No abstract

T-cell regulation in adipose tissue provides a link between inflammation and insulin resistance. Because of alterations in adipose tissue T-cell composition in obesity, we aimed to identify the antigen-presenting cells in adipose tissue of obese mice and patients with insulin resistance. Dendritic cells (DCs) and T cells were studied in mice and in two cohorts of obese patients. In lean mice, only CD11c+ DCs were detected in adipose tissue. Adoptive transfer of naive CD4+ T cells in Rag1−/− mice led to a predominant Th1 response in adipose tissue. In contrast, during obesity DCs (human CD11c+CD1c+ and mouse CD11chighF4/80low) accumulated in adipose tissue. CD11chighF4/80low DCs from obese mice induced Th17 differentiation. In patients, the presence of CD11c+CD1c+ DCs correlated with the BMI and with an elevation in Th17 cells. In addition, these DCs led to ex vivo Th17 differentiation. CD1c gene expression further correlated with homeostatic model assessment-insulin resistance in the subcutaneous adipose tissue of obese patients. We show for the first time the presence and accumulation of specific DCs in adipose tissue in mouse and human obesity. These DCs were functional and could be important regulators of adipose tissue inflammation by regulating the switch toward Th17 cell responses in obesity-associated insulin resistance.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

BackgroundObesity modulates inflammation and activation of immune pathways which can lead to liver complications. We aimed at identifying expression patterns of inflammatory and immune response genes specifically associated with obesity and NASH in the liver of morbidly obese patients.Methodology/Principal FindingsExpression of 222 genes was evaluated by quantitative RT-PCR in the liver of morbidly obese patients with histologically normal liver (n = 6), or with severe steatosis without (n = 6) or with NASH (n = 6), and in lean controls (n = 5). Hepatic expression of 58 out of 222 inflammatory and immune response genes was upregulated in NASH patients. The most notable changes occurred in genes encoding chemokines and chemokine receptors involved in leukocyte recruitment, CD and cytokines involved in the T cell activation towards a Th1 phenotype, and immune semaphorins. This regulation seems to be specific for the liver since visceral adipose tissue expression and serum levels of MCP1, IP10, TNFα and IL6 were not modified. Importantly, 47 other genes were already upregulated in histologically normal liver (e.g. CRP, Toll-like receptor (TLR) pathway). Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis.Conclusion/SignificanceThe liver of obese patients without histological abnormalities already displayed a low-grade inflammation and could be more responsive to activators of the TLR pathway. NASH was then characterized by a specific gene signature. These findings help to identify new potential actors of the pathogenesis of NAFLD.

Background An important aspect of a new surgical technique is whether it can be performed by other surgeons in other institutions. The authors report the first 297 cases in a multi-institutional and multinational review of laparoscopic cholecystectomy performed via a single portal of entry. Methods Data were collected retrospectively for the initial patients undergoing single-port cholecystectomy by 13 surgeons who performed these procedures in their institutions after training by the authors. The review included operative time, blood loss, incision length, length of hospital stay (LOS), necessary additional trocars, and other parameters important to cholecystectomy. A database of all the single-port-access (SPA) surgeries performed by the surgeons included demographic and procedural details, LOS, complications, and initial follow-up data. Results To date, 297 single-port cholecystectomies have been performed for a variety of diagnoses, primarily cholelithiasis. The average operative time was 71 min, and the average LOS was 1-2 days. The average blood loss was minimal. The use of additional port sites outside the umbilicus occurred in 34 of the cases. Of the 35 intraoperative cholangiograms performed, 34 were successful. No significant complications occurred except for seromas and minor postoperative wound infections. These results are comparable with those for standard multiport cholecystectomy. In addition, no access site hernias (ASH) occurred. SPATM is a Trademark

Significant aspects of COVID-19 pandemic remain obscure. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system, whose expression dominates on lung alveolar epithelial cells, is the human cell receptor of SARS-CoV-2, the causative agent of COVID-19. We strongly encourage the concept that thorough considerations of receptorligand interactions should be kept at the heart of scientific debate on infection. In this idea, the whole renin-angiotensin system has to be evaluated. We hypothesize that factors related to ethnicity, environment, behaviors, associated illness, and medications involving this complex system are probably responsible for situations regarded as anomalous from both an epidemiological and a clinical point of view, but, taken together, such factors may explain most of the aspects of current outbreak. We decided to use the analogy of a play and speculate about the possible impact in this tragedy of 1) air pollution via the interference of nitrogen dioxide on ACE2 expression; 2) the dual role of nicotine; 3) the hypothetical involvement of ACE2 polymorphisms, the relationships of which with ethnic factors and susceptibility to cardiovascular disease seems intriguing; 4) the impact on the severity of infection of hypertension and related medications acting on the renin/angiotensin system, and, finally, 5) the possible helpful role of chloroquine, thanks to its capacity of modifying ACE2 affinity to the viral spike protein by altering glycosylation. This hypothesis paper is an urgent call for the development of research programs that aim at questioning whether the putative protagonists of this tragedy are real-life actors in COVID-19. Highlights• Significant aspects of COVID-19 pandemic remain obscure • Angiotensin converting enzyme 2 (ACE2) is the human cell receptor of SARS-CoV-2• Receptor-ligand interactions, should be kept at the heart of scientific debate • Ethnicity, environment, and behaviors factors interfere with these interactions • Associated illness, and medications also interfere in a possibly dual manner

Elevated MCs counts are a key feature of the low-grade inflammatory infiltrate in the caecal mucosa of IBS. Fatigue and depression are associated with mucosal cell counts, in particular MCs, suggesting that psychological factors are associated with the low-grade inflammatory infiltrate in IBS.

IH after LRYGBP has an incidence of 2.51%. Closure of mesenteric defects with non-absorbable running suture and antecolic Roux limb are recommended. Surgical exploration for suspicion of IH after LRYGBP should be first done by laparoscopy.