Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

OBJECTIVE: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product. RESULTS: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein. CONCLUSION The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.
Cerebroside-Sulfatase/genetics* ; DNA ; Genetic Association Studies ; Humans ; Leukodystrophy, Metachromatic/genetics* ; Mutation

Objective:To evaluate the role of acetaldehyde dehydrogenase 2 (ALDH2) in hippocampus in memory decline after myocardial ischemia-reperfusion (I/R) in rats.Methods:Twenty-four healthy male Sprague-Dawley rats, aged 2-3 months, weighing 220-280 g, were divided into 3 groups ( n=8 each) using a random number table method: sham operation group (group S), myocardial I/R group (group I/R) and ALDH2 agonist ALDA-1 group (group ALDA-1). Myocardial I/R was induced by 30 min occlusion of left anterior descending branch of coronary artery followed by 120 min reperfusion in anesthetized animals.ALDA-1 10 mg/kg was intraperitoneally injected at 5 min before ischemia in group ALDA-1.The positioning navigation training in Morris water maze test was started from 6 days before developing the model.The spatial exploration in Morris water maze test was performed at 24 h after developing the model.The rats were sacrificed after the end of behavioral experiment, and the hippocampus was extracted for microscopic examination of the pathological changes (by hematoxylin and eosin staining) and for determination of the apoptosis index (AI) (by TUNEL staining), activity of ALDH2 (by colorimetry), contents of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) (by enzyme-linked immunosorbent assay), and expression of ALDH2 and 4-HNE (by Western blot). Results:Compared with group S, the number of crossing the original platform was significantly decreased, the time spent in the target quadrant was shortened, the activity of ALDH2 in the hippocampus was decreased, the expression of 4-HNE was up-regulated, and the contents of 4-HNE and MDA and AI were increased in group I/R ( P<0.05). Compared with group I/R, the number of crossing the original platform was significantly increased, the time spent in the target quadrant was prolonged, the ALDH2 activity was increased, the expression of 4-HNE was down-regulated, and the contents of 4-HNE and MDA and AI were decreased in group ALDA-1 ( P<0.05). There was no significant difference in ALDH2 expression in hippocampus among the three groups ( P>0.05). Conclusions:The mechanism of memory decline developed after myocardial I/R may be related to the decrease in ALDH2 activity and promotion of accumulation of aldehydes in the hippocampus of rats.

Objective:To evaluate the association between the use of emergency medical services (EMS) and the severity of disease among patients admitted to the emergency room, to analyze the characteristics of the patients, and to build prediction model providing evidence-based use of EMS resources.Methods:The data of patients admitted to the Emergency Room of the First Affiliated Hospital of University of Science and Technology of China from January 2020 to July 2021 were extracted from the Chinese Emergency Triage Assessment and Treatment (CETAT) database. Patients were divided into the EMS use group (AB+ group) and self-seeing group (AB-group) according to whether they used EMS. The patients’ general condition, vital signs and laboratory tests results were recorded. The severity of patients’ condition was judged based on whether the patient was admitted to the department of critical medicine, specialized care unit, emergency operation and/or emergency percutaneous intervention. A 9-variable model that did not require laboratory inspection and 22-variable model that required laboratory inspection were established to correct the propensity score to analyze the correlation between the severity of disease and the EMS use. In the subgroup analysis, the correlation between the EMS use and severity of the patients was analyzed according to the reason of the patient’s visit.Results:During the study period, 16 489 patients were admitted to the emergency room, and 6975 patients were finally enrolled in this study. There were 2768 patients (39.7%) in the AB+ group and 4207 patients (60.3%) in the AB-group. In the AB+ group 522 patients (18.9%) were in high risk, and in the AB-group 563 patients (13.4%) were in high risk. Compared with the AB-group, patients in the AB+ group were older and had a higher proportion of coma, a faster autonomic heart rate, and a lower diastolic blood pressure and peripheral oxygen saturation (SpO 2). In the 9-variable model, sex, consciousness, temperature, heart rate and diastolic blood pressure were associated with the EMS use. In the 22-variable model, consciousness, SpO 2, neutrophils, and albumin were the relevant factors for patients using EMS. Before the correction of propensity score, the EMS use was an independent risk factor for critically ill patients ( OR=1.5, 95% CI 1.32-1.72, P<0.001). After adjusted using 9-variable propensity score, the EMS use ratio decreased significantly compared with that without correction ( OR=1.24,95% CI 1.08-1.42, P<0.001). Interestingly, after adjusted with propensity score match with 22-variable model, there was no association between the severity of disease and t the EMS use ( OR=1.10,95% CI 0.95-1.28, P=0.195). In subgroup analysis, patients’ chief complaint of central nervous system, cardiovascular system, and trauma were the top three reasons at admission. Before the propensity score correction, the EMS calling patients with chief complaint of central nervous system, digestive system, and trauma were related to the severity of the patients. After adjusted with 9-variable model the EMS use was associated with the severity of the disease only in trauma patients, and after adjusted with 22-variable model there was no statistical difference considering the severity of the disease in all subgroups. Conclusions:The EMS use is common. However, the association of the EMS use with the severity of disease is decreased with variable models using propensity score. These findings indicate that the EMS use should be based on multivariable models, which may be important in detecting critically ill patients, optimizing the EMS use, and avoiding unnecessary call in the future.

Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure-activity relationship was elaborated. Together with metabolic stability tests and pharmacokinetic profiling, a representative compound () was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.

BACKGROUND: The Id2 gene is an endogenous negative regulator of basic helix-loop-helix factor, which is involved in the cell proliferation, differentiation and existence. Id2 also shows functional diversity in the progression and infiltration of different types of tumors OBJECTIVE: To observe the changes of proliferation and invasiveness of PC-3 human prostate cancer stem cells after shRNA-Id2 transfection. METHODS: PC-3 human prostate cancer stem cells in logarithmic growth phase were harvested to isolate tumor stem cell spheres by serum-free suspension culture. The expression of CD44+CD24-on the surface of tumor stem cells was detected by flow cytometry. The shRNA-Id2 expression vector was constructed and transfected into PC-3 human prostate cancer stem cells. Untransfected PC-3 human prostate cancer stem cells were used as control. At 48 hours after transfection, the expression of Id2 gene and protein in shRNA-Id2 transfected prostate cancer stem cells, NC-shRNA empty vector transfected prostate cancer stem cells and untransfected prostate cancer stem cells were detected by RT-PCR and western blot, respectively. The proliferation and invasion of shRNA-Id2 transfected prostate cancer stem cells and untransfected prostate cancer stem cells were detected by MTT assay and Transwell chamber, respectively. The expressions of E-cadherin, vimentin and Twist were detected by western blot and RT-PCR. RESULTS AND CONCLUSION: Tumor stem cell spheres were successfully isolated by the serum-free suspension culture. The expression rate of CD44+CD24-on the surface of the third-generation PC-3 human prostate cancer stem cells was (85.69±8.96) ％, indicating that the cultured tumor stem cell spheres overexpressed the phenotype of tumor stem cells. At 48 hours after transfection, the expression of Id2 gene and protein was significantly lower in the shRNA-Id2 transfection group than the non-transfection group (P < 0.05) , indicating that the expression of Id2 was successfully interfered with the expression of PC-3 prostate cancer stem cells. The invasive ability of the cells in the shRNA-Id2 transfection group was significantly lower than that in the non-transfection group (P < 0.05). Western blot and RT-PCR detection showed that the expression of E-cadherin, an epithelial marker of PC-3 prostate cancer stem cells, in the shRNA-Id2 transfection group was significantly higher than that in non-transfection group (P < 0.05) , while the expression of vimentin, a marker of mesenchymal stem cells, and Twist, a transcription factor regulating cell-mesenchymal transformation, in the shRNA-Id2 transfection group was significantly lower than that in the non-transfection group (P < 0.05). These findings indicate that RNA interference with Id2 gene can inhibit the proliferation and invasion of PC-3 prostate cancer stem cells by regulating the expression of E-cadherin, vimentin and Twist.

