Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice

Background: Gastrointestinal complications are the main cause of death in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Available treatments often restore biochemical homeostasis, but fail to cure gastrointestinal symptoms. Methods: We evaluated the small intestine neuromuscular pathology of an untreated MNGIE patient and two recipients of hematopoietic stem cells, focusing on enteric neurons and glia. Additionally, we evaluated the intestinal neuromuscular pathology in a mouse model of MNGIE treated with hematopoietic stem cell gene therapy. Quantification of muscle wall thickness and ganglion cell density was performed blind to the genotype with ImageJ. Significance of differences between groups was determined by two-tailed Mann-Whitney U test (P < 0.05). Results: Our data confirm that MNGIE presents with muscle atrophy and loss of Cajal cells and CD117/c-kit immunoreactivity in the small intestine. We also show that hematopoietic stem cell transplantation does not benefit human intestinal pathology at least on short-term. Conclusions: We suggest that hematopoietic stem cell transplantation may be insufficient to restore intestinal neuropathology, especially at later stages of MNGIE. As interstitial Cajal cells and their networks play a key role in development of gastrointestinal dysmotility, alternative therapeutic approaches taking absence of these cells into account could be required

Primary mediastinal large B-cell lymphoma (PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B

The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in CHOP and 75.7% in the MACOP-B/VACOP-B group (P<0.001). The addition of IF-RT as consolidation improved the outcome, irrespectively of the type of chemotherapy (P=0.04). At a multivariate analysis, achievement of CR (P<0.0001) and type of CT (MACOP-B/VACOP-B) retained the significance for OS (P=0.008) and EFS (P=0.03). In our experience, MACOP-B/VACOP-B appears to positively influence OS and EFS in patients affected by PMLBCL, as compared to CHOP. Consolidation IF-RT on mediastinum further improves the outcome of CR patients

Combined NADPH Oxidase 1 and Interleukin 10 Deficiency Induces Chronic Endoplasmic Reticulum Stress and Causes Ulcerative Colitis-Like Disease in Mice

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1(dKO) mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2 alpha phosphorylation preceding inflammation. In IL10/Nox1(dKO) mice, salubrinal preserved eIF2 alpha phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2 alpha pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2 alpha pathway could lead to the molecular remission needed to treat UC

Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia

Data availability: Research data are not shared.Supplementary Information oi available online at: https://www.nature.com/articles/s41598-021-98012-w#Sec14 .Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.Grants from MSD-Avenir and APHP funded the SURVIBIO study; Alexandre Nuzzo received Ph.D. Grants from “Fondation de l'Avenir” and the French Gastroenterology Society (SNFGE)

Acute extrahepatic infectious or inflammatory diseases are a cause of transient mosaic pattern on CT and MR imaging related to sinusoidal dilatation of the liver

Purpose: To report the association of a mosaic enhancement pattern on contrast-enhanced CT or MR imaging and hepatic sinusoidal dilatation (SD) with acute inflammatory conditions affecting extrahepatic organs. Methods: From 2007 to 2012, patients with acute inflammatory diseases who underwent contrast-enhanced CT and/or MRI of the liver with a mosaic enhancement pattern were selected. Clinico-biological and other imaging features were collected at diagnosis and during follow-up. Results: Sixteen patients were included (15 women, median age 27\ua0years; range 18\u201368). Five women (33\ua0%) were receiving oral contraceptives. Acute inflammatory diseases included pyelonephritis (n = 10), pancreatitis (n = 2), pneumonia (n = 1), septicemia (n = 1), active Crohn's disease (n = 1), and infectious colitis (n = 1). Median white blood cell count was 13,250 cells/\u3bcL (range 11,500-18,000 cells/\u3bcL) and CRP level 94\ua0mg/L (range 60\u2013121\ua0mg/L). Mosaic enhancement pattern was present in the whole liver and was prominent in the subcapsular areas. Four patients underwent liver biopsy confirming SD. Eleven patients underwent follow-up imaging showing normalized aspect in 9/11 patients after a median of 2\ua0months. Conclusion: Acute diseases of extrahepatic organs, associated with a marked systemic inflammatory syndrome should be added to the list of conditions causing a reversible hepatic sinusoidal dilatation as manifested by a mosaic enhancement pattern on contrast-enhanced CT or MR imaging. Key Points: \u2022 Acute extrahepatic infectious/inflammatory diseases are a cause of transient MP. \u2022 In most patients, MP was seen during both arterial and portal venous phase. \u2022 In all patients, the mosaic enhancement pattern was diffuse, but more conspicuous in subcapsular areas. \u2022 MP was no longer seen after resolution of the acute disease. \u2022 No liver biopsy should be performed

Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome

Background: Isolated sinusoidal dilatation is an uncommon hepatic lesion and the cause is largely unknown. Objective: To investigate whether prothrombotic disorders or perisinusoidal cell changes could be involved in pure idiopathic hepatic sinusoidal dilatation (HSD). Methods: Evaluation for associated conditions, prothrombotic disorders, and studies of hepatic perisinusoidal cell activation in consecutive patients, seen between 1993 and 2002, with isolated sinusoidal dilatation unrelated to outflow block, sinusoidal infiltration, or hepatic granulomas. Results: Among 11 patients, associated conditions were prothrombotic disorders (n = 5) and oral contraceptive use (n = 3). Prothrombotic disorders were polycythemia vera (n = 1) and anticardiolipin antibodies combined with lupus anticoagulant (n = 4). No genetic thrombophilia factor was found. Of four patients with lupus anticoagulant, three had antinuclear factors and high serum levels of anticardiolipin antibodies at repeated testing. There was no evidence of intrahepatic or extrahepatic thrombosis in any of the patients. Sinusoidal dilatation was marked in six of 11 patients (54%), including two patients with antiphospholipid antibodies. Activated perisinusoidal cells were only found around markedly dilated sinusoids. Conclusion: Idiopathic pure HSD is frequently associated with the immunological features of the antiphospholipid syndrome. Therefore, finding pure HSD in a liver biopsy specimen should prompt the search for antiphospholipid antibodies