The Mechanism of Astragaloside IV in NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome-mediated Pyroptosis after Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is one of the most common subtypes of stroke. OBJECTIVES: This study aimed to investigate the mechanism of Astragaloside IV (AS-IV) on inflammatory injury after ICH. METHODS: The ICH model was established by the injection of collagenase and treated with ASIV (20 mg/kg or 40 mg/kg). The neurological function, water content of the bilateral cerebral hemisphere and cerebellum, and pathological changes in brain tissue were assessed. The levels of interleukin-1 beta (IL-1ß), IL-18, tumor necrosis factor-alpha, interferon-gamma, and IL-10 were detected by enzyme-linked immunosorbent assay. The levels of Kruppel-like factor 2 (KLF2), NOD-like receptor family pyrin domain containing 3 (NLRP3), GSDMD-N, and cleaved-caspase-1 were detected by reverse transcription-quantitative polymerase chain reaction and Western blot assay. The binding relationship between KLF2 and NLRP3 was verified by chromatin-immunoprecipitation and dual-luciferase assays. KLF2 inhibition or NLRP3 overexpression was achieved in mice to observe pathological changes. RESULTS: The decreased neurological function, increased water content, severe pathological damage, and inflammatory response were observed in mice after ICH, with increased levels of NLRP3/GSDMD-N/cleaved-caspase-1/IL-1ß/IL-18 and poorly-expressed KLF2 in brain tissue. After AS-IV treatment, the neurological dysfunction, high brain water content, inflammatory response, and pyroptosis were alleviated, while KLF2 expression was increased. KLF2 bonded to the NLRP3 promoter region and inhibited its transcription. Down-regulation of KLF2 or upregulation of NLRP3 reversed the effect of AS-IV on inhibiting pyroptosis and reducing inflammatory injury in mice after ICH. CONCLUSION: AS-IV inhibited NLRP3-mediated pyroptosis by promoting KLF2 expression and alleviated inflammatory injury in mice after ICH.

Artificial intelligence in endoscopic ultrasonography: risk stratification of gastric gastrointestinal stromal tumors.

Background: Previous studies have identified useful endoscopic ultrasonography (EUS) features to predict the malignant potential of gastrointestinal stromal tumors (GISTs). However, the results of the studies were not consistent. Artificial intelligence (AI) has shown promising results in medicine. Objectives: We aimed to build a risk stratification EUS-AI model to predict the malignancy potential of GISTs. Design: This was a retrospective study with external validation. Methods: We developed two models using EUS images from two hospitals to predict the GIST risk category. Model 1 was the four-category risk EUS-AI model, and Model 2 was the two-category risk EUS-AI model. The diagnostic performance of the models was validated with external cohorts. Results: A total of 1320 images (880 were very low-risk, 269 were low-risk, 68 were intermediate-risk, and 103 were high-risk) were finally chosen for building the models and test sets, and a total of 656 images (211 were very low-risk, 266 were low-risk, 88 were intermediate-risk, and 91 were high-risk) were chosen for external validation. The overall accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the four-category risk EUS-AI model in the external validation sets by tumor were 74.50%, 55.00%, 79.05%, 53.49%, and 81.63%, respectively. The accuracy, sensitivity, specificity, PPV, and NPV for the two-category risk EUS-AI model for the prediction of very low-risk GISTs in the external validation sets by tumor were 86.25%, 94.44%, 79.55%, 79.07%, and 94.59%, respectively. Conclusion: We developed a EUS-AI model for the risk stratification of GISTs with promising results, which may complement current clinical practice in the management of GISTs. Registration: The study has been registered in the Chinese Clinical Trial Registry (No. ChiCTR2100051191).

Silencing of ALOX15 reduces ferroptosis and inflammation induced by cerebral ischemia-reperfusion by regulating PHD2/HIF2α signaling pathway.

