Allograft rejection and the role of the immunoregulatory cytokine interleukin-12

This aim of this study was to examine the effect of neutralising endogenous IL-12 on skin allograft survival in a mouse experimental model. The immune response following treatment was investigated to determine whether anti-IL-12 antibody could switch a Th1 to a Th2 response and whether this was associated with prolonged graft survival. C57B1/6 and DBA/2 mice were grafted with tail skin from semi- allogeneic (C57B1/6 X DBA/2) F1 (BDFi) donors. Skin graft survival was compared between untreated mice and those treated with a neutralising goat anti-mouse IL-12 polyclonal antibody. In addition, mice were pre-treated with donor specific transfusion in the form of BDF1 spleen cells injected intravenously prior to grafting, or with a combination of both anti-IL-12 antibody and donor cell pretreatment. Skin graft survival was not prolonged in animals which had been treated with anti-IL-12 antibody or donor cell injection alone compared to unmodified controls. Allograft survival was, however, significantly prolonged in animals pretreated with both anti-IL-12 antibody plus donor cell injection. Interestingly, when a fully allogeneic mismatch was used, this combined treatment did not prolong graft survival. The immunological processes involved with the rejection response were investigated. The spleens of treated and untreated mice were removed at various time points after grafting and single cell suspensions prepared and maintained in vitro. When re-stimulated with irradiated BDF1 cells in a MLR, cells from unmodified C57B1/6 graft recipients proliferated well. However, where animals had been pre-treated with donor cells, either with or without anti-IL-12 antibody, proliferation was markedly reduced, although such a reduction was not associated with prolonged graft survival. Pre-treatment with anti-IL-12 antibody alone did not reduce proliferation in vitro. Supernatants from cultures of spleen cells from treated animals re-stimulated with donor-specific antigen were analysed for their cytokine content by ELISA. Unmodified graft rejection was associated with increased production of the Ti1 cyokines, IL-2 and IFN-gamma. Treatment with donor cells prior to grafting abolished this Th1 response in vitro, with cells producing little Th1 or Th2 cytokines, although grafts were still rejected at the normal time. Treatment with anti-IL-12 antibody alone induced cells to produce less IFN-gamma in vitro and also slightly increased production of the Th2 cytokines, IL-5 and IL-10, although this did not alter allograft rejection. Pre-treatment with both anti-IL-12 antibody and donor cells abolished a Th1 response and significantly increased Th2 cytokine production and this was associated with prolonged allograft survival. In this model, therefore, prolonged skin graft survival appeared to be associated with an increased Th-2 response and a down-regulated Th-1 response when cells from treated animals were re-stimulated in vitro. Specific cytotoxicity, as measured by CTL activity in spleen cell preparations was not reduced by neutralising endogenous IL-12, but NK cell activity was reduced. NK cells are responsible for the elimination of injected foreign cells, and persistence of such injected cells within the host has been shown by others to prolong allograft survival. However, using FACS analysis, it was not possible to demonstrate that reduced NK cell activity directly led to increased survival of injected BDF1 cells in treated animals in this model. Thus inhibition of endogenous IL-12, together with donor cell pretreatment, prolonged skin graft survival and this was associated with an up-regulated Th2 response and a down-regulated Th1 response. This indicates that effecting a switch to a Th2 response can prove beneficial for allograft survival

Hate Crime in the News: The Media’s Role in Agenda Setting

Examining the extant literature on hate crimes shows that there has been an evolutionary process of Hate Crime legislation (HC). Similar to other social movements such as civil rights, the hate crime movement also had various waves which eventually lead to the passage of legislation. By and large, however, HC research has focused on victims and offenders of hate crimes as well as motivations of bias. Moreover, less research has been done on the media’s portrayal and coverage of HC. Since the media is a noted influencer in social issues (Culotta, 2002; Quisenberry, 2001), we sought to answer how the news media are reporting incidences of hate crimes – particularly LGBTQ+- and compare them with official crime statistics reported by law enforcement agencies. In order to answer these questions, our research utilized a qualitative content analysis using QSR NVivo 12.0 to identify potential themes and trends which may be overlooked in simple quantitative methods. Our dataset comes from the Hate Crime Index ("ProPublica," 2018), for the month of June 2018. Official FBI data is also utilized for comparison, spanning from 2012 to 2016. Our results suggest that the media reports HC within an overall internal Agenda Setting Orientation. During analysis, two main themes were identified that show the (i) media report both the failures and challenges of law enforcement in dealing with HC issue and, (ii) that media highlights various best practices some agencies engage in. Limitations and future research directions are discussed

Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis

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Rubisco and carbon-concentrating mechanism co-evolution across chlorophyte and streptophyte green algae.

