Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-dependent neuroprotective protein(ADNP),has been implicated in social and cognitive protection.However,the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood.In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice.The neuropathological basis was also explored using Golgi staining,morphological analysis,western blotting,electrophysiological analysis,and behavioral analysis.Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane.In adulthood,anterior cingulate cortex(ACC)neurons exposed to sevoflurane exhibited a decrease in dendrite number,total dendrite length,and spine density.Furthermore,the expression levels of Homer,PSD95,synaptophysin,and vglut2 were significantly reduced in the sevoflurane group.Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents(mEPSCs).Notably,davunetide significantly ameliorated the synaptic defects,social behavior deficits,and cognitive impairments induced by sevoflurane.Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca^(2+)activity via the Wnt/β-catenin signaling,resulting in decreased expression of synaptic proteins.Suppression of Wnt signaling was restored in the davunetide-treated group.Thus,ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics.This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

Long-term effect of clopidogrel in patients with and without diabetes: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND Previous studies have shown that patients with diabetes mellitus(DM) respond poorly to clopidogrel treatment.AIM To systematically evaluate the efficacy of clopidogrel for the treatment of acute coronary syndromes or ischemic stroke in patients with or without DM.METHODS Pub Med,the Cochrane Central Register of Controlled Trials,and EMBASE were searched from 1980 on 27 June 2019 to identify relevant randomized controlled trials that compared the effect of a combination of clopidogrel and aspirin with aspirin alone.A random-effects meta-analysis was used to estimate the hazard ratio(HR) and its 95% confidence interval(CI).Sensitivity analysis was performed using a fixed-effect model.The I2 statistic was used to evaluate the heterogeneity of the study data.RESULTS Six randomized controlled trials,comprising 43352 participants(13491 with and 29861 without DM) who had received antiplatelet therapy for≥3 mo,were included in the meta-analysis.Compared with aspirin alone,a combination of clopidogrel and aspirin significantly reduced the risk of any cardiovascular event in patients without DM(HR=0.78,95%CI:0.71–0.86,P<0.001;I2=23%,P=0.26).Clopidogrel plus aspirin also significantly reduced cardiovascular risk in patients with DM,although the effect was smaller(HR=0.89,95%CI:0.81–0.99,P=0.030;I2=0%,P=0.74).Nevertheless,there was no significant difference in the efficacy of clopidogrel at reducing the risk of cardiovascular events in patients with DM vs those without(P for interaction=0.062).CONCLUSION Thus,the present study shows that the addition of clopidogrel to aspirin significantly lowers cardiovascular risk in patients with or without DM who have experienced ischemic cardiovascular disease.The beneficial effect of the addition of clopidogrel to aspirin for patients with DM was lower than that in patients without DM,although the modifying effect of DM did not reach significance.

Role of R.E.N.A.L.Nephrometry Score in Laparoscopic Partial Nephrectomy

Background：Preoperative anatomical scoring system is conducive to comparison between treatment options and evaluation of postoperative outcomes in patients with small renal tumors.This study aimed to evaluate the clinical application efficacy of the R.E.N.A.L.nephrometry score （RNS） in predicting perioperative outcomes in patients with renal tumor who underwent laparoscopic partial nephrectomy （LPN）.Methods：The clinical data of 139 patients with renal tumors who underwent LPN between 2009 and 2015 were collected and analyzed.Patients were divided into three groups according to their RNS （low,moderate,and high）.Clinical characteristics including perioperative variables,complications,and RNS were compared to evaluate the differences between the three groups.Multivariable logistic regression analysis was used to analyze the risk factors of postoperative complications.Results：According to the RNS,there were 74,50,and 15 patients in the low,moderate,and high RNS groups,respectively.There were significant differences in estimated blood loss （EBL;χ^2 =7.285,P =0.026）,warm ischemia time （WIT;χ^2 =13.718,P =0.001）,operation time （OT;χ^2 =6.882,P =0.032）,perioperative creatinine clearance change （PCCC;χ^2 =6.206,P =0.045）,and number of patients with complications （NPC;P =0.002） among the three groups.The values for EBL,WIT,OT,PCCC,and NPC for patients in the high RNS group were higher than those for patients in the low RNS group.After adjustment for OT,WIT,and EBL,RNS was statistically significantly associated with the risk of postoperative complications in a multivariable logistic regression model （odds ratio =1.541,95% confidence interval：1.0592.242,P =0.024）.Conclusions：The RNS is a valuable tool for evaluating the complexity of renal tumor anatomy.It can aid surgeons in preoperative decision-making concerning management therapy.Future multicenter,large sample size studies are warranted for evaluating its predicting performance of perioperative outcomes.