Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes

BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis.Our previous study found that milk fat globule epidermal growth factor 8(MFG-E8)alleviates acinar cell damage during SAP via binding toαvβ3/5 integrins.MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50μg/kg cerulein plus lipopolysaccharide.mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAPinduced liver injury.Cilengitide,a specificαvβ3/5 integrin inhibitor,was used to investigate the possible mechanism of MFG-E8.RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice,enhanced autophagy flux in hepatocyte,and worsened the degree of ferroptosis.Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner.Mechanistically,MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells.Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury.MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrinαVβ3/5.

Novel magnetic compression technique for establishment of a canine model of tracheoesophageal fistula

BACKGROUND Clinically,tracheoesophageal fistula(TEF)is lack of effective surgical strategies.One reason is due to the lack of appropriate animal models of acquired TEF,which is usually complex and difficult.Recently,the magnetic compression technique has been applied for digestive tract anastomosis or vascular anastomosis in animals.In this study,an animal model of TEF in dogs was developed by using the magnetic compression technique,hoping to provide a new method for mimicking TEF.AIM To establish a TEF model in dogs by using the magnetic compression technique.METHODS Six male beagles were used as models with two Nd-Fe-B permanent magnets for TEF.The parent magnet and the daughter magnet were placed in the cervical esophagus and trachea,respectively.The anterior wall of the esophagus and the posterior wall of the trachea were compressed when the two magnets coupled.After 4-6 d,the necrotic tissue between the two magnets fell off and the parent and daughter magnets disengaged from the target location,leaving a fistula.Gastroscopy/bronchoscopy,upper gastrointestinal contrast study,and histological analysis were performed.RESULTS The establishment of the TEF model in all six beagles was successful.The average time of magnet placement was 4.33±1.11 min(range,3-7 min).Mean time for the magnets to disengage from the target location was 4.67±0.75 d(range,4-6 d).TEFs were observed by gastroscopy/bronchoscopy and esophageal angiography.The gross anatomical structure of the esophagus and the trachea was in good condition.There was no esophageal mucosa or pseudostratified ciliated columnar epithelium at the site of the fistula according to histological analysis.CONCLUSION It is simple,feasible,and minimally invasive to use the magnetic compression technique for the establishment of the TEF model in dogs.

Irisin attenuates intestinal injury,oxidative and endoplasmic reticulum stress in mice with L-arginine-induced acute pancreatitis

BACKGROUND Acute pancreatitis(AP)is often associated with intestinal injury,which in turn exaggerates the progression of AP.Our recent study has shown that a low level of serum irisin,a novel exercise-induced hormone,is associated with poor outcomes in patients with AP and irisin administration protects against experimental AP.However,the role of irisin in intestinal injury in AP has not been evaluated.AIM To investigate the effect of irisin administration on intestinal injury in experimental AP.METHODS AP was induced in male adult mice by two hourly intraperitoneal injections of Larginine.At 2 h after the last injection of L-arginine,irisin(50 or 250μg/kg body weight)or 1 mL normal saline(vehicle)was administered through intraperitoneal injection.The animals were sacrificed at 72 h after the induction of AP.Intestinal injury,apoptosis,oxidative and endoplasmic reticulum(ER)stress were evaluated.RESULTS Administration of irisin significantly mitigated intestinal damage,reduced apoptosis,and attenuated oxidative and ER stress in AP mice.In addition,irisin treatment also effectively downregulated serum tumor necrosis factor-alpha and interleukin-6 levels and alleviated injury in the pancreas,liver and lung of AP mice.CONCLUSION Irisin-mediated multiple physiological events attenuate intestinal injury following an episode of AP.Irisin has a great potential to be further developed as an effective treatment for patients with AP.

Value of pretransplant albumin-bilirubin score in predicting outcomes after liver transplantation

