Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Chronic pain associated with the Chikungunya Fever: long lasting burden of an acute illness

<p>Abstract</p> <p>Background</p> <p>Chikungunya virus (CHIKV) is responsible for major epidemics worldwide. Autochthonous cases were recently reported in several European countries. Acute infection is thought to be monophasic. However reports on chronic pain related to CHIKV infection have been made. In particular, the fact that many of these patients do not respond well to usual analgesics suggests that the nature of chronic pain may be not only nociceptive but also neuropathic. Neuropathic pain syndromes require specific treatment and the identification of neuropathic characteristics (NC) in a pain syndrome is a major step towards pain control.</p> <p>Methods</p> <p>We carried out a cross-sectional study at the end of the major two-wave outbreak lasting 17 months in Réunion Island. We assessed pain in 106 patients seeking general practitioners with confirmed infection with the CHIK virus, and evaluated its impact on quality of life (QoL).</p> <p>Results</p> <p>The mean intensity of pain on the visual-analogical scale (VAS) was 5.8 ± 2.1, and its mean duration was 89 ± 2 days. Fifty-six patients fulfilled the definition of chronic pain. Pain had NC in 18.9% according to the DN4 questionnaire. Conversely, about two thirds (65%) of patients with NC had chronic pain. The average pain intensity was similar between patients with or without NC (6.0 ± 1.7 vs 6.1 ± 2.0). However, the total score of the Short Form-McGill Pain Questionnaire (SF-MPQ)(15.5 ± 5.2 vs 11.6 ± 5.2; p < 0.01) and both the affective (18.8 ± 6.2 vs 13.4 ± 6.7; p < 0.01) and sensory subscores (34.3 ± 10.7 vs 25.0 ± 9.9; p < 0.01) were significantly higher in patients with NC. The mean pain interference in life activities calculated from the Brief Pain Inventory (BPI) was significantly higher in patients with chronic pain than in patients without it (6.8 ± 1.9 vs 5.9 ± 1.9, p < 0.05). This score was also significantly higher in patients with NC than in those without such a feature (7.2 ± 1.5 vs 6.1 ± 1.9, p < 0.05).</p> <p>Conclusions</p> <p>There exists a specific chronic pain condition associated to CHIKV. Pain with NC seems to be associated with more aggressive clinical picture, more intense impact in QoL and more challenging pharmacological treatment.</p

Short-term risk prediction after major lower limb amputation: PERCEIVE study

This multicentre cohort study of 537 patients evaluated the accuracy of preoperative predictions of outcomes by healthcare professionals and several relevant risk prediction tools. Surgeons and anaesthetists predicted 30-day outcomes after major lower limb amputation more accurately than most risk prediction tools. The best performing method of predicting mortality was a tool that incorporated healthcare professional estimation of risk.Background The accuracy with which healthcare professionals (HCPs) and risk prediction tools predict outcomes after major lower limb amputation (MLLA) is uncertain. The aim of this study was to evaluate the accuracy of predicting short-term (30 days after MLLA) mortality, morbidity, and revisional surgery. Methods The PERCEIVE (PrEdiction of Risk and Communication of outcomE following major lower limb amputation: a collaboratIVE) study was launched on 1 October 2020. It was an international multicentre study, including adults undergoing MLLA for complications of peripheral arterial disease and/or diabetes. Preoperative predictions of 30-day mortality, morbidity, and MLLA revision by surgeons and anaesthetists were recorded. Probabilities from relevant risk prediction tools were calculated. Evaluation of accuracy included measures of discrimination, calibration, and overall performance. Results Some 537 patients were included. HCPs had acceptable discrimination in predicting mortality (931 predictions; C-statistic 0.758) and MLLA revision (565 predictions; C-statistic 0.756), but were poor at predicting morbidity (980 predictions; C-statistic 0.616). They overpredicted the risk of all outcomes. All except three risk prediction tools had worse discrimination than HCPs for predicting mortality (C-statistics 0.789, 0.774, and 0.773); two of these significantly overestimated the risk compared with HCPs. SORT version 2 (the only tool incorporating HCP predictions) demonstrated better calibration and overall performance (Brier score 0.082) than HCPs. Tools predicting morbidity and MLLA revision had poor discrimination (C-statistics 0.520 and 0.679). Conclusion Clinicians predicted mortality and MLLA revision well, but predicted morbidity poorly. They overestimated the risk of mortality, morbidity, and MLLA revision. Most short-term risk prediction tools had poorer discrimination or calibration than HCPs. The best method of predicting mortality was a statistical tool that incorporated HCP estimation