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Limited value of the D-dimer based YEARS algorithm to rule out pulmonary embolism in sickle cell disease and sickle cell trait Further research is needed to establish whether an altered SCD-specific PERC rule might be more suitable in ruling out PE in patients with SCD. Sickle cell disease (SCD) is associated with hypercoagulability and an increased risk of venous thromboembolism (VTE) including pulmonary embolism (PE).1-4 In patients with SCD, overlapping symptoms between PE and acute complications such as vaso-occlusive crisis (VOC) and/or acute chest syndrome lead to diagnostic challenges.5 Therefore, reliable diagnostic algorithms to rule out PE and avoid the frequent use of computed tomography pulmonary angiography (CTPA) are urgently needed for patients with SCD.6 In patients without SCD with clinically suspected PE, D-dimer-based PE algorithms are recommended. CTPA could be withheld in only 7% of patients with SCD and 24% of HbAS individuals, while the YEARS algorithm can safely avoid a CTPA in 48% of unselected individuals with clinically suspected PE.14 It is therefore vital to develop diagnostic algorithms for patients with SCD that are not based on D-dimer levels. [Extracted from the article]

A series of cyclic ketones with better catalytic properties have been synthesized from the corresponding diacids. The derived ketones are highly effective in catalyzing the oxidation of olefins due to their steric and electronic effects as well as the ring strains. Ketone recovery is greater than 90% and product yield is excellent in the epoxidation of olefins and catalysis of alcohols. The synthesized ketones are robust, recyclable and environment-friendly catalysts that should find wide use in oxidation reactions.

The synthesis of a series of novel C2 symmetrical chiral ketones and their activities in catalytic asymmetric epoxidations are described. The first cyclic ketone obtained from the process acted as the ideal template for the introduction of chiral elements. Results also showed that the ester groups that provide rigid and C2 symmetric structures to the cyclic ketones significantly influence the effectiveness of asymmetric epoxidations.

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. [ABSTRACT FROM AUTHOR]

The use of chiral ketone catalysts with C2 symmetry enables the asymmetric epoxidation of trans-stilbenes with high enantioselectivity. However, the increase in enantioselectivity reaches a plateau and subsequently drops with increasing size of the steric sensor. Such catalysts, however, may also be used as probes to show that dioxirane epoxidation proceeds as a spiro transition state.

The feasibility of using the C2 symmetric chiral ketone as a catalyst for asymmetric epoxidation of unfunctionalized trans-olefins and trisubstituted olefins is evaluated through experimental studies. Results indicate that the C2 ketone is very stable under reaction conditions and can be recovered in high yield without any loss of catalytic activity. It also gives excellent ennantioselectivity for epoxidation of trans-olefins and trisubstituted olefins.

Objectives: We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development., Methods: Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo., Results: Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development., Conclusions: A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA., Competing Interests: Competing interests: PPT is a former employee and DMG a current employee of GlaxoSmithKline, UK. GlaxoSmithKline was not involved in the design and/or execution of the study. NdV reports grants from AbbVie, Janssen Biologics, Ergomed Clinical Research, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Roche, as well as personal fees from MSD, UCB, Janssen, non-financial support from Roche, personal fees and non-financial support from Pfizer, all outside the submitted work. In addition, NdV has a patent method for determining the risk of developing arthritis pending. MS reports a research grant from AstraZeneca (received in August 2015). AstraZeneca was not involved in this study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL-21-producing cells T cells has been neglected. We sought to investigate the role of IL-21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4 + IL-21 + T cells. We show that the frequency of both synovial fluid (SF) CD4 + IL-21 + or CD4 + IL-21 + TNF + T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL-21 + CD4 + T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti-CCP) antibodies and IgM-rheumatoid factor (IgM-RF). IL-21 levels in RA SF were associated with matrix metalloproteinase (MMP)-1 and MMP-3. Related to this, IL-21 induced significantly the secretion of MMP-1 and MMP-3 in RA synovial biopsies. Sorted SF CD4 + IL-21 + T cells significantly induced the release of MMP-1 and MMP-3 by fibroblast-like synoviocytes (FLS) compared with medium or CD4 + IL-21 - T cells in a coculture system. Neutralization of both IL-21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4 + IL-21 + TNF + T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL-21 blockade in combination with anti-TNF might be an effective therapy in patients with RA by inhibiting MMP-induced inflammation/joint destruction., (© Society for Leukocyte Biology.)