Objective To evaluate the relationship between the failed mechanism of sevoflurane postconditioning-induced myocardial protection and the activity of dynamin-related protein 1(Drp1)in dia-betic rats. Methods Pathogen-free healthy adult male Sprague-Dawley rats, weighing 220-280 g, in which diabetes mellitus was induced by combination of high-fat and high-sucrose diet and intraperitoneal injection of streptozotoein 30 mg∕kg, were studied.Sixty rats with diabetes mellitus were divided into 5 groups(n=12 each)using a random number table: sham operation group(group Sham), myocardial ischemia∕reperfusion (I∕R)group(group I∕R), sevoflurane postconditioning group(group SP), Drp1 inhibitor mitochondrial division inhibitor-1(Mdivi-1)group(group M)and Mdivi-1 plus sevoflurane postconditioning group(group M-SP). Myocardial I∕R was induced by occluding the left anterior descending branch of the coronary artery for 30 min followed by 120 min reperfusion except for group Sham. Mdivi-1 1.2 mg∕kg was intraperito-neally injected at 15 min before ischemia in M and M-SP groups, and 2.5% sevoflurane was inhaled starting from 5 min of reperfusion in SP and M-SP groups. Blood samples were collected from the right internal jugular vein at 120 min of reperfusion for measurement of serum cardiac troponin I(cTnI)concentrations(by en-zyme-linked immunosorbent assay). Rats were then sacrificed and myocardial specimens were obtained for de-termination of the myocardial infarct size(by TTC), cell apoptosis(by TUNEL), expression of Bax, Bcl-2 and activated caspase-3(by Western blot)and nicotinamide adenine dinucleotide(NAD+)content(by spectrophotometry). Apoptosis index(AI)and Bax∕Bcl-2 ratio were calculated. Results Compared with group Sham, the percentage of myocardial infarct size, serum concentration of cTnI, AI and Bax∕Bcl-2 ratio were significantly increased, the expression of activated caspase-3 was up-regulated, and the NAD+content was decreased in the other four groups(P<0.05). Compared with group I∕R, the percentage of myocardial infarct size, serum concentration of cTnI, AI and Bax∕Bcl-2 ratio were significantly decreased, the expres-sion of activated caspase-3 was down-regulated, and the NAD+content was increased in group M-SP(P<0.05), and no significant change was found in the parameters mentioned above in SP and M groups(P>0.05). Compared with group SP, the percentage of myocardial infarct size, serum concentration of cTnI, AI and Bax∕Bcl-2 ratio were significantly decreased, the expression of activated caspase-3 was down-regulated, and the NAD+content was decreased in group M-SP(P<0.05), and no significant change was found in the parameters mentioned above in group M(P>0.05). ConclusionThe failed mechanism of sevoflurane postconditioning-induced myocardial protection may be related to the activity of Drp1 in diabetic rats.

Objective To explore the role of hydrogen sulfide (H 2S ) in acute liver injury induced by crush-ing hind lim bs of rats. Methods The rats w ere random ly divided into the follow ing groups:control, crush-ing, H 2S donor sodium hydrosulfide (NaHS) + crushing, H 2S inhibitor propargylglycine (PAG ) + crush-ing group. The acute liver injury m odel w as established by crushing the hind lim bs of rats w ith standard w eight. R ats w ere sacrificed at 30 m in and 120 m in after the crush. The activities of serum aspartate am inotransferase (AST) and alanine am inotransferase (ALT) w ere m easured by colorim etric m ethod, and the content of H 2S in plasm a and the contents of m alondialdehyde (MDA), protein carbonyl, glutathione (GSH) in the liver and the activity of H 2S generating enzym e (cystathionine γ-lyase, CSE) w ere deter-m ined by chem ical m ethod. The expression of CSEm R N Ain liver w as detected by R T-PCR . Results For crush injury group, the levels of ASTand ALTin serum , MDAand protein carbonyl in liver in-creased. The levels of GSH, CSE, CSEm R N Ain liver and H 2S in serum decreased. The adm inistration of NaHS before lim bs crush could attenuate the changes of liver injury, but the pre-treatm ent w ith PAG could exacerbate the changes. Conclusion The decrease of H 2S production could involve in m ediating the acute liver injury induced by traum atic stress in rats.

