OBJECTIVE To investigate the inhibitory effect and mechanism of lead(Pb2+)on γ-amino-butyric acid(GABA)A receptor-mediated currents(IGABA)and GABAergic synaptic transmission in rat cortical neurons.METHODS ①The cortical neurons from 0 d Sprague Dawley(SD)rats were cultured for experiments.The cultured cells(7-14 d)were recorded using the patch-clamp technique to analyze the effects of Pb2+ at different concentrations(1,5,10,50 and 100 μmol·L-1)on IGABA induced by GABA 100 μmol·L-1.② The effects of Pb2+ 50 μmol·L-1 on IGABA induced by GABA at different concentrations(1,10,50,100,500 and 100 μmol·L-1)were detected.③Brain slices(350 μm)were prepared from SD rats(15-19 d).The spontaneous inhibitory post-synaptic currents(sIPSCs),miniature inhibitory post-synaptic currents(mIPSCs)and current injection-induced action potential(AP)were recorded to detect the effects of Pb2+ 10 μmol·L-1 on the amplitude and frequency of sIPSCs and mIPSCs,and the frequency of AP.RESULTS ①Pb2+ inhibited IGABA in a concentration-dependent manner,and IC50 was(68±20)μmol·L-1.②Pb2+ also suppressed the maximum current induced by GABA(P<0.01),with a significant increase of the GABA′s EC50 from(20±6)μmol·L-1 to(87±39)μmol·L-1,indicating that Pb2+ might inhibit IGABA in a non-competitive mechanism.③Pb2+ 10 μmol·L-1 inhibited the frequency(P<0.01)rather than the ampli-tude of sIPSCs reversibly,but had no effect on eigher the frequency or amplitude of mIPSCs.In addi-tion,Pb2+ decreased the frequency of evoked AP by current injection(P<0.01)and reduced the overall excitability of rat cortical neurons.CONCLUSION Pb2+ can significantly inhibit IGABA in primary cultured neurons.In the brain slice experiment,Pb2+ may affect sIPSCs frequency by inhibiting the AP of cortical neurons,suggesting that there are different intrinsic mechanisms through which Pb2+ inhibits both IGABA in primary cultured neurons and the frequency of sIPSCs in brain slice neurons,which points to the complexity of the mechanism of Pb2+ poisoning.

Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Objective:To investigate the perioperative impact of closure of mesenteric fissure in laparoscopic right hemicolectomy.Methods:The prospective randomized controlled trial was conducted. The clinical data of 320 patients who underwent laparoscopic right hemicolectomy in 11 medical centers, including The First Affiliated Hospital of China Medical University et al, from November 2022 to August 2023 were selected. Based on block randomization, patients were alloca-ted into the mesenteric fissure non-closure group and the mesenteric fissure closure group. Observa-tion indicators: (1) grouping of the enrolled patients; (2) intraoperative conditions; (3) postopera-tive conditions. Measurement data with skewed distribution were represented as M( Q1, Q3) and com-parison between groups was conducted using the Mann-Whitney U test. Count data were represen-ted as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher's exact probability. Comparison of ordinal data was conducted using the rank sum test. Comparison of visual analog scores was analyzed using generalized estimating equations. Results:(1) Grouping of the enrolled patients. A total of 320 patients with colon cancer were screened for eligibility, including 156 males and 164 females, aged 68(59,73)years. All the 320 patients were allocated into the mesenteric fissure non-closure group with 164 cases and the mesenteric fissure closure group with 156 cases. There was no significant difference in the age, body mass index, American Society of Anesthesiologist score, maximum tumor diameter, anastomosis location, anastomosis method, surgical approach, range of lymph node dissection, tumor staging between the two groups ( P>0.05) and there was a significant difference in the sex between them ( P<0.05). (2) Intraoperative conditions. There was no significant difference between the mesenteric fissure closure group and the mesenteric fissure non-closure group in the volume of intraoperative blood loss, operation time, conversion to laparotomy, intraoperative complication ( P>0.05). Three patients in the mesenteric fissure non-closure group were converted to laparotomy. One patient in the mesenteric fissure closure group was converted to laparotomy, and 2 cases with intraoperative complication were mesenteric hematoma. (3) Postoperative conditions. There was no significant difference between the mesenteric fissure non-closure group and the mesenteric fissure closure group in the overall postoperative complications ( χ2=0.28, P>0.05). There was no significant difference in the occurrence of postoperative intestinal obstruction, abdominal distension, ascites, pleural effusion, gastric paralysis, anastomotic bleeding, anastomotic leakage, or surgical wound infection between the two groups ( P>0.05). There was no significant difference between the two groups in the reoperation, postoperative gastric tube replacement. There was no significant differ-ence in time to postoperative first flatus, time to postoperative initial liquid food intake, time to post-operative resumption of bowel movements, duration of postoperative hospital stay, total hospital expenses between the two groups ( Z=-0.01, 0.43, 1.04, -0.54, -0.36, P>0.05). One patient in the mesenteric fissure non-closure group received reoperation. No perioperative internal hernia or death occurred in either group. The visual analog score decreased with time in both groups. There was no significant difference in the visual analog score between the mesenteric fissure closure group and the mesenteric fissure non-closure group [ β=-0.20(-0.53,0.13), P>0.05]. Conclusion:Compared with closure of mesenteric fissure, non-closure of mesenteric fissure during laparoscopic right hemi-colectomy dose not increase perioperative complications or postoperative management risk.

