Background and Aims:Complex choledocholithiasis often coexists with stenosis of the ampulla of Vater,which increases the difficulty and complexity of treatment.If only the stones in the bile duct are removed without addressing the ampullary stenosis,the disease is prone to recurrence.Previously,most treatments involved the use of endoscopic retrograde cholangiopancreatography(ERCP)to guide the wire for sphincterotomy and stone extraction,followed by laparoscopic cholecystectomy.However,ERCP has limitations in handling complex cases.In response,our team pioneered a new method of treating choledocholithiasis combined with stenosis of the ampulla of Vater via a transabdominal approach.This study was performed to investigate the feasibility and efficacy of this method,aiming to provide a new therapeutic option for clinical practice.Methods:A randomized controlled study was conducted with 120 patients treated at Chengdu Second People's Hospital from 2021 to 2023 for gallbladder stones and choledocholithiasis with stenosis of the ampulla of Vater.Patients were divided into an observation group and a control group,with 60 cases in each group.The observation group underwent laparoscopic cholecystectomy with choledochotomy for stone extraction,followed by retrograde guidance of duodenal papillary sphincterotomy through the opened bile duct,simultaneously treating gallbladder,bile duct stones,and stenosis of the ampulla of Vater.The control group underwent traditional ERCP approach for sphincterotomy,stone extraction,and laparoscopic cholecystectomy.Perioperative variables were collected for both groups and the surgical outcomes were compared.Results:Among the 120 patients,54 were male and 66 were female.There were no statistically significant differences between the two groups in terms of stone extraction success rate,intraoperative blood loss,postoperative 24-h total bilirubin,direct bilirubin,transaminases,white blood cell count,jaundice relief time,or incidence rates of bile leakage,retroperitoneal bleeding/infection,and severe pancreatitis(all P>0.05).The observation group had significantly shorter average operative time and postoperative hospital stay compared to the control group(98.67 min vs.110.8 min,P<0.05;3.81 d vs.5.61 d,P<0.05).Additionally,the observation group had a significantly lower incidence of postoperative hyperamylasemia and/or hyperlipasemia and mild pancreatitis(1.67%vs.25.00%,P<0.001;0 vs.10%,P=0.027).Conclusion:The novel transabdominal approach is superior to the ERCP approach in terms of reducing surgery time and hospitalization time,and it carries a lower risk of postoperative mild pancreatitis and hyperamylasemia and/or hyperlipasemia.The stone extraction success rate is comparable to that of ERCP,making it a viable alternative treatment option.

Background and Aims:Complex choledocholithiasis often coexists with stenosis of the ampulla of Vater,which increases the difficulty and complexity of treatment.If only the stones in the bile duct are removed without addressing the ampullary stenosis,the disease is prone to recurrence.Previously,most treatments involved the use of endoscopic retrograde cholangiopancreatography(ERCP)to guide the wire for sphincterotomy and stone extraction,followed by laparoscopic cholecystectomy.However,ERCP has limitations in handling complex cases.In response,our team pioneered a new method of treating choledocholithiasis combined with stenosis of the ampulla of Vater via a transabdominal approach.This study was performed to investigate the feasibility and efficacy of this method,aiming to provide a new therapeutic option for clinical practice.Methods:A randomized controlled study was conducted with 120 patients treated at Chengdu Second People's Hospital from 2021 to 2023 for gallbladder stones and choledocholithiasis with stenosis of the ampulla of Vater.Patients were divided into an observation group and a control group,with 60 cases in each group.The observation group underwent laparoscopic cholecystectomy with choledochotomy for stone extraction,followed by retrograde guidance of duodenal papillary sphincterotomy through the opened bile duct,simultaneously treating gallbladder,bile duct stones,and stenosis of the ampulla of Vater.The control group underwent traditional ERCP approach for sphincterotomy,stone extraction,and laparoscopic cholecystectomy.Perioperative variables were collected for both groups and the surgical outcomes were compared.Results:Among the 120 patients,54 were male and 66 were female.There were no statistically significant differences between the two groups in terms of stone extraction success rate,intraoperative blood loss,postoperative 24-h total bilirubin,direct bilirubin,transaminases,white blood cell count,jaundice relief time,or incidence rates of bile leakage,retroperitoneal bleeding/infection,and severe pancreatitis(all P>0.05).The observation group had significantly shorter average operative time and postoperative hospital stay compared to the control group(98.67 min vs.110.8 min,P<0.05;3.81 d vs.5.61 d,P<0.05).Additionally,the observation group had a significantly lower incidence of postoperative hyperamylasemia and/or hyperlipasemia and mild pancreatitis(1.67%vs.25.00%,P<0.001;0 vs.10%,P=0.027).Conclusion:The novel transabdominal approach is superior to the ERCP approach in terms of reducing surgery time and hospitalization time,and it carries a lower risk of postoperative mild pancreatitis and hyperamylasemia and/or hyperlipasemia.The stone extraction success rate is comparable to that of ERCP,making it a viable alternative treatment option.