Objective To investigate the effect of inhibition of glycogen synthase kinase?3 beta ( GSK?3β) activity on sevoflurane postconditioning?induced cardioprotection in diabetic rats. Methods Healthy adult male Sprague?Dawley rats, weighing 250-300 g, in which diabetes mellitus was induced by intraperitoneal 1% streptozotocin 60 mg∕kg combined with high?fat and high?sucrose diet and confirmed by blood glucose level >16. 7 mmol∕L. Forty rats with diabetes mellitus were divided into 5 groups ( n=8 each) using a random number table: sham operation group ( S group ) , ischemia?reperfusion ( I∕R ) group, sevoflurane postconditioning group ( SP group) , GSK?3β inhibitor SB216763 group ( SB group) , and sevoflurane postconditioning plus SB216763 group ( SS group ) . Myocardial ischemia was induced by 30 min occlusion of the left anterior descending branch of the coronary artery followed by 120 min reperfu?
sion. The rats inhaled sevoflurane with the end?tidal concentration of 2.5% for 5 min starting from 1 min be?fore reperfusion in group SP. SB216763 0.2 mg∕kg was injected via the caudal vein at 1 min before reperfu?sion in group SB. In group SS, the rats inhaled sevoflurane with the end?tidal concentration of 2.5% for 5 min starting from 1 min before reperfusion, and SB216763 0.2 mg∕kg was injected via the caudal vein at 1 min before reperfusion. At 120 min of reperfusion, blood samples were collected from the carotid artery for determination of serum creatine kinase?MB (CK?MB) activity and cardiac troponin I (cTnI) concentra?tions. Myocardial specimens were collected at 120 min of reperfusion for microscopic examination of the pathological changes and for determination of myocardial infarct size ( by 2,3,5?triphenyltetrazolium chlo?ride staining) and phosphorylated GSK?3β (p?GSK?3β) expression (by Western blot). Results Com?pared with group S, the myocardial infarct size and serum CK?MB activity and cTnI concentration were sig?nificantly increased, and the expression of p?GSK?3βwas significantly down?regulated in I∕R, SP, SB and SS groups (P<0.05). Compared with group I∕R, the myocardial infarct size and serum CK?MB activity and cTnI concentration were significantly decreased, and the expression of p?GSK?3β was significantly up?regulated in SB and SS groups (P<0.05), and no significant change was found in the parameters men?tioned above in group SP ( P>0.05) . Compared with group SB, the myocardial infarct size and serum CK?MB activity and cTnI concentration were significantly decreased, and the expression of p?GSK?3β was sig?nificantly up?regulated in group SS (P<0.05). The pathological changes of myocardium were significantly attenuated in SB and SS groups as compared with group I∕R and group SP . Conclusion Inhibition of GSK?3β activity can improve sevoflurane postconditioning?induced cardioprotection in diabetic rats.

Objective To investigate effects of antioxidant stress protein hem e oxygenase-1 (HO-1) on lipopolysaccharide (LPS)-induced endoplasm ic reticulum stress (ERS) of rat hepatocytes. Methods The BRL cells (rat hepatocyte cell line) were cultured. The hepatocytes were treated with LPS, LPS+HO-1 si RNA , HO-1 siRNA and PB S solution, respectively. The cell viability was m easured by trypan blue ex-clusion test. The apoptosis cells were detected by the fluorescent dye Hoechst 33258. E xpressions of GR P78, C HO P, caspase-12 and HO-1 were detected by Western blotting. Results LPS caused an in-crease of HO-1 protein expression of rat hepatocytes in a dose-dependent and tim e-dependent m anner, a up-regulation of GRP78, CHO P and caspase-12, a decrease in cellviability,and an increase in apopto-sis rate of hepatocytes. Pretreatm ent of HO-1 siRNA inhibited the up-regulation of LPS-induced HO-1, however, aggravated ERS and cellular injury. Conclusion HO-1 inhibites ERS-m ediated cellular injury of rat hepatocytes induced by LPS.