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Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

In the 1990s, tumour necrosis factor-alpha inhibitor therapy ushered in the biologic therapy era for inflammatory bowel disease, leading to marked improvements in treatment options and patient outcomes. There are currently four tumour necrosis factor-alpha inhibitors approved as treatments for ulcerative colitis and/or Crohn's disease: infliximab, adalimumab, golimumab and certolizumab pegol. Despite the clear benefits of tumour necrosis factor-alpha inhibitors, a subset of patients with inflammatory bowel disease either do not respond, experience a loss of response after initial clinical improvement or report intolerance to anti-tumour necrosis factor-alpha therapy. Optimizing outcomes of these agents may be achieved through earlier intervention, the use of therapeutic drug monitoring and thoughtful switching within class. To complement these approaches, evolving predictive biomarkers may help inform and optimize clinical decision making by identifying patients who might potentially benefit from an alternative treatment strategy. This review will focus on the current use of tumour necrosis factor-alpha inhibitors in inflammatory bowel disease and the application of personalized medicine to improve future outcomes for all patients.

The global prevalence of cancer is increasing, largely as more patients are living into old age. Therefore, gastroenterologists caring for patients with inflammatory bowel disease [IBD] increasingly are managing patients with cancer, or a previous history of cancer. This often requires joint management with the patient’s oncologist, enabling case-by-case decision-making based on the characteristics and expected evolution of the index cancer. Previously, no European guidelines existed describing the impact of IBD on malignancy. For this reason, the European Crohn’s and Colitis Organisation [ECCO] Guidelines Committee [GuiCom] decided to elaborate a set of Consensus Statements on optimal risk/benefit strategies for treating IBD patients with cancer or a history of cancer. The development of clinical practice guidelines is expensive and time consuming, and it is the Committee’s hope that these statements will facilitate and accelerate future efforts to elaborate formal guidelines, providing useful information on areas for which evidence is lacking and where controlled studies are needed. The strategy used to produce the Consensus Statements involved five steps: 1. Two members of Guicom [VA and RE] identified four main topics that needed to be addressed: a] IBD and solid tumours; b] IBD and skin and haematological malignancies; c] malignancy related to therapy: risk and prevention; and d] management of IBD patients with a history of malignancy. During 2014, calls for participation in the drafting of consensus statements were issued to ECCO members, and selected oncologists known for their expertise and active research in the field were invited to join the Consensus. Participants were selected by the Committee, and four working groups were created, each composed of a chairperson [LE, RE, LB, and VA], two ECCO members including young members [Y-ECCO], and one or two experienced oncologists. The chairmen and their groups elaborated relevant questions on topics dealing with current practice and/or areas …

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Studies in rodent models demonstrated an association of CNS-infiltrating monocyte-derived macrophages with disease severity. However, little is known about humans. Here,we performed an exploratory analysis of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and drug-naïve patients with early MS using multiplexed single-cell mass cytometry and algorithm-based data analysis. Two antibody panels comprising a total of 64 antibodies were designed to comprehensively analyse diverse immune cell populations, with particular emphasis on monocytes. PBMC composition and marker expression were overall similar between the groups. However, an increased abundance of CCR7(+) and IL-6(+) T cells was detected in early MS-PBMCs, whereas NFAT1(hi)T-bet(hi)CD4(+) T cells were decreased. Similarly, we detected changes in the subset composition of the CCR7(+) and MIPβ(hi) HLA-DR(+) lymphocyte compartment. Only mild alterations were detected in monocytes/myeloid cells of patients with early MS, namely a decreased abundance of CD141(hi)IRF8(hi)CXCR3(+)CD68(−) dendritic cells. Unlike in Crohn’s disease, no significant differences were found in the monocyte fraction of patients with early MS compared to healthy controls. This study provides a valuable resource for future studies designed to characterise and target diverse PBMC subsets in MS.

Aberrant innate bacterial handling is one of the key mechanisms underlining Crohn’s disease (CD). Recently, in several inflammatory disorders defects in immunometabolism have been described but it is not clear whether this is a primary or secondary effect. Several monogenic immunodeficiencies that affect phagocyte activity present as Mendelian disorder associated inflammatory bowel disease. One intriguing subgroup is the group of patients with Glycogen storage disease type Ib (GSD-Ib) and congenital neutropenia. These patients have defective Glucose-6-phosphate metabolism caused due to genetic mutation in Glucose-6-phosphatase b and Glucose-6 phosphate-translocase (G6PT) and a subgroup develops CD-like intestinal inflammation.

After prolonged periods of energy depletion, myocardial cells may rapidly deteriorate during the early stage of reperfusion. It has now been clearly demonstrated that this kind of acute lethal reperfusion injury is due to specific processes elicited by cellular re-energization. The most prominent single cause of acute harm to the reoxygenated myocardial cells is myofibrillar hypercontraction. Hypercontraction is caused by a resupply of energy of the myofibrils at excessive cytosolic Ca2+ concentrations. Additionally, the ability of the cytoskeleton to withstand large mechanical forces seems to be weakened after a prolonged period of energy depletion. Intracellular acidosis during the early stage of reperfusion represents a natural mechanism of protection against acute reperfusion injury. The reperfused myocardial cell may also suffer from uncontrolled water uptake and increased sarcolemmal fragility, favoring osmotic damage of cell membranes. As yet therapeutical interventions trying to specifically interfere with these pathomechanisms of reperfusion injury have only been tested experimentally. It seems promising to evaluate their utility for myocardial protection in cardio-surgical operations.

Pre-War Period.-Prior to the war the bulk of men's ready-to-wear clothing sold in America was retailed at from $15 to $25. An investigation made in 1911 disclosed that about 6292 per cent of men's ready-to-wear clothing was sold at $15 to $20 retail; about 25 per cent of men's ready-to-wear clothing was sold at $25 to $35; about 10 per cent was sold below $15; and about 21 per cent was sold above $35. This investigation excluded such men's clothing as is made by custom tailors or sold by agencies representing madeto-measure houses. The investigation covered only ready-to-wear clothing sold by retailers throughout the country, and represented probably 85 per cent of all the men's clothing consumed in the United States. The demand being so diversified, running the gamut of so large a range of prices, permitted the utilization of all raw mate

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.