Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients

OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases

Les Houches 2011: Physics at TeV Colliders New Physics Working Group Report

We present the activities of the "New Physics" working group for the "Physics at TeV Colliders" workshop (Les Houches, France, 30 May-17 June, 2011). Our report includes new agreements on formats for interfaces between computational tools, new tool developments, important signatures for searches at the LHC, recommendations for presentation of LHC search results, as well as additional phenomenological studies.Comment: 243 pages, report of the Les Houches 2011 New Physics Group; fix three figure

Recommendations for active correction of hypernatremia in volume-resuscitated shock or sepsis patients should be taken with a grain of salt: A systematic review

Background: Healthcare-acquired hypernatremia (serum sodium >145 mEq/dL) is common among critically ill and other hospitalized patients and is usually treated with hypotonic fluid and/or diuretics to correct a “free water deficit.� However, many hypernatremic patients are eu- or hypervolemic, and an evolving body of literature emphasizes the importance of rapidly returning critically ill patients to a neutral fluid balance after resuscitation. Objective: We searched for any randomized- or observational-controlled studies evaluating the impact of active interventions intended to correct hypernatremia to eunatremia on any outcome in volume-resuscitated patients with shock and/or sepsis. Data sources: We performed a systematic literature search with studies identified by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, IndexCatalogue of the Library of the Surgeon General’s Office, DARE (Database of Reviews of Effects), and CINAHL and scanning reference lists of relevant articles with abstracts published in English. Data synthesis: We found no randomized- or observational-controlled trials measuring the impact of active correction of hypernatremia on any outcome in resuscitated patients. Conclusion: Recommendations for active correction of hypernatremia in resuscitated patients with sepsis or shock are unsupported by clinical research acceptable by modern evidence standards.ECU Open Access Publishing Support Fun

Interleukin‐7 induced immunopathology in arthritis

Interleukin (IL)‐7 is a potent immunoregulatory cytokine that is detected in joints of patients with rheumatoid and juvenile idiopathic arthritis and which correlates with parameters of disease. Several synovial cell types that play an important role in inflammation and immunopathology, such as macrophages, dendritic cells, and fibroblasts, produce IL‐7. IL‐7 induces cytokines produced by arthritogenic T cells (for example, interferon γ (IFNγ), IL‐17), T cell differentiating factors (for example, IL‐12), chemokines capable of attracting inflammatory cells (for example, macrophage induced gene (MIG), macrophage inflammatory protein (MIP)‐1α) as well as molecules involved in cell adhesion, migration, and costimulation (for example, lymphocyte function associated antigen (LFA)‐1, CD40, CD80). In addition, IL‐7 can induce bone loss by stimulating osteoclastogenesis that is dependent on receptor activator of nuclear factor κB ligand (RANKL). IL‐7 induces tumour necrosis factor α (TNFα) secretion by T cells and by monocytes after T cell dependent monocyte/macrophage activation. Importantly, induction of both IL‐7 and IL‐7 induced effects seems to be able to operate independent of TNFα. Together this suggests that IL‐7 is an important cytokine in several rheumatic conditions, capable of inducing inflammation and immunopathology. Thus it may be an important target for immunotherapy

Brief report: Enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid

OBJECTIVE: Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). METHODS: ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls, patients with psoriasis, and patients with PsA and in the synovial fluid (SF) of patients with PsA and patients with rheumatoid arthritis (RA). Cell surface marker expression and intracellular cytokine production following stimulation were analyzed using flow cytometry. RESULTS: ILCs were identified in the SF and were 4-fold more abundant in PsA SF than in PsA PB. Fewer CCR6+ ILCs were found in PsA PB than in healthy control PB, while PsA SF was enriched for CCR6+ ILCs compared to PsA PB and RA SF. Natural cytotoxicity receptor NKp44+ group 3 ILCs were rare in PB and RA SF, but abundant in PsA SF. Increased numbers of interleukin-17A (IL-17A)-producing ILCs were present in PsA SF compared to RA SF. CCR6, NKp44, and melanoma cell adhesion molecule (MCAM) were expressed on the cell surface of SF ILCs that produced IL-17A. The number of circulating NKp44+, CCR6+, and MCAM+ ILCs in blood was inversely correlated with PsA disease activity. CONCLUSION: Our findings indicate that PsA SF is enriched for group 3 ILCs that express CCR6 and NKp44, which distinguishes the synovial compartment from RA. The increased IL-17A production by SF ILCs indicates a novel role for ILCs in PsA

Top polarization in stop production at the LHC

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