OBJECTIVE: To investigate the potential mechanism of arachidonic acid deoxyribozyme 15 (ALOX15) in ferroptosis and inflammation induced by cerebral ischemia reperfusion injury. METHODS: The mice and cell models of cerebral ischemia-reperfusion injury were constructed. Western Blot was used to detect the protein expression levels of ALOX15, glutathione peroxidase (GPX4), hypoxia-inducible factor-2α (HIF-2α), prolyl hydroxylase (PHD) and inflammatory factors (NLRP3, IL-1ß, IL-18) in brain tissues and cells. Cell proliferation activity was detected by CCK-8 method. LDH assay was used to detect the release of lactate dehydrogenase. TTC staining was used to observe cerebral infarction. RESULTS: In cerebral ischemia-reperfusion mice and cell models, the expression of ALOX15 protein was increased, the expression of GPX4, a key marker of ferroptosis was decreased, and silencing of ALOX15 down-regulated the GPX4 expression. HIF-2α expression was down-regulated in animal and cell models of cerebral ischemia reperfusion, and silencing of ALOX15 increased the HIF-2α expression by inhibiting PHD2 expression. Inhibition of ALOX15 expression reduced inflammatory factors levels (NLRP3, IL-1ß, and IL-18) in cerebral ischemia. Inhibitor of PHD2 (IXOC-4) alleviating brain injury and cell death induced by cerebral ischemia reperfusion and stabilize HIF-2α expression in vivo. CONCLUSION: The expression of ALOX15 was up-regulated in cerebral ischemia-reperfusion animals and cells model. Inhibition of ALOX15 up-regulated the GPX4 expression, and promoted HIF-2α expression by inhibiting PHD2, thus alleviating ferroptosis and inflammation caused by cerebral ischemia-reperfusion injury.

dupA + H. pylori reduces diversity of gastric microbiome and increases risk of erosive gastritis.

Helicobacter pylori is believed to induce gastropathy; however, the exact pathogenic molecules involved in this process have not been elucidated. Duodenal ulcer promoting gene A (DupA) is a virulence factor with a controversial role in gastric inflammation and carcinogenesis. To explore and confirm the function of DupA in gastropathy from the perspective of the microbiome, we investigated the microbial characteristics of 48 gastritis patients through 16S rRNA amplicon sequencing. In addition, we isolated 21 H. pylori strains from these patients and confirmed the expression of dupA using PCR and qRT-PCR. Bioinformatics analysis identified diversity loss and compositional changes as the key features of precancerous lesions in the stomach, and H. pylori was a characteristic microbe present in the stomach of the gastritis patients. Co-occurrence analysis revealed that H. pylori infection inhibits growth of other gastric inhabiting microbes, which weakened the degradation of xenobiotics. Further analysis showed that dupA+ H. pylori were absent in precancerous lesions and were more likely to appear in erosive gastritis, whereas dupA- H. pylori was highly abundant in precancerous lesions. The presence of dupA in H. pylori caused less disturbance to the gastric microbiome, maintaining the relatively richness of gastric microbiome. Overall, our findings suggest that high dupA expression in H. pylori is correlated with a high risk of erosive gastritis and a lower level of disturbance to the gastric microbiome, indicating that DupA should be considered a risk factor of erosive gastritis rather than gastric cancer.

Artificial Intelligence in the Prediction of Gastrointestinal Stromal Tumors on Endoscopic Ultrasonography Images: Development, Validation and Comparison with Endosonographers.

Background/Aims: The accuracy of endosonographers in diagnosing gastric subepithelial lesions (SELs) using endoscopic ultrasonography (EUS) is influenced by experience and subjectivity. Artificial intelligence (AI) has achieved remarkable development in this field. This study aimed to develop an AI-based EUS diagnostic model for the diagnosis of SELs, and evaluated its efficacy with external validation. Methods: We developed the EUS-AI model with ResNeSt50 using EUS images from two hospitals to predict the histopathology of the gastric SELs originating from muscularis propria. The diagnostic performance of the model was also validated using EUS images obtained from four other hospitals. Results: A total of 2,057 images from 367 patients (375 SELs) were chosen to build the models, and 914 images from 106 patients (108 SELs) were chosen for external validation. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the model for differentiating gastrointestinal stromal tumors (GISTs) and non-GISTs in the external validation sets by images were 82.01%, 68.22%, 86.77%, 59.86%, and 78.12%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in the external validation set by tumors were 83.75%, 71.43%, 89.33%, 60.61%, and 80.56%, respectively. The EUS-AI model showed better performance (especially specificity) than some endosonographers. The model helped improve the sensitivity, specificity, and accuracy of certain endosonographers. Conclusions: We developed an EUS-AI model to classify gastric SELs originating from muscularis propria into GISTs and non-GISTs with good accuracy. The model may help improve the diagnostic performance of endosonographers. Further work is required to develop a multi-modal EUS-AI system.