During his studies at the Peking Union Medical College(1921-1929),Chen Zhiqian formed his thoughts on public health under the influences of modern medical education and the advanced thinking of the times,which laid an ideological foundation for his later engagement in rural health care and reflected the medical progress in China at that time.In the 1920s,Chen Zhiqian's thoughts on public health mainly encompassed five aspects.First,health was a cornerstone of the country's wealth and people's well-being.Second,he belived in comprehensive"big medicine"which emphasized the combination of prevention and treatment.Third,he advoca-ted the return of medicine to the state and the building of a medical system covering all people.Fourth,he advo-cated maternal training and institutional standardization,emphasizing child health protection.Fifth,he was com-mitted to the popularization of health science and advocated health education reform.Summarizing the above five aspects is of great significance for enriching and improving the academic evaluation about Chen Zhiqian and pro-vides a reference for today's work on public health.

Objective To explore the effects of long non-coding RNA(lncRNA)small nucleolar molecule RNA host gene 12(SNHG12)targeting inhibition of miR-495-3p/phospholipinositol-3-kinase(PI3K)/protein kinase B(Akt)signaling pathway on the proliferation,migration and invasion of prostate cancer cells.Methods The expressions of SNHG12 and miR-495-3p in prostate cancer tissues and cells(LNCaP,C4-2,DU145)were detected with real-time fluorescence quantitative PCR(qRT-PCR).After DU145 cells were divided into si-NC,si-SNHG12,si-SNHG12+anti-miR-NC and si-SNHG12+anti-miR-495-3p groups,the expressions of SNHG12 and miR-495-3p were detected with qRT-PCR;the targeting relationship between SNHG12 and miR-495-3p was determined with dual luciferase assay;cell proliferation was assessed with MTT assay;cell migration and invasion were evaluated with Transwell assay;the protein expressions of proliferating cell nuclear antigen(PCNA),N-cadherin,and E-cadherin were detected with Western blot.Results The expressions of SNHG12 were significantly increased,while the expression of miR-495-3P was significantly decreased in prostate cancer tissues and cells(LNCaP,C4-2,DU145)(P＜0.05).Knockdown of SNHG12 decreased DU145 cell activity,lowered the protein expressions of PCNA and N-cadherin,reduced the number of migrating and invading cells,but increased the protein expression of E-cadherin(P＜0.05).SNHG12 targeted and negatively regulated miR-495-3p,and down-regulation of miR-495-3p reversed the effects of SNHG12 knockdown on the proliferation,migration and invasion of prostate cancer cells.Compared with the si-NC group,the si-SNHG12 group had significantly decreased expressions of p-PI3K and p-Akt(P＜0.05).Compared with the si-SNHG12+anti-miR-NC group,the si-SNHG12+anti-miR-495-3p group had significantly increased protein expressions of p-PI3K and p-Akt(P＜0.05).Conclusion lncRNA SNHG12 can promote the proliferation,migration and invasion of prostate cancer cells through targeted inhibition of miR-495-3p/PI3K/Akt signaling pathway.

Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.

