No abstract

The capsaicin-sensitive vanilloid receptor (VR1) was recently shown to play an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. We hypothesized that pain-producing inflammatory mediators activate capsaicin receptors by inducing the production of fatty acid agonists of VR1. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain. V R1, a cloned capsaicin receptor, is a nonspecific cation channel expressed preferentially in small sensory neurons and activated by the vanilloids, capsaicin and resiniferatoxin (1). Because VR1 is also activated by heat and acid (1, 2), it is now considered to be a molecular sensor that detects a variety of painful stimuli. Indeed, recent experiments performed in mice that lack VR1 demonstrated that the receptor is essential for inflammation-induced heat hyperalgesia (3, 4). Therefore, understanding the cellular mechanisms by which capsaicin receptors are activated by inflammatory mediators may be a key to identifying novel therapeutic targets for pain treatment. Because of the presence of VR1 in sensory neurons and an apparent role in inflammatory hyperalgesia, endogenous activators of VR1 have been suspected. We recently demonstrated that products of the lipoxygenase pathway of arachidonic acid (AA) metabolism can activate capsaicin receptors (5). Among the eicosanoids tested, the 12-lipoxygenase product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), structurally similar to capsaicin, was the most potent VR1 agonist. Thus, metabolic products of lipoxygenases become candidates for the endogenous capsaicinlike substances. However, the upstream signals that stimulate lipoxygenase and activate VR1 are elusive.Bradykinin (BK) is a potent inflammatory mediator that causes pain and hyperalgesia. BK is known to activate as well as sensitize sensory neurons to other stimuli. Various signaling pathways have been suggested to mediate the sensitizing effect of BK on sensory neurons (6, 7). However, activation mechanism by BK is not known. BK is now known to stimulate the production of AA in sensory neurons (8), a key substrate of lipoxygenases. Therefore, on the basis of previous observations that products of lipoxygenase activate VR1 (5), we hypothesized that BK excites sensory neurons by opening the capsaicin receptor via production of 12-lipoxygenase products of AA metabolism. Materials and MethodsCell Culture. Experiments were carried out according to the Ethical Guidelines of the International Association for the Study of Pain and approved by the research ethics committee for the use of animals of the Seoul National University and the University of California, San Francisco. Thoracic and lumbar dorsal root ganglia (DRGs) were dissected from 1-to 2 day-...

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

Severe fever with thrombocytopenia syndrome (SFTS), a tickborne viral disease, has been identified in China, South Korea, and Japan since 2009. We found retrospective evidence of SFTS virus (SFTSV) infection in Vietnam, which suggests that SFTSV infections also occur in Vietnam, where the virus has not been known to be endemic.