Microbiota analysis with next-generation 16S rDNA gene sequencing in recurrent common bile duct stones.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is the main remedy for gallstones, but the postoperative recurrence rate is high. Recent research has indicated that the biliary microbiome takes part in the pathogenesis of cholelithiasis. However, it is not yet known whether biliary microbiome dysbiosis is relevant to recurrent cholelithiasis. Methods: Thus, we investigated the bacterial communities of the biliary microbiomes of patients with recurrent common bile duct (CBD) stones and analyzed the relationship between recurrent CBD stones and biliary microbiota. The bile specimens of 5 patients with recurrent CBD stones (FF) and 45 patients with primary CBD stones (YF) were collected during the ERCP process. The microbiota was analyzed using 16S ribosomal DNA (rDNA) high-throughput sequencing. We also identified the link between recurrent CBD stones and biliary microbiota. Results: Our results showed that at the phylum level, proteobacteria and firmicutes were the main two genera groups, and proteobacteria was high in FF patients. Additionally, synergistetes were high, but Bacteroidetes and actinobacteria were low in FF patients. The microbiomes in the bile of the YF patients were more evenly distributed than those in the bile of the FF patients. We also discovered that FF patients had decreased microbial bile diversity. At the genus level, klebsiella dominated in the FF patients, while Escherichia-shigella dominated in the YF patients. Additionally, klebsiella was higher in the FF patients than the YF patients. Conclusions: The observed differences in the genera between the recurrent CBD stone FF patients and the YF patients provide novel insights into the link between biliary microbiota changes and recurrent CBD stones.

Real-Time Artificial Intelligence-Based Histologic Classifications of Colorectal Polyps Using Narrow-Band Imaging.

Background and Aims: With the development of artificial intelligence (AI), we have become capable of applying real-time computer-aided detection (CAD) in clinical practice. Our aim is to develop an AI-based CAD-N and optimize its diagnostic performance with narrow-band imaging (NBI) images. Methods: We developed the CAD-N model with ResNeSt using NBI images for real-time assessment of the histopathology of colorectal polyps (type 1, hyperplastic or inflammatory polyps; type 2, adenomatous polyps, intramucosal cancer, or superficial submucosal invasive cancer; type 3, deep submucosal invasive cancer; and type 4, normal mucosa). We also collected 116 consecutive polyp videos to validate the accuracy of the CAD-N. Results: A total of 10,573 images (7,032 images from 650 polyps and 3,541 normal mucous membrane images) from 478 patients were finally chosen for analysis. The sensitivity, specificity, PPV, NPV, and accuracy for each type of the CAD-N in the test set were 89.86%, 97.88%, 93.13%, 96.79%, and 95.93% for type 1; 93.91%, 95.49%, 91.80%, 96.69%, and 94.94% for type 2; 90.21%, 99.29%, 90.21%, 99.29%, and 98.68% for type 3; and 94.86%, 97.28%, 94.73%, 97.35%, and 96.45% for type 4, respectively. The overall accuracy was 93%. We also built models for polyps ≤5 mm, and the sensitivity, specificity, PPV, NPV, and accuracy for them were 96.81%, 94.08%, 95%, 95.97%, and 95.59%, respectively. Video validation results showed that the sensitivity, specificity, and accuracy of the CAD-N were 84.62%, 86.27%, and 85.34%, respectively. Conclusions: We have developed real-time AI-based histologic classifications of colorectal polyps using NBI images with good accuracy, which may help in clinical management and documentation of optical histology results.

Microbiologic risk factors of recurrent choledocholithiasis post-endoscopic sphincterotomy.

