Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA

Polyamide-Scorpion Cyclam Lexitropsins Selectively Bind AT-Rich DNA Independently of the Nature of the Coordinated Metal

Cyclam was attached to 1-, 2- and 3-pyrrole lexitropsins for the first time through a synthetically facile copper-catalyzed “click” reaction. The corresponding copper and zinc complexes were synthesized and characterized. The ligand and its complexes bound AT-rich DNA selectively over GC-rich DNA, and the thermodynamic profile of the binding was evaluated by isothermal titration calorimetry. The metal, encapsulated in a scorpion azamacrocyclic complex, did not affect the binding, which was dominated by the organic tail

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

The Greek-Orthodox version of the Brief Religious Coping (B-RCOPE) instrument: psychometric properties in three samples and associations with mental disorders, suicidality, illness perceptions, and quality of life

Background: The B-RCOPE is a brief measure assessing religious coping. We aimed to assess the psychometric properties of its Greek version in people with and without long-term conditions (LTCs). Associations between religious coping and mental illness, suicidality, illness perceptions, and quality of life were also investigated. Methods: The B-RCOPE was administered to 351 patients with diabetes, chronic pulmonary obstructive disease (COPD), and rheumatic diseases attending either the emergency department (N = 74) or specialty clinics (N = 302) and 127 people without LTCs. Diagnosis of mental disorders was established by the MINI. Associations with depressive symptom severity (PHQ-9), suicidal risk (RASS), illness perceptions (B-IPQ), and health-related quality of life (WHOQOL-BREF) were also investigated. Results: The Greek version of B-RCOPE showed a coherent two-dimensional factor structure with remarkable stability across the three samples corresponding to the positive (PRC) and negative (NRC) religious coping dimensions. Cronbach’s alphas were 0.91–0.96 and 0.77–0.92 for the PRC and NRC dimensions, respectively. Furthermore, NRC was associated with poorer mental health, greater depressive symptom severity and suicidality, and impaired HRQoL. In patients with LTCs, PRC correlated with lower perceived illness timeline, while NRC was associated with greater perceived illness consequences, lower perceived treatment control, greater illness concern, and lower illness comprehensibility. Conclusions: These findings indicate that the Greek-Orthodox B-RCOPE version may reliably assess religious coping. In addition, negative religious coping (i.e., religious struggle) is associated with adverse illness perceptions, and thus may detrimentally impact adaptation to medical illness. These findings deserve replication in prospective studies

Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines

There are more than 400-reported bisbenzylisoquinoline alkaloids, many with interesting biological activity, but the reported syntheses are long and low yielding. As a result, there have been no systematic attempts at exploitation of the potential therapeutic applications. The concept of a sulfur 'stitch', restricting the conformational freedom of intermediates in the synthesis, will potentially allow analogues of the natural products to be prepared using relatively efficient routes. The synthesis of intermediate sulfur heterocycles is reported, based on 2,8-dimethylphenoxathiin, leading via 2,8-bis(bromomethyl) phenoxathiin-10,10-dioxide to a synthesis of 3,4,8,9-tetrahydro-13-oxa-6-thia-2, 10-diazapentacene, a key potential intermediate on the route to a variety of macrocyclic bisbenzylisoquinolines.link_to_subscribed_fulltex