Green algae expressing a carbon-concentrating mechanism (CCM) are usually associated with a Rubisco-containing micro-compartment, the pyrenoid. A link between the small subunit (SSU) of Rubisco and pyrenoid formation in Chlamydomonas reinhardtii has previously suggested that specific RbcS residues could explain pyrenoid occurrence in green algae. A phylogeny of RbcS was used to compare the protein sequence and CCM distribution across the green algae and positive selection in RbcS was estimated. For six streptophyte algae, Rubisco catalytic properties, affinity for CO2 uptake (K0.5 ), carbon isotope discrimination (δ13 C) and pyrenoid morphology were compared. The length of the βA-βB loop in RbcS provided a phylogenetic marker discriminating chlorophyte from streptophyte green algae. Rubisco kinetic properties in streptophyte algae have responded to the extent of inducible CCM activity, as indicated by changes in inorganic carbon uptake affinity, δ13 C and pyrenoid ultrastructure between high and low CO2 conditions for growth. We conclude that the Rubisco catalytic properties found in streptophyte algae have coevolved and reflect the strength of any CCM or degree of pyrenoid leakiness, and limitations to inorganic carbon in the aquatic habitat, whereas Rubisco in extant land plants reflects more recent selective pressures associated with improved diffusive supply of the terrestrial environment.NE/L002507/1, BB/M007693/1, BB/I024518/1 (NERC, BBSRC and NSF). A Cambridge Trust Vice Chancellor’s award and Lucy Cavendish College, Cambridge, for supporting the PhD scholarship of MMMG. DJO and ECS acknowledge support from (BBSRC; grant number BB/I024488/1)

Frailty Assessment in Vascular OUtpatients Review (FAVOUR) PROTOCOL – single-centre prospective cohort study comparing feasibility and prognostic value of commonly used frailty assessment tools

Introduction: Frailty has consistently demonstrated associations with poorer healthcare outcomes. Vascular guidelines have recognised the importance of frailty assessment. However, an abundance of frailty tools and a lack of prospective studies confirming suitability of routine frailty assessment in clinical practice has delayed the uptake of these guidelines. The Frailty Assessment in Vascular OUtpatients Review study speaks to this evidence gap. The primary aim is to assess feasibility of implementing routine frailty assessment in a reproducible outpatient setting. Secondary objectives include comparing prognostic values and interuser agreement across five frailty assessment tools. Methods and analysis: This single-centre prospective cohort study of feasibility is conducted in a rapid-referral vascular surgery clinic, serving a population of 2 million. Adults with capacity (>18 years), attending a clinic for any reason, are eligible for inclusion. Five assessments are completed by patient (Rockwood Clinical Frailty Scale (CFS) and Frail NonDisabled Questionnaire), clinician (CFS, Healthcare Improvement Scotland FRAIL tool and ‘Initial Clinical Evaluation’) and researcher (11-item modified Frailty Index). Consistent with feasibility objectives, outcome measures include recruitment rates, frailty assessment completion rates, time-to-complete assessments and interuser variability. Electronic follow-up at 30 days and 1 year will assess home-time and mortality as prognostic indicators. Patients treated surgically/endovascularly will undergo additional 30-day and 1-year postoperative follow-up, outcome measures include: surgical procedure, mortality, complications (according to Clavien-Dindo Classification), length of stay, readmission rates, non-home discharge, home-time, higher social care requirements on discharge and amputation-free survival. Prognostic value will be compared by area under receiver operating characteristic curves. Continuous outcome variables will be analysed using Spearman’s rank correlation coefficient. Interuser agreement will be compared by percentage agreement in Cohen’s kappa coefficient.  Ethics and dissemination: The study is sponsored by National Health Service Greater Glasgow and Clyde (R&IUGN23CE014). London-Riverside REC (23/PR/0062) granted ethical approval. Results will be disseminated through publication in peer-reviewed vascular surgery and geriatric medicine themed journals and presentation at similar scientific conferences. Trials registration number: NCT06040658. Stage of study: pre-results

