Fas-Mediated Apoptosis Regulates the Composition of Peripheral αβ T Cell Repertoire by Constitutively Purging Out Double Negative T Cells

BACKGROUND: The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4(-)CD8(-) double negative alphabeta T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells. METHODOLOGY AND PRINCIPAL FINDINGS: We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation. CONCLUSIONS/SIGNIFICANCE: The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation

What Is Direct Allorecognition?

Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes, typically presented by donor-derived ‘passenger’ dendritic cells, are recognised directly by recipient T cells. In this review, we discuss the two principle theories which have been proposed to explain why individuals possess a high-precursor frequency of T cells with direct allospecificity and how self-restricted T cells recognise allogeneic MHCpeptide complexes. These theories, both of which are supported by functional and structural data, suggest that T cells recognising allogeneic MHC-peptide complexes focus either on the allopeptides bound to the allo-MHC molecules or the allo-MHC molecules themselves. We discuss how direct alloimmune responses may be sustained long term, the consequences of this for graft outcome and highlight novel strategies which are currently being investigated as a potential means of reducing rejection mediated through this pathway

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.The OPTIMISE II trial is supported by Edwards Lifesciences (Irvine, CA) and the UK National Institute for Health Research through RMP’s NIHR Professorship

Use of ecological niche models to predict the distribution of invasive species: a scientometric analysis

We conducted a scientometric analysis to determine the main trends and gaps of studies on the use of ecological niche models (ENMs) to predict the distribution of invasive species. We used the database of the Thomson Institute for Scientific Information (ISI). We found 190 papers published between 1991 and 2010 in 82 journals. The number of papers was low in the 1990s, but began to increase after 2003. One-third of the papers were published by researchers from the United States of America, and consequently, the USA was also the most studied region. The majority of studies were carried out in terrestrial environments, while only a few investigated aquatic systems, probably because important aquatic predictor variables are scarce or unavailable for most regions in the world. Species-occurrence records were mainly composed of presence-only records, and almost 70% of the studies were carried out with plants and insects. Twenty-three different distribution modelling methods were used. The Genetic Algorithm for Rule-set Production (GARP) was used most often. Our scientometric analysis showed a growing interest in the use of ENMs to predict the distribution of invasive species, especially in the last decade, which is probably related to the increase in species introductions worldwide. Among some important gaps that need to be filled, the relatively small number of studies conducted in developing countries and in aquatic environments deserves careful attention

Preventive effect of bariatric surgery on type 2 diabetes onset in morbidly obese inpatients: a national French survey between 2008 and 2016 on 328509 morbidly obese

Background: The association between bariatric surgery (BS) and the prevention of type 2 diabetes (T2D) and its complications in patients with obesity has been rarely addressed in large nationwide database studies. Objective: To estimate the preventive effect of BS against T2D and its vascular complications in patients with obesity without comorbidity at baseline. Setting: All French public and private hospitals Methods: Data were extracted from the French National Health Service database between 2008 and 2016. All patients with obesity aged 18 to 60 years old, free of T2D and major comorbidities, and with at least one year of follow-up were analyzed. Patients who had undergone gastric bypass (GB), sleeve gastrectomy (SG), or adjustable gastric banding (AGB) were included in the BS group and patients with obesity with no history of BS were considered as controls. Results: Of the 328,509 patients with obesity included, 102,627 had BS. Between 2009 and 2016, 9.7% (31,946 of 328,509) of patients had a diagnosis of T2D associated with morbid obesity, 13.2% of the control group versus 2.0% of the BS group (p<0.001). BS was associated with favorable 8-year T2D event-free survival estimates of 92.3% in the BS group against 58.2% in the control group. The hazard ratio for the diagnosis of T2D was 0.18 (95% CI, 0.17 to 0.19) for the BS group versus controls, after adjustment on age, gender, BMI, and baseline differences. A significant difference was found between the type of bariatric procedure (p<0.001) with more T2D after AGB (4.5%) than after GB (1.2%) or SG (0.9%). T2D complications were more common in controls (p<0.001) with multiple T2D complications occurring in 1% of patients in the control group and 0.1% in the BS group (p<0.001). GB and SG were more effective than AGB. Conclusions: This nationwide study shows that BS reduces the new onset of T2D in patients with obesity by 82%. SG and GB give comparable results and both are more effective than AGB