BACKGROUND Due to the significant shortage of organs and the increasing number of candidates on the transplant waiting list, there is an urgent need to identify patients who are most likely to benefit from liver transplantation. The albuminbilirubin(ALBI) grading system was recently developed to identify patients at risk for adverse outcomes after hepatectomy. However, the value of the pretransplant ALBI score in predicting outcomes after liver transplantation has not been assessed.AIM To retrospectively investigate the value of the pretransplant ALBI score in predicting outcomes after liver transplantation.METHODS The clinical data of 272 consecutive adult patients who received donation after cardiac death and underwent liver transplantation at our centre from March 2012 to March 2017 were analysed in the cohort study. After the exclusion of patients who met any of the exclusion criteria, 258 patients remained. The performance of the ALBI score in predicting overall survival and postoperative complications after liver transplantation was evaluated. The optimal cut-off value of preoperative ALBI was calculated according to long-term survival status. The outcomes after liver transplantation, including postoperative complications and survival analysis, were measured.RESULTS The remaining 258 consecutive patients were included in the analysis. The median follow-up time was 17.30(interquartile range: 8.90-28.98) mo. Death occurred in 35 patients during follow-up. The overall survival rate was 81.0%.The preoperative ALBI score had a significant positive correlation with the overall survival rate after liver transplantation. The calculated cut-off for ALBI scores to predict postoperative survival was-1.48. Patients with an ALBI score >-1.48 had a significantly lower survival rate than those with an ALBI score ≤-1.48(73.7% vs 87.6%, P < 0.05), and there were no statistically significant differences in survival rates between patients with a model for end stage liver disease score ≥ 10 and < 10 and different Child-Pugh grades. In terms of the specific complications,a high ALBI score was associated with an increased incidence of biliary complications, intraabdominal bleeding, septicaemia, and acute kidney injury after liver transplantation(P < 0.05 for all).CONCLUSION The ALBI score predicts overall survival and postoperative complications after liver transplantation. The ALBI grading system may be useful in risk-stratifying patients on the liver transplant waiting list.

T-tube vs no T-tube for biliary tract reconstruction in adult orthotopic liver transplantation:An updated systematic review and metaanalysis

BACKGROUND Whether to use a T-tube for biliary anastomosis during orthotopic liver transplantation(OLT)remains a debatable question.Some surgeons chose to use a T-tube because they believed that it reduces the incidence of biliary strictures.Advances in surgical techniques during the last decades have significantly decreased the overall incidence of postoperative biliary complications.Whether using a T-tube during OLT is still associated with the reduced incidence of biliary strictures needs to be re-evaluated.AIM To provide an updated systematic review and meta-analysis on using a T-tube during adult OLT.METHODS In the electronic databases MEDLINE,PubMed,Scopus,ClinicalTrials.gov,the Cochrane Library,the Cochrane Hepato-Biliary Group Controlled Trails Register,and the Cochrane Central Register of Controlled Trials,we identified 17 studies(eight randomized controlled trials and nine comparative studies)from January 1995 to October 2020.The data of the studies before and after 2010 were separately extracted.We chose the overall biliary complications,bile leaks or fistulas,biliary strictures(anastomotic or non-anastomotic),and cholangitis as outcomes.Odds ratios(ORs)with 95%confidence intervals(CIs)were calculated to describe the results of the outcomes.Furthermore,the test for overall effect(Z)was used to test the difference between OR and 1,where P≤0.05 indicated a significant difference between OR value and 1.RESULTS A total of 1053 subjects before 2010 and 1346 subjects after 2010 were included in this meta-analysis.The pooled results showed that using a T-tube reduced the incidence of postoperative biliary strictures in studies before 2010(P=0.012,OR=0.62,95%CI:0.42-0.90),while the same benefit was not seen in studies after 2010(P=0.60,OR=0.76,95%CI:0.27-2.12).No significant difference in the incidence of overall biliary complications(P=0.37,OR=1.41,95%CI:0.66-2.98),bile leaks(P=0.89,OR=1.04,95%CI:0.63-1.70),and cholangitis(P=0.27,OR=2.00,95%CI:0.59-6.84)was observed between using and not using a T-tube before 2010.However,using a T-tube appeared to increase the incidence of overall biliary complications(P=0.049,OR=1.49,95%CI:1.00-2.22),bile leaks(P=0.048,OR=1.91,95%CI:1.01-3.64),and cholangitis(P=0.02,OR=7.21,95%CI:1.37-38.00)after 2010.A random-effects model was used in biliary strictures(after 2010),overall biliary complications(before 2010),and cholangitis(before 2010)due to their heterogeneity(I2=62.3%,85.4%,and 53.6%,respectively).In the sensitivity analysis(only RCTs included),bile leak(P=0.66)lost the significance after 2010 and a random-effects model was used in overall biliary complications(before 2010),cholangitis(before 2010),bile leaks(after 2010),and biliary strictures(after 2010)because of their heterogeneity(I2=92.2%,65.6%,50.9%,and 80.3%,respectively).CONCLUSION In conclusion,the evidence gathered in our updated meta-analysis showed that the studies published in the last decade did not provide enough evidence to support the routine use of T-tube in adults during OLT.