To explore the operation methods and indications of the duodenoscopic papillotomy (IEST) with endoscopic nasobiliary drainage (IENBD) for the treatment of duodenal papilla stenosis during the course of common bile duct operation.The clinical data of 219 cases of cholecystolithiasis with choledocholith and the stenosis of papillary underwent endoscopic sphincterotomy (IEST) plus endoscopic nasobiliary drainage (IENBD) in the Second People's Hospital of Chengdu were retrospectively analyzed.It was successful in 198 cases who had the gallbladder and common bile duct stones removed,and endoscopic papillary dissection was performed and the nasobiliary tube was successfully inserted.Nasobiliary drainage was successful in 186 cases (93.9％) of 198 cases.No liquid outflow was observed in nasobiliary drainage in 7 cases (3.5％).Nasal bile duct slipped early in 5 case (2.5％).Primary closure of bile duct incision was completed in 198 cases.It failed in 4 cases (2.0％) who had the bile leakage with primary closure of duct incision.Mild pancreatitis after operation occurred in 3 cases (1.5％).Nose bile duct ligation was performed in 1 case (0.5％).The overall postoperative complication rate was 4.0％ (8/198).IEST + IENBD in open laparotomy was successful in 21 cases.No perforation of intestine and bile duct,bleeding,severe pancreatitis and other complications and death were detected postoperatively in two groups.During the course of laparoscopy and open laparotomy,IEST + IENBD in treating cholecystolithiasis with choledocholith and the stenosis of papillary and primary closure of duct incision after the endoscopic nasobiliary drainage is safe and effective.

Objective To compare using the transabdominal route versus the transoral route in establishing naso-biliary drainage in laparoscopic surgery.Methods The combined use of laparoscopy with choledochoscopy and duodenoscopy to establish naso-biliary drainage was carried out in 204 patients with gallbladder and common bile duct calculi.In 162 patients,the naso-biliary drainage was established transabdominally and in 42 patients it was established transorally.The success and the complication rates in the two groups were compared.Results Of 162 patients using the transabdominal route,4 patients failed.There were 6 patients (3.7％) who had no output from the nasobiliary drain.There were 3 patients (1.8％) who had only intestinal juice outflow from the nasobiliary drain.Primary closure failed in 3 patients (1.8％),all resulting in bile leak.Pancreatitis occurred in 2 patients (1.2％) after the operation.There was 1 patient (0.6％) whose nasobiliary drain was wrongly ligated.Of 42 patients with nasobiliary drainage using the transoral route,6 patients failed.There was 1 patient (2.4％) who had no output from the nasobiliary drain.There was 1 patient (2.4％) who had intestinal juice output from the nasobiliary drain.Primary closure failed in 1 patient (2.4％) with resultant bile leakage.Pancreatitis occurred in 4 patients (9.5％) after the operation.The success rate of establishing a nasobiliary drainage in the transabdominal group was significantly higher than that in the transoral group,but the complications were less.Conclusions Nasobiliary drainage established through the transabdominal route in laparoscopy surgery for patients with gallbladder and common bile duct calculi was technically easier and had a high success rate.It had less complications.

OBJECTIVETo explore the effects of hydrogen-rich saline (HS) on liver of severely scalded rats with delayed resuscitation.

METHODSTwenty-four SD rats were inflicted with 40% TBSA full-thickness scald using a temperature-controlled scalding apparatus. The injured rats were divided into lactated Ringer's solution (RS) and HS groups according to the random number table, with 12 rats in each group. Rats in groups RS and HS were respectively resuscitated with an intraperitoneal injection of 4 mL × kg⁻¹ × %TBSA⁻¹ of RS or HS (self-prepared, with concentration of hydrogen 0.6 mmol/L) 6 hours after injury up to 48 hours after scald. The infusion volume of the second 24 hours after injury was a half of that of the first 24 hours. At post scald hour (PSH) 6 (before resuscitation), 12, 24, and 48, blood was collected from the heart of 3 rats in each group, and then the rats were sacrificed for harvesting liver tissue. The pathological change in liver tissue was observed with HE staining. The number of hepatic neutrophils was counted with a hematocytometer. Serum levels of AST and ALT were determined with full-automatic biochemical analyzer. Contents of TNF-α, IL-1β, IL-6, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in liver tissue were determined with ELISA. Absorbance value of malondialdehyde (MDA) in liver tissue was detected and quantified with spectrophotometer. Data were processed with analysis of variance of repeated measurement and LSD-t test.