BACKGROUND: Choledocholithiasis is a severe disorder that affects a significant portion of the world's population. Treatment using endoscopic sphincterotomy (EST) has become widespread; however, recurrence post-EST is relatively common. The bile microbiome has a profound influence on the recurrence of choledocholithiasis in patients after EST; however, the key pathogens and their functions in the biliary tract remain unclear. AIM: To investigate the biliary microbial characteristics of patients with recurrent choledocholithiasis post-EST, using next-generation sequencing. METHODS: This cohort study included 43 patients, who presented with choledocholithiasis at the Guangdong Second Provincial General Hospital between May and June 2020. The patients had undergone EST or endoscopic papillary balloon dilation and were followed up for over a year. They were divided into either the stable or recurrent groups. We collected bile samples and extracted microbial DNA for analysis through next-generation sequencing. Resulting sequences were analyzed for core microbiome and statistical differences between the diagnosis groups; they were examined using the Kyoto Encyclopedia of Genes and Genomes pathway hierarchy level using analysis of variance. Correlation between the key genera and metabolic pathways in bile, were analyzed using Pearson's correlation test. RESULTS: The results revealed distinct clustering of biliary microbiota in recurrent choledocholithiasis. Higher relative abundances (RAs) of Fusobacterium and Neisseria (56.61% ± 14.81% vs 3.47% ± 1.10%, 8.95% ± 3.42% vs 0.69% ± 0.32%, respectively) and the absence of Lactobacillus were observed in the bile of patients with recurrent disease, compared to that in stable patients. Construction of a microbiological co-occurrence network revealed a mutual relationship among Fusobacterium, Neisseria, and Leptotrichia, and an antagonistic relationship among Lactobacillales, Fusobacteriales, and Clostridiales. Functional prediction of biliary microbiome revealed that the loss of transcription and metabolic abilities may lead to recurrent choledocholithiasis. Furthermore, the prediction model based on the RA of Lactobacillales in the bile was effective in identifying the risk of recurrent choledocholithiasis (P = 0.03). CONCLUSION: We demonstrated differences in the bile microbiome of patients with recurrent choledocholithiasis compared to that in patients with stable disease, thereby adding to the current knowledge on its microbiologic etiology.

Quantum electric-dipole liquid on a triangular lattice.

Geometric frustration and quantum fluctuations may prohibit the formation of long-range ordering even at the lowest temperature, and therefore liquid-like ground states could be expected. A good example is the quantum spin liquid in frustrated magnets. Geometric frustration and quantum fluctuations can happen beyond magnetic systems. Here we propose that quantum electric-dipole liquids, analogues of quantum spin liquids, could emerge in frustrated dielectrics where antiferroelectrically coupled electric dipoles reside on a triangular lattice. The quantum paraelectric hexaferrite BaFe12O19 with geometric frustration represents a promising candidate for the proposed electric-dipole liquid. We present a series of experimental lines of evidence, including dielectric permittivity, heat capacity and thermal conductivity measured down to 66 mK, to reveal the existence of an unusual liquid-like quantum phase in BaFe12O19, characterized by itinerant low-energy excitations with a small gap. The possible quantum liquids of electric dipoles in frustrated dielectrics open up a fresh playground for fundamental physics.

Diagnostic Utility of Endoscopic Retrograde Cholangiography/Intraductal Ultrasound (ERC/IDUS) in Distinguishing Malignant from Benign Bile Duct Obstruction.

BACKGROUND AND AIM: Accurately differentiating malignant diseases from benign ones in patients having bile duct obstruction is of significant importance and remains a major clinical problem. This study investigated the diagnostic yield of endoscopic retrograde cholangiography/intraductal ultrasound (ERC/IDUS) in distinguishing malignant from benign bile duct obstruction and assessed some image findings from ERC/IDUS which might be useful in differentiation. METHODS: From January 2008 to January 2015, patients who underwent ERC/IDUS for bile duct obstruction were enrolled. Patient's ERC/IDUS diagnosis was compared with the final diagnosis determined by pathologic findings and/or clinical outcome of follow-up. RESULTS: One hundred and ninety-three patients with bile duct obstruction were included. IDUS correctly identified 94 of 97 malignant diseases and 76 of 96 benign diseases with sensitivity, specificity, and accuracy rate of 96.91, 79.17, and 88.08 %, respectively. Additionally, the accuracy rate of IDUS for diagnosis of proximal bile duct obstruction was higher than that of distal bile duct obstruction (98.08 vs. 82.73 %, p = 0.006). Besides, there was a significant difference in the length at the obstruction site between benign and malignant diseases (13.76 ± 7.37 vs. 19.97 ± 11.37 mm, p < 0.001) as well as thickness of bile duct wall at the site of obstruction (3.06 ± 0.92 vs. 7.03 ± 3.70 mm, p = 0.008). Biliary wall thickness >7 mm without extrinsic compression had a positive predictive value (PPV) of 100 % for including malignancy, while length ≧20 mm demonstrated a PPV of 93.44 %. CONCLUSIONS: ERC/IDUS is effective in distinguishing malignant from benign bile duct obstruction, thus helping in further clinical management.