Effect of low-dose aspirin administration on long-term survival of cirrhotic patients after splenectomy: A retrospective single-center study

BACKGROUND Cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC). Portal vein thrombosis is not uncommon after splenectomy in cirrhotic patients, and many such patients take oral anticoagulants including aspirin. However, the long-term impact of postoperative aspirin on cirrhotic patients after splenectomy remains unknown. AIM The main purpose of this study was to investigate the effect of postoperative long-term low-dose aspirin administration on the development of HCC and longterm survival of cirrhotic patients after splenectomy. METHODS The clinical data of 264 adult patients with viral hepatitis-related cirrhosis who underwent splenectomy at the First Affiliated Hospital of Xi’an Jiaotong University from January 2000 to December 2014 were analyzed retrospectively. Among these patients, 59 who started taking 100 mg/d aspirin within seven days were enrolled in the aspirin group. The incidence of HCC and overall survival were analyzed.RESULTS During follow-up, 41 (15.53%) patients developed HCC and 37 (14.02%) died due to end-stage liver diseases or other serious complications. Postoperative longterm low-dose aspirin therapy reduced the incidence of HCC from 19.02% to 3.40% after splenectomy (log-rank test, P=0.028). Univariate and multivariate analyses showed that not undertaking postoperative long-term low-dose aspirin therapy [odds ratio (OR)=6.211, 95% confidence interval (CI): 1.142-27.324, P=0.016] was the only independent risk factor for the development of HCC. Similarly, patients in the aspirin group survived longer than those in the control group (log-rank test, P=0.041). Univariate and multivariate analyses showed that the only factor that independently associated with improved overall survival was postoperative long-term low-dose aspirin therapy [OR = 0.218, 95%CI: 0.049- 0.960, P=0.044]. CONCLUSION In patients with viral hepatitis-related cirrhosis, long-term post-splenectomy administration of low-dose aspirin reduces the incidence of HCC and improves the long-term overall survival.

Fedora-type magnetic compression anastomosis device for intestinal anastomosis

BACKGROUND Although previous studies have confirmed the feasibility of magnetic compression anastomosis(MCA),there is still a risk of long-term anastomotic stenosis.For traditional MCA devices,a large device is associated with great pressure,and eventually increased leakage.AIM To develop a novel MCA device to simultaneously meet the requirements of pressure and size.METHODS Traditional nummular MCA devices of all possible sizes were used to conduct ileac anastomosis in rats.The mean(±SD)circumference of the ileum was 13.34±0.12 mm.Based on short-and long-term follow-up results,we determined the appropriate pressure range and minimum size.Thereafter,we introduced a novel“fedora-type”MCA device,which entailed the use of a nummular magnet with a larger sheet metal.RESULTS With traditional MCA devices,the anastomoses experienced stenosis and even closure during the long-term follow-up when the anastomat was smaller thanΦ5 mm.However,the risk of leakage increased when it was larger thanΦ4 mm.On comparison of the different designs,it was found that the“fedora-type”MCA device should be composed of aΦ4-mm nummular magnet with aΦ6-mm sheet metal.CONCLUSION The diameter of the MCA device should be greater than 120%of the enteric diameter.The novel“fedora-type”MCA device controls the pressure and optimizes the size.

Characteristics of fecal microbial communities in patients with non-anastomotic biliary strictures after liver transplantation

AIM To explore the possible relationship between fecal microbial communities and non-anastomotic stricture(NAS) after liver transplantation(LT).METHODS A total of 30 subjects including 10 patients with NAS, 10 patients with no complications after LT, and 10 nonLT healthy individuals were enrolled. Fecal microbial communities were assessed by the 16 S r RNA gene sequencing technology.RESULTS Different from the uncomplicated and healthy groups, unbalanced fecal bacterium ratio existed in patients with NAS after LT. The results showed that NAS patients were associated with a decrease of Firmicutes and Bacteroidetes and an increase of Proteobacteria at the phylum level, with the proportion-ratio imbalance between potential pathogenic families including Enterococcaceae, Streptococcaceae, Enterobacteriaceae, Pseudomonadaceae and dominant families including Bacteroidaceae. CONCLUSION The compositional shifts of the increase of potential pathogenic bacteria as well as the decrease of dominant bacteria might contribute to the incidence of NAS.

Miniature magnetically anchored and controlled camera system for trocar-less laparoscopy

AIM To design a miniature magnetically anchored and controlled camera system to reduce the number of trocars which are required for laparoscopy.METHODS The system consists of a miniature magnetically anchored camera with a 30° downward angle, an external magnetically anchored unit, and a vision output device. The camera weighs 12 g, measures Φ10.5 mm × 55 mm and has two magnets, a vision model, a light source, and a metal hexagonal nut. To test the prototype, the camera was inserted through a 12-mm conventional trocar in an ex vivo real liver laparoscopic training system. A trocar-less laparoscopic cholecystectomy was performed 6 times using a 12-mm and a 5-mm conventional trocar. In addition, the same procedure was performed in four canine models.RESULTS Both procedures were successfully performed using only two conventional laparoscopic trocars. The cholecystectomy was completed without any major complication in 42 min(38-45 min) in vitro and in 50 min(45-53 min) using an animal model. This camera was anchored and controlled by an external unit magnetically anchored on the abdominal wall. The camera could generate excellent image. with no instrument collisions.CONCLUSION The camera system we designed provides excellent optics and can be easily maneuvered. The number of conventional trocars is reduced without adding technical difficulties.