RESULTSAt PSH 48, moderate infiltration of inflammatory cells and hepatic hyperemia were observed in rats of group HS as compared with group RS. At PSH 12, 24, and 48, the number of neutrophils in group HS was respectively (25.3 ± 1.8) × 10⁵, (19.6 ± 0.6) × 10⁵, and (14.1 ± 3.2) × 10⁵ cells per mililitre, and they were significantly lower than those in group RS \[(31.9 ± 2.0) × 10⁵, (30.9 ± 2.2) × 10⁵, and (23.8 ± 3.0) × 10⁵ cells per mililitre, with t values respectively 5.6, 7.6, and 8.7, P values below 0.05\]. At PSH 6 and 12, the serum levels of AST and ALT and the levels of TNF-α, IL-1β, and IL-6 in liver tissue were close between the two groups (with t values respectively 0.3-3.9 and 0.9-3.8, P values above 0.05). At PSH 24 and 48, the serum levels of AST and ALT in group HS were respectively (308 ± 24) and (210 ± 15) U/L and (93 ± 7) and (70 ± 5) U/L, which were significantly lower than those in group RS \[(541 ± 39) and (505 ± 18) U/L, with t values respectively 17.5 and 16.7, P values below 0.05; (156 ± 9) and (166 ± 21) U/L, with t values respectively 30.3 and 6.9, P values below 0.05\]. At PSH 24 and 48, the levels of TNF-α, IL-1β, and IL-6 in liver tissue in group HS were respectively (20.7 ± 1.6) and (13.7 ± 1.5) pg/mg, (7.7 ± 1.5) and (6.3 ± 1.2) pg/mg, and (8.7 ± 1.2) and (6.0 ± 2.0) pg/mg, which were significantly lower than those in group RS \[(32.7 ± 5.0) and (25.7 ± 4.0) pg/mg, with t values respectively 5.2 and 5.7, P values below 0.05; (16.3 ± 2.5) and (12.0 ± 2.7) pg/mg, with t values both as 4.7, P values below 0.05; (14.7 ± 2.1) and (13.3 ± 1.5) pg/mg, with t values respectively 10.4 and 4.4, P values below 0.05\]. The level of MDA at PSH 6 and levels of 8-OHdG at PSH 6 and 12 in liver tissue were close between the two groups (with t values respectively 0.1, 0.7, and 4.3, P values above 0.05). In group HS, the levels of MDA in liver tissue at PSH 12, 24, and 48 were respectively (15.3 ± 1.5), (8.7 ± 1.2), and (6.7 ± 1.5) mmol/mg, and the levels of hepatic 8-OHdG at PSH 24 and 48 were respectively (124 ± 12) and (79 ± 10) pg/mg, which were significantly lower than those in group RS \[(27.3 ± 4.7), (20.3 ± 1.5), and (14.0 ± 1.0) mmol/mg, with t values respectively 5.2, 5.7, and 5.1, P values below 0.05; (191 ± 10) and (136 ± 15) pg/mg, with t values respectively 8.0 and 8.1, P values below 0.05\].

CONCLUSIONSResuscitation with HS could protect liver of severely scalded rats with delayed resuscitation possibly by reducing infiltration of neutrophils, thus lowering the content of inflammatory cytokines, and effectively alleviating oxidative stress.

Animals ; Burns ; metabolism ; physiopathology ; Deoxyguanosine ; analogs & derivatives ; blood ; Hydrogen ; pharmacology ; Interleukin-6 ; Liver ; drug effects ; metabolism ; physiopathology ; Male ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Resuscitation ; Sodium Chloride ; pharmacology ; Soft Tissue Injuries ; Time Factors ; Tumor Necrosis Factor-alpha ; blood