Success Rate and Utility of Ultrasound-guided Synovial Biopsies in Clinical Practice

OBJECTIVE: The utility of synovial biopsy in increasing our understanding of the pathogenesis of inflammatory arthropathies, as well as in evaluating treatments, is well established. Ultrasound (US) allows synovial assessment and therefore assists in biopsying synovial tissue in a safe and well-tolerated manner. This study's objectives were to (1) determine the rate of success in retrieving synovial tissue using US guidance, (2) describe the indications for US-guided synovial biopsies in the clinical setting, (3) determine how frequently the synovial biopsy can lead to a clear diagnosis, and (4) assess the quality of the synovial tissue obtained using this technique. METHODS: Synovial biopsies of small and large joints were performed under US guidance between February 2007 and December 2014 using a semiautomatic core biopsy needle. The biopsy procedure was considered successful if synovial tissue was found at histological examination. RESULTS: Seventy-four patients with undifferentiated arthritis underwent 76 synovial biopsies. The success rate in retrieving synovial tissue was 81.6% (62/76). One patient taking acetyl salicylic acid at 75 mg at the time of the biopsy presented with hemarthrosis 48 h after the procedure, which resolved following simple arthrocentesis. A definitive diagnosis was achieved in 16% of the patients where synovial tissue was sampled successfully. CONCLUSION: US-guided synovial biopsies in clinical practice can be performed safely on patients with undifferentiated arthritis and with heterogeneous presentations. The rate of success in acquiring synovial tissue is high. The procedure usually retrieves quality tissue and leads to a definite diagnosis in a significant minority of patients

Climatic and vegetational drivers of insect beta diversity at the continental scale

Aim: We construct a framework for mapping pattern and drivers of insect diversity at the continental scale and use it to test whether and which environmental gradients drive insect beta diversity. Location: Global; North and Central America; Western Europe. Time period: 21st century. Major taxa studied: Insects. Methods: An informatics system was developed to integrate terrestrial data on insects with environmental parameters. We mined repositories of data for distribution, climatic data were retrieved (WorldClim), and vegetation parameters inferred from remote sensing analysis (MODIS Vegetation Continuous Fields). Beta diversity between sites was calculated and then modeled with two methods, Mantel test with multiple regression and generalized dissimilarity modeling. Results: Geographic distance was the main driver of insect beta diversity. Independent of geographic distance, bioclimate variables explained more variance in dissimilarity than vegetation variables, although the particular variables found to be significant were more consistent in the latter, particularly, tree cover. Tree cover gradients drove compositional dissimilarity at denser coverages, in both continental case studies. For climate, gradients in temperature parameters were significant in driving beta diversity more so than gradients in precipitation parameters. Main conclusions: Although environmental gradients drive insect beta diversity independently of geography, the relative contribution of different climatic and vegetational parameters is not expected to be consistent in different study systems. With further incorporation of additional temporal information and variables, this approach will enable the development of a predictive framework for conserving insect biodiversity at the global scale

Radio spectra and polarisation properties of a bright sample of Radio-Loud Broad Absorption Line Quasars

The origin of broad-absorption-line quasars (BAL QSOs) is still an open issue. Accounting for ~20% of the QSO population, these objects present broad absorption lines in their optical spectra generated from outflows with velocities up to 0.2c. In this work we present the results of a multi-frequency study of a well-defined radio-loud BAL QSO sample, and a comparison sample of radio-loud non-BAL QSOs, both selected from the Sloan Digital Sky Survey (SDSS). We aim to test which of the currently-popular models for the BAL phenomenon - `orientation' or 'evolutionary' - best accounts for the radio properties of BAL quasars. Observations from 1.4 to 43 GHz have been obtained with the VLA and Effelsberg telescopes, and data from 74 to 408 MHz have been compiled from the literature. The fractions of candidate GHz-peaked sources are similar in the two samples (36\pm12% vs 23\pm8%), suggesting that BAL QSOs are not generally younger than non-BAL QSOs. BAL and non-BAL QSOs show a large range of spectral indices, consistent with a broad range of orientations. There is weak evidence (91% confidence) that the spectral indices of the BAL QSOs are steeper than those of non-BAL QSOs, mildly favouring edge-on orientations. At a higher level of significance (\geq97%), the spectra of BAL QSOs are not flatter than those of non-BAL QSOs, which suggests that a polar orientation is not preferred.Comment: Accepted by A&