Based on single-cell sequencing of the hippocampi of 5x familiar Alzheimer's disease(5x FAD)and wild type mice at 2-,12-,and 24-month of age,we found an increased percentage of microglia in aging and Alzheimer's disease(AD)mice.Blood brain barrier injury may also have contributed to this increase.Immune regulation by microglia plays a major role in the progression of aging and AD,according to the functions of 41 intersecting differentially expressed genes in microglia.Signaling crosstalk between C-C motif chemokine ligand(CCL)and major histocompatibility complex-1 bridges intercellular communi-cation in the hippocampus during aging and AD.The amyloid precursor protein(APP)and colony stimulating factor(CSF)signals drive 5x FAD to deviate from aging track to AD occurrence among intercellular communication in hippocampus.Microglia are involved in the progression of aging and AD can be divided into 10 functional types.The strength of the interaction among microglial subtypes weakened with aging,and the CCL and CSF signaling pathways were the fundamental bridge of communication among microglial subtypes.

Objective:To study the real-world outcome of China FDA-approved Sofosbuvir (SOF)/Velpatasvir (VEL) in Northwest China.Methods:In this multicenter, prospective, real-world cohort study, we recruited patients from 10 sites from Northwest China, who were chronically infected with HCV GTs 1-6 from 06/2018 to 09/2019. Patients received SOF (400mg)/VEL (100mg) for 12 weeks, and with ribavirin 900-1200 mg for GT3 cirrhosis and for any genotype decompensated cirrhosis. The primary endpoint was sustained virological response at 12-weeks post-treatment (SVR12) and safety. The secondary endpoint was the change of liver function after the achievement of SVR12.Results:Totally, 143 patients were enrolled in the study, four patients were lost to follow-up and one died during the follow-up, 138 patients were included in per-protocol analysis. Of the 138 patients, the mean age 53 years, 53.6% male, 94.2% Han nationality, 53.6% liver cirrhosis, 10.1% HBsAg +, 6.5% renal dysfunction, 5.1% treatment-experienced, and 16.7% patients received ribavirin treatment. The genotype distribution was as follows: 35.5% GT1, 42.8% GT2, 15.9% GT3, and 5.8% un-typed. The SVR12 rate was 96.5% (138/143, 95% CI: 93.5%-99.6%) for intention-to-treat analysis, and in per-protocol analysis, all 138 patients obtained SVR12 (100%). Compared with baseline, the serum total bilirubin, ALT and AFP levels decreased (all P < 0.05), as well as increased ALB and platelet count (all P < 0.001) at post-treatment 12-weeks. Overall adverse events (AEs) rate is 29.0%, and the most common AEs were anemia (14.5%) and fatigue (8.0%). Severe side effects (edema and fatigue) occurred in 2 patients, one of whom needed a short-term interruption of treatment due to fatigue. Conclusion:In this real-world cohort study, 12-week SOF/VEL regimen with or without ribavirin achieved high SVR12 rates (96.5%-100% overall) with excellent safety profile among patients with HCV GT1/2/3 infection including patients with GT3 and cirrhosis, and led to improvement of liver function.

Objective:To explore the predictive value of regional leptomeningeal collateral circulation scale (rLMC) based on multimodal CT in recanalization of blood vessels in patients with acute ischemic stroke after thrombectomy.Methods:A retrospective analysis was conducted on clinical data of patients with acute ischemic stroke within 6 h of first onset, admitted to our hospital from October 2017 to December 2019. Before operation, the conditions of their vessels were evaluated by rLMC based on multimodal CT. Two areas, anterior cerebral artery (ACA)-middle cerebral artery (MCA) area and posterior cerebral artery (PCA)-MCA area, were divided. The total rLMC scores of two areas (0-10) were calculated: scores of 0-3, scores of 4-7, scores of 8-10. After admission, the recanalization of the blood vessels after thrombectomy was evaluated immediately according to grading of thrombolysis in cerebral infarction (TICI) after completion of thrombectomy within the time window; TICI grading≥II was defined as succeed recanalization. The correlation between rLMC scores and vascular recanalization in patients with acute ischemic stroke was evaluated.Results:Among the 80 patients, 17 were in the rLMC scores of 0-3 group, 25 in the group of rLMC scores of 4-7, and 38 in the group of rLMC scores of 8-10; 68 patients (85.00%) had vascular recanalization, and the success rate of vascular recanalization in patients from the group of rLMC scores of 8-10 was significantly higher than that in the group of rLMC scores of 0-3 (97.36% vs. 58.82%, P<0.05). Correlation analysis results showed that the rLMC score was positively correlated with success rate of vascular recanalization ( r s=0.625, P=0.000); whose sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 89.5%, 90.9%, 94.45%, 83.3% and 90.0%, respectively. Conclusion:The rLMC is closely related to the recanalization rate in patients with acute ischemic stroke after thrombectomy; the success rate of recanalization after intravascular treatment is relatively high in patients with rLMC scores of 8-10.