Aim To investigate the effects of CYP2C19 polymorphism on the pharmacokinetics and comparative bioavailability of omeprazole in Chinese population.Methods Eighteen healthy male volunteers were selected,of whom 6 were CYP2C19 wild type(w/w),6 were CYP2C19 heterozygous variant(w/m) and the rest were CYP2C19 homozygous variant(m/m).A randomized two-period crossover study was performed.Subjects were assigned to receive test or reference omeprazole as a single oral dose of 40 mg randomly.After a washout period of one week,subjects received the alternative omeprazole formulation.Multiple blood samples of 3 ml were obtained over 12 h after dosing and plasma concentrations of omeprazole were measured by LC/MS method.The modeling of individual pharmacokinetics and the pharmacokinetic parameters of omeprazole were estimated by 3P97.Results The AUC and Cmax of reference omeprazole formulation in w/w,w/m,m/m groups were 1178.44±340.24,2328.10±1011.83,5062.02±1097.29 μg·h·L~(-1) and 602.87±118.25,926.43±134.48,1406.29±233.58 μg·L~(-1),respectively,with significant differences among the three groups(P<0.05).Significant differences were also observed in other pharmacokinetic parameters such as k_e、CL/F、t_(1/2) and Vd/F among the three groups(P<0.05).With regard to test omeprazole formulation,the AUC and C_(max) in w/w,w/m,m/m groups were 1224.82±531.67,2723.34±519.29,5692.49±1575.35 μg·h·L~(-1) and 618.74±231.43,910.67±125.99,1303.31±152.01 μg·L~(-1),respectively,which,as well as k_e,CL/F,t_(1/2) and Vd/F were significant different among the three groups(P<0.05).No significant differences were observed in comparative bioavailability among groups with the values of 94.29%±14.06%,93.08%±11.22%,91.84%±13.03% in w/w,w/m,m/m groups respectively(P>0.05).Conclusions Different CYP2C19 genotypes,leading to functional heterogeneity of CYP2C19,may affect pharmacokinetic profile of omeprazole.Therefore,genotyping CYP2C19 gene before omeprazole therapy will be of great benefit for optimizing individual therapy regimen.There is no significant difference of omeprazole comparative bioavailability with regard to CYP2C19 genetic polymorphism.

In order to successfully develop the effective population pharmacokinetic model to predict the concentration of propofol administrated intravenously, the data including the concentrations across both distribution and elimination phases from five hospitals were analyzed using nonlinear mixed effect model (NONMEM). Three-compartment pharmacokinetic model was applied while the exponential model was used to describe the inter-individual variability and constant coefficient model to the intra-individual variability, accordingly. Covariate effect including the body weight on the parameter CL, V1, Q2, V2, Q3 and V3 were investigated. The performance of final model was assessed by Bootstrapping, goodness-of-fit and visual predictive checking (VPC). The context-sensitive half-times and the infusion rates necessary to maintain the concentration of 1 microg x mL(-1) were simulated to six subpopulations. The results were as follows: the typical value of CL, V1, Q2, V2, Q3 and V3 were 0.965 x (1 + 0.401 x VESS) x (BW/59)(0.578) L x min(-1), 13.4 x (AGE/45)(-0.317) L, 0.659 x (1 + GENDER x 0.385) L x min(-1), 28.8 L, 0.575 x (1 + GENDER x 0.367) x (1 - 0.369 x VESS) L x min(-1) and 196 L respectively. Coefficients of the inter-individual variability of CL, V1, Q2, V2, Q3 and V3 were 29.2%, 46.9%, 35.2%, 40.4%, 67.0% and 49.9% respectively, and the coefficients of residual variability were 24.7%, 16.1% and 22.5%, the final model indicated a positive influence of a body weight on CL, and also that a negative correlation of age with V1. Q2 and Q3 in males were higher than those in females at 38.5% and 36.7%. The CL and Q3 were 40.1% increased and 36.9% decreased in arterial samples compared to those in venous samples. The determination coefficient of observations (DV)-individual predicted value (IPRED) by the final model was 0.91 which could predict the propofol concentration fairly well. The stability and the predictive performance were accepted by Bootstrapping, the goodness-of-fit and VPC. The context-sensitive half-times and infusion rates necessary to maintain the concentration of 1 microg x mL(-1) were different obviously among the 6 sub-populations obviously. The three-compartment model with first-order elimination could describe the pharmacokinetics of propofol fairly well. The involved fixed effects are age, body weight, gender and sampling site. The simulations in 6 subpopulations were available in clinical anesthesia. The propofol anesthesia monitor care could be improved by individualization of pharmacokinetic parameter estimated from the final model.