Efficacy and safety of photodynamic therapy for unresectable cholangiocarcinoma: A meta-analysis.

BACKGROUND: Photodynamic therapy with the placement of a biliary stent may improve the prognosis in patients with unresectable cholangiocarcinoma. The aim of this research is to determine the hazard ratio of photodynamic therapy with stent compared to biliary stenting alone or other therapies for the treatment of cholangiocarcinoma. METHODS: Several databases were searched from inception to December 31 2013 for trials comparing photodynamic therapy+stent vs. stent-only or other treatments for cholangiocarcinoma. The outcomes of interest included patient survival, the changes of serum bilirubin levels, the quality of life (Karnofsky performance status), and adverse events. The hazard ratios (HR) were extracted from the survival curves using Tierney's Method. LnHR and its variance were pooled using an inverse variance-weighted average. Inconsistency was quantified using I(2) statistics. RESULTS: In all, 8 trials comparing PDT+stent with other therapeutic methods were selected. We made a meta-analysis based on the 7 trials, which compared the result of PDT+stent and the stent-only group. HR summarizes the survival for the two groups. Overall survival was significantly better in patients who received photodynamic therapy than those who did not [HR=0.49, 95% confidence interval (CI), 0.33∼0.73, P=0.0005]. Among the 8 trials (642 subjects), 5 assessed the changes of serum bilirubin levels, and/or Karnofsky performance status, as other indications for improvement. In all, the incidence for phototoxic reaction is 11.11%. The incidence for other events in photodynamic therapy and the stent-only group was 13.64% and 12.79%, respectively. CONCLUSION: The palliative treatment of cholangiocarcinoma, with photodynamic therapy, is associated with an increased survival benefit, an improved biliary drainage, and a better quality of life. However, the quality of this evidence is low.

Endoscopic retrieval technique of proximally migrated pancreatic stents: a retrospective study in a tertiary centre.

Background. There were scarce trials concerning the treatments and outcomes of proximal pancreatic stent migration. Herein, we did a retrospective study to discuss this problem from an endoscopist's point of view. Patients and Methods. From January 2009 to June 2014, patients with proximally migrated pancreatic duct stents were identified. Their clinical information was viewed. Retrieval techniques, success rates, and adverse events were analyzed. Results. A total of 36 procedures were performed in 34 patients; the median age of the patients was 53 years, with 17 males and 17 females. Eight patients' pancreatic duct stents could still be seen in the major or minor papilla and were pulled out with a snare forceps or a grasping forceps; in the remaining 28 procedures, the management was somewhat thorny; the retrieval called for several devices. Final success was achieved in 31 patients. No adverse event was observed in the process of ERCP procedures, 5 patients developed post-ERCP pancreatitis (PEP), 1 patient got infection, and 1 patient had haemorrhage. Conclusions. Endoscopic retrieval of migrated pancreatic stent is safe and less invasive; nonetheless, attention should be paid so as to reduce the incidence and degree of related adverse events, especially PEP.

Short-term and long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation for bile duct stones.

OBJECTIVE: The aim of this study was to compare the short-term and long-term outcomes of endoscopic sphincterotomy (EST) with endoscopic papillary balloon dilation (EPBD), and to find out risk factors for long-term complications. PATIENTS AND METHODS: From January 2008 to June 2011, patients who underwent endoscopic retrograde cholangiopancreatography for common bile duct stone removal were included, and they were divided into EST and EPBD groups. Clinical information was retrospectively viewed, and the patients were contacted through telephone or by searching for the medical records to get long-term outcomes. RESULTS: A total of 863 patients were included, with 636 patients in the EST group and 227 patients in the EPBD group. There was no difference in the rate of complete stone removal and early complications, except for pancreatitis. In all, 493 patients in the EST group and 170 patients in the EST group were followed up for 36.7-77.6 months. More patients in the EST group developed cholangitis, stone recurrence, and cholecystitis in the long term. Multivariate analysis showed that EPBD was a protective factor for cholangitis, stone recurrence, and cholecystitis. Gall stones were risk factors for cholangitis and cholecystitis. Mechanical lithotripsy may also be a risk factor for stone recurrence. CONCLUSION: EST shows better results in early outcomes, but during long-term follow-up patients following EST experienced more number of late complications. Gall stones and mechanical lithotripsy may be risk factors for long-term complications.