduce the incidence of mild, moderate, and severe myoclonus; compared with midazolam, patients receiving remifentanil experienced lower occurrence of severe myoclonus; compared with fentanyl, pretreatment with remifentanil associated with significant low occurrence of moderate and severe myoclonus. 3) The outcomes also indicated that pretreatment with remifentanil could prevent excessive hemodynamic changes after endotracheal intubation compared to fentanyl. Conclusions: Pretreatment with remifentanil could be considered as one operative option to reduce both incidence and severity of etomidate-induced myoclonus. Compared with fentanyl, it also provides efficacy in preventing excessive hemodynamic changes after endotracheal intubation. However, the best treatment and the proper prophylactic dosage calls for more high quality evidence with large sample size.

ObjectiveOne conundrum that frequently occurs during clinical anesthesia is etomidate-induced myoclonus, which results in multiple risks. The aim of the study was to evaluate systematically the effect of pretreatment with lidocaine on preventing etomidate-induced myoclonus.Materials and methodsThe literature search was performed from the inception to April 2018 in PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure. All randomized controlled trials that used lidocaine to prevent etomidate-induced myoclonus were enrolled. The primary outcome included the incidence and severity of etomidate-induced myoclonus. The data were combined to calculate the risk ratio and relevant 95% CI. A meta-analysis was performed following the guidelines of the Cochrane Reviewer’s Handbook and the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement.ResultsA total of eight studies were enrolled, and the existing evidence indicated that 1) pretreatment with lidocaine can reduce the incidence of etomidate-induced myoclonus (the incidence of myoclonus: 37.6% in lidocaine vs 73.6% in saline, risk ratio =0.46, with 95% CI [0.34, 0.63], P<0.0001); 2) the pretreatment with lidocaine can reduce the incidence of mild, moderate, and severe myoclonus; 3) a dose of pretreatment with lidocaine cannot significantly decrease the duration of myoclonus compared to placebo; 4) the administration of lidocaine produced no effect on the stable hemodynamic parameters and no more additional adverse effects.ConclusionPretreatment with lidocaine could be served as one effective approach to decrease both the incidence and the severity of etomidate-induced myoclonus, with limited influence on the hemodynamic stability of patients. However, to confirm precise safety and efficacy of such intervention, more high-quality evidence is necessary.

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BackgroundTic disorders (TDs) are common neuropsychiatric disorders in children. Typical antipsychotics, such as haloperidol and pimozide have been prescribed to control tic symptoms as first-line agents. However, adverse effects have led to the use of newer atypical antipsychotics. Aripiprazole is one of alternatives. The aim of this study was to evaluate the efficacy and safety of aripiprazole for children with TDs.MethodsRandomized controlled trials (RCTs), quasi-RCTs and control studies evaluating aripiprazole for children with tic disorders were identified from PubMed, Embase, Cochrane library, Cochrane Central, four Chinese database and relevant reference lists. Quality assessment referred to the Cochrane Handbook for Systematic Reviews of Interventions.ResultsTwelve studies involving 935 participants were included. The general quality of included studies was poor. Only one study used placebo as a control and others used positive drug controls. Participants were aged between 4 and 18 years. The period of treatment ranged from 8 to 12 weeks. Seven studies (N = 600 patients) used the YGTSS scale as the outcome measurement, and there was no significant difference in reduction of the total YGTSS score between the aripiprazole and positive control groups (MD = −0.48, 95 % CI [−6.22, 5.26], P = 0.87, I2 = 87 %). Meta-analysis of four of the studies (N = 285 patients) that compared aripiprazole with haloperidol showed that there was no significant difference in reduction of the total YGTSS score (MD = 2.50, 95 % CI [−6.93, 11.92], P = 0.60, I2 = 88 %). Meta-analysis of two studies (N = 255 patients) that compared aripiprazole with tiapride showed that there was no significant difference in reduction of the total YGTSS score (MD = −3.15, 95 % CI [−11.38, 5.09], P = 0.45, I2 = 86 %). Adverse events (AEs) were reported in 11 studies. Drowsiness (5.1 %–58.1 %), increased appetite (3.2 %–25.8 %), nausea (2 %–18.8 %) and headache (2 %–16.1 %) were common AEs.ConclusionIn conclusion, aripiprazole appears to be a promising therapy for children with TDs. Further well-conducted RCTs are required to confirm this issue.