Objective To investigate the effectiveness and safety of intravenous thrombolytic therapy with low-dose alteplase for elderly patients with acute ischemic stroke.Methods The elderly patients with acute ischemic stroke were enrolled prospectively (onset within 4.5 h,aged ≥75 years).They were randomly divided into either a low-dose group (0.6 mg/kg) or a standard-dose group (0.9 mg/kg).The primary outcome was the modified Rankin Scale (mRS) score determined the good outcome (mRS score 0-2) and poor outcome (mRS score ＞2) at 90 d after treatment;the secondary outcome was intracranial hemorrhage and symptomatic intracranial hemorrhage at 24 h after thrombolysis,and death within 90 d.Results A total of 65 elderly patients with acute ischemic stroke were enrolled,including 32 in the low-dose group and 33 in the standard-dose group.There were no significant differences in all baseline clinical data between the two groups.Compared with before treatment,the proportions of patients with the mRS score 0-2 were significantly higher in both groups at 7 d,14 d,and 90 d after treatment,but there were no significant differences in good outcome rate at the same time point after treatment between the two groups.In addition,there were no significant differences in intracranial hemorrhage (36.4％ vs.25.0％;x2 =0.985,P =0.321),symptomatic intracerebral hemorrhage (21.2％ vs.9.4％;x2 =1.749,P =0.186) at 24 h after treatment,and incidence of death within 90 d after treatment (12.1％ vs.6.3％;x2 =0.151,P=0.697)between the two groups.Conclusions The effectiveness and safety of intravenous thrombolytic therapy with low-dose alteplase (0.6 mg/kg) in elderly patients with acute ischemic stroke is equivalent to the standard dose.

The present study aimed to research pathogenesis and therapeutics of hepatocellular carcinoma (HCC) with the method of tissue metabolomics.A combined gas chromatography-mass spectrometry (GC-MS) method was developed suitable for analyzing the endogenous small molecule of liver cancer tissues and adjacent tissues.The unidimensional and multidimensional statistics were used to look for differential metabolites.And then,the KEGG and HMDB database were utilized to find related differential pathways and pathogenesis of HCC.The PCA and PLS-DA showed that there were significant differences on the endogenous small molecule of liver cancer tissues and adjacent tissues.Through the OPLS-Loading plot analysis,there were 25 differential metabolites and 36 relevant pathways.The differential pathways belong to carbohydrate metabolism,amino acid metabolism and mitochondrial transfer.There were 16 metabolites' area under the ROC curve which was bigger than 0.8,which were related with ATP-binding cassette (ABC) transporters,galactose metabolism,amino sugar and nucleotide sugar metabolism.It was concluded that the Warburg effect exists in HCC cells.The energy of HCC cell was from glycolytic function,because the glycolysis was enhanced and the citric acid cycle decreased.Mitochondrial dysfunction and the increased cobalt content may correlate with the Warburg effect,which may be one of the pathogenesis of liver cancer,and expected to become the breakthrough point of a new targeting therapeutic approach.

Objective To evaluate the effectiveness of biofeedback in preventing chronic daily headaches. Methods One hundred patients experiencing daily headaches were randomly divided into a biofeedback group ( n=50) and a drug therapy group (n=50). The patients in the drug therapy groupwere administered a predetermined course of medication. Those in the biofeedback group were given 30 minutes of biofeedback therapy twice a week for 8 weeks, followed by 10 months of intensive therapy once a month. The headache frequency, duration of headache at-tacks, days of using acute pain medication and any other adverse events were recorded 3, 6 and 12 months after the treatment. Results The patients in the biofeedback group had significantly less-frequent headaches, shorter headache attacks and fewer days of using acute pain medications. Conclusion Compared to drug therapy, biofeed-back can prevent chronic daily headachesmore safely and effectively.

Objective To investigate the correlation between prostacyclin synthase (prostaglandin I2 synthase, PGIS) gene rs5602 single nucleotide polymorphism and ischemia stroke in Chinese Han population. Methods The patients with ischemia stroke and healthy controls in Chinese Han population were enroled. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) was used to detect the rs5602 polymorphism. Results A total of 297 patients with ischemic stroke (male 177 and female 120) and 291 healthy controls (male 165, female 126) over the same period were enroled. The frequencies of TT genotype (31. 1% vs. 43. 6% ; χ2 = 5. 773, P = 0. 016) and T alele (56. 8% vs. 65. 8% ; χ2 = 5. 793, P = 0. 016) in the male patients with ischemic stroke were significantly lower than those in the male healthy controls. Multivariate logistic regression analysis showed that the rs5602 TT genotype was a protective factor for ischemic stroke in male (odds ratio 0. 260, 95% confidence interval 0. 118-0. 570; P = 0. 001). Conclusions PGIS gene rs5602 polymorphism is associated with ischemic stroke in male in Chinese Han population.