Background: Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in CKD. We explored the potential impact of indoxyl sulfate on pro-inflammatory activation of macrophages and its underlying mechanisms. Methods: We examined in viro the effects of clinically relevant concentrations of indoxyl sulfate on pro-inflammatory responses of macrophages and the roles of organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics, bioinformatics, and network analysis, then explored potential key pathways. To address the role of Dll4 in indoxyl sulfate-induced macrophage activation and atherogenesis in CKD in vivo, we used 5/6 nephrectomy and Delta-like 4 (Dll4) antibody in LDL receptor-deficient (Ldlr−/−) mice. To further determine the relative contribution of OATP2B1 or Dll4 to pro-inflammatory activation of macrophages and atherogenesis in vivo, we used siRNA delivered by macrophage-targeted lipid nanoparticles in mice. Results: We found that indoxyl sulfate-induced pro-inflammatory macrophage activation is mediated by its uptake through transporters, including OATP2B1, encoded by the SLCO2B1 gene. The global proteomics identified potential mechanisms, including Notch signaling and the ubiquitin-proteasome pathway, that mediate indoxyl sulfate-triggered pro-inflammatory macrophage activation. We chose the Notch pathway as an example of key candidates for validation of our target discovery platform and for further mechanistic studies. As predicted computationally, indoxyl sulfate triggered Notch signaling, which was preceded by the rapid induction of Dll4 protein. Dll4 induction may result from inhibition of the ubiquitin-proteasome pathway, via the deubiquitinating enzyme USP5. In mice, macrophage-targeted OATP2B1/Slco2b1 silencing and Dll4 antibody inhibited pro-inflammatory activation of peritoneal macrophages induced by indoxyl sulfate. In Ldlr−/− mice, Dll4 antibody abolished atherosclerotic lesion development accelerated in CKD mice. Moreover, co-administration of indoxyl sulfate and OATP2B1/Slco2b1 or Dll4 siRNA encapsulated in macrophage-targeted lipid nanoparticles in Ldlr−/− mice suppressed lesion development. Conclusion: These results suggest that novel crosstalk between OATP2B1 and Dll4-Notch signaling in macrophages mediates indoxyl sulfate-induced vascular inflammation in CKD.

No abstract

Peroral endoscopic myotomy (POEM) and Heller myotomy with fundoplication (HMF) effectively treat achalasia, an esophageal motor disease. Although a significant number of meta-analyses have compared POEM and HMF, these studies showed discrepant postoperative gastroesophageal reflux disease (GERD) conclusions. This review aimed to objectively compare GERD over time, as well as the efficiency, safety, and adverse events in POEM versus HMF for treating achalasia.We performed a systematic review and meta-analysis by searching Medline, Embase, Cochrane Library, Scopus, and Clinicaltrials.gov. The evaluated outcomes included early (within 12 months) and late (beyond 12 months) endoscopic assessment of GERD using the Lyon Consensus, clinical success, operative duration (OD), length of stay (LOS), and major adverse events (MAE).A total of 29 observational studies and two randomized clinical trials (RCTs) with 13,914 patients were included. GERD was 28% higher among RCTs discussing POEM at early assessment (95%CI 0.02, 0.54) and was not different at late evaluation (95% confidence interval (CI) = 0.00, 0.22). No difference in reflux was observed among observational studies in both periods. The clinical success was 9% higher (95% CI = 0.05, 0.12), and the OD was 37.74 minutes shorter (95% CI = -55.44, -20.04) in POEM among observational studies, whereas it was not different among RCTs. The LOS and MAE were similar in the groups.Comparisons among studies yielded divergent results. RCTs revealed that POEM had a higher incidence of GERD in the early assessment, whereas observational studies showed higher clinical success and a shorter OD in POEM. Ultimately, the between-group difference waned over time in GERD in all comparisons, resulting in no difference among RCTs in the late evaluation. Our meta-analysis demonstrated a nonpreferential treatment of achalasia between endoscopic or surgical cardiomyotomy, prioritizing an individualized approach in the long term.

Gastric cancer is an aggressive disease with low long-term survival rates. An early diagnosis is essential to offer a better prognosis and curative treatment. Upper gastrointestinal endoscopy is the main tool for the screening and diagnosis of patients with gastric pre-neoplastic conditions and early lesions. Image-enhanced techniques such as conventional chromoendoscopy, virtual chromoendoscopy, magnifying imaging, and artificial intelligence improve the diagnosis and the characterization of early neoplastic lesions. In this review, we provide a summary of the currently available recommendations for the screening, surveillance, and diagnosis of gastric cancer, focusing on novel endoscopy imaging technologies.

BACKGROUND AND AIMS: Self-expanding metal stents (SEMS) are an effective palliative endoscopic therapy to reduce dysphagia in esophageal cancer. Gastroesophageal reflux disease (GERD) is a relatively common complaint after non-valved conventional self-expanding metal stent placement. Therefore, valved self-expanding metal stents (SEMS-V) were designed to reduce the rate of GERD symptoms. We aim to perform a systematic review and meta-analysis comparing the two stents. MATERIAL AND METHODS: This is a systematic review and meta-analysis including only randomized clinical trials (RCT) comparing the outcomes between SEMS-V and non-valved self-expanding metal stents (SEMS-NV) following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Data were analyzed with the Review Manager Software. Quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. RESULTS: Ten randomized clinical trials including a total of 467 patients, 234 in the SEMS-V group and 233 in the SEMS-NV group, were included. There were no statistically significant differences regarding GERD qualitative analysis (RD -0.17; 95% CI -0.67, 0.33; p = 0.5) and quantitative analysis (SMD -0.22; 95% CI -0.53, 0.08; p = 0.15) technical success (RD -0.03; 95% CI -0.07, 0.01; p = 0.16), dysphagia improvement (RD -0.07; 95% CI -0.19, 0.06; p = 0.30), and adverse events (RD 0.07; 95% CI -0.07, 0.20; p = 0.32). CONCLUSION: Both SEMS-V and SEMS-NV are safe and effective in the palliation of esophageal cancer with similar rates of GERD, dysphagia relief, technical success, adverse events, stent migration, stent obstruction, bleeding, and improvement of the quality of life.

No abstract

Amyloidosis is a condition related to the extracellular deposition of abnormal fibrillar proteins. Gastric involvement may present as a systemic or localized form of the disease. The endoscopic presentation can vary from nodular, ulcerated, or infiltrative lesions. Clinical manifestations are nonspecific, including hyporexia, nausea, vomiting, weight loss, epigastralgia, and abdominal discomfort. Thus, amyloidosis can clinically and endoscopically mimic other diseases, such as neoplasms, syphilis, tuberculosis, and Crohn's disease, requiring a high suspicion. When it manifests with gastrointestinal bleeding, it most commonly occurs as intermittent melena. This report aims to present an unusual case of a patient with upper gastrointestinal bleeding exteriorized through melena secondary to amyloidosis with gastric involvement.

No abstract