Magnetic-assisted laparoscopic liver transplantation in swine

Background:Although laparoscopic technology has achieved rapid development in the surgical field,it has not been applied to liver transplantation,primarily because of difficulties associated with laparoscopic vascular anastomosis.In this study,we introduced a new magnetic-assisted vascular anastomosis technique and explored its application in laparoscopic liver transplantation in pigs.Methods:Two sets of magnetic vascular anastomosis rings(MVARs)with different diameters were developed.One set was used for anastomosis of the suprahepatic vena cava(SHVC)and the other set was used for anastomosis of the infrahepatic vena cava(IHVC)and portal vein(PV).Six laparoscopic orthotopic liver transplantations were performed in pigs.Donor liver was obtained via open surgery.Hepatectomy was performed in the recipients through laparoscopic surgery.Anastomosis of the SHVC was performed using hand-assisted magnetic anastomosis,and the anastomosis of the IHVC and PV was performed by magnetic anastomosis with or without hand assistance.Results:Liver transplants were successfully performed in five of the six cases.Postoperative ultrasonographic examination showed that the portal inflow was smooth.However,PV bending and blood flow obstruction occurred in one case because the MVARs were attached to each other.The durations of loading of MVAR in the laparoscope group and manual assistance group for IHVC and PV were 13±5 vs.5±1 min(P<0.01)and 10±2 vs.4±1 min(P<0.05),respectively.The durations of MVAR anastomosis in the laparoscope group and manual assistance group for IHVC and PV were 5±1 vs.1±1 min(P<0.01),and 5±1 vs.1±1 min(P<0.01),respectively.The anhepatic phase was 43±4 min in the laparoscope group and 23±2 min in the manual assistance group(P<0.01).Conclusions:Our study showed that magnetic-assisted laparoscopic liver transplantation can be successfully carried out in pigs.

Neutrophil-to-lymphocyte ratio predicts acute kidney injury occurrence after gastrointestinal and hepatobiliary surgery

BACKGROUND Postoperative acute kidney injury(AKI) is a complex pathological process involved intrarenal and systemic inflammation caused by renal hypoperfusion, nephrotoxic drugs and urinary obstruction. Neutrophil-to-lymphocyte ratio(NLR) is a marker of inflammation reflecting the progress of many diseases. However, whether NLR at admission can predict the occurrence of AKI after surgery in the intensive care unit(ICU) remains unknown.AIM To clarify the relationship between NLR and the occurrence of AKI in patients with gastrointestinal and hepatobiliary surgery in the ICU.METHODS A retrospective analysis of 282 patients receiving surgical ICU care after gastrointestinal and hepatobiliary surgery in our hospital from December 2014 to December 2018 was performed.RESULTS Postoperative AKI occurred in 84 patients(29.79%) in this cohort. NLR by the multivariate analysis was an independent risk factor for occurrence of postoperative AKI in patients with gastrointestinal and hepatobiliary surgery in the ICU. In this cohort, receiver operating characteristic curves of AKI occurrence showed that the optimal cut-off value of NLR was 8.380. NLR was found to be significantly correlated with the white blood cell count, neutrophil count, lymphocyte count, arterial lactate and dialysis(P < 0.05). Additionally, NLR value at admission was higher in AKI patients compared with the non-AKI patients and increased with the severity of AKI. Patients with NLR ≥ 8.380 exhibited significantly higher incidences of postoperative AKI and severe AKI than patients with NLR < 8.380(AKI: 38.12% vs 14.85%, P < 0.001;severe AKI: 14.36% vs 1.98%, P = 0.001).CONCLUSION NLR at admission is a predictor of AKI occurrence in patients with gastrointestinal and hepatobiliary surgery in ICU. NLR should be included in the routine assessment of AKI occurrence.

Compromised immune status of patients with post-liver transplant biliary complications

Immunosuppression(IS)is indispensable for liver trans-plant(LTx)patients to control the unwanted alloimmune responses,which are mainly mediated by T cells.However,antigen-independent homeostasis of T cells is vital for sustaining long-lived T cell-mediated immunity,and excessive IS may increase the risk of opportunistic infections and malignancies.Therefore,IS therapy for LTx patients should be tailored to the immune status of the individual patient.[1]Biliary complications(BC),including biliary strictures with cholangitis,are the most common complications after LTx.However,the immunological characteristics especially T cell-mediated immunity of these patients are unknown yet.