Thermott: A comprehensive online tool for protein–ligand binding constant determination

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Self-paced exercise performance in the heat with neck cooling,menthol application,and abdominal cooling

Objectives

To investigate whether the exercise performance benefits with neck cooling in the heat are attributable to neck-specific cooling, general body cooling, a cooler site-specific thermal perception or a combination of the above.

Expression and effect of sodium-potassium-chloride cotransporter on dorsal root ganglion neurons in a rat model of chronic constriction injury

Sodium-potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) are associated with the transmission of peripheral pain.We investigated whether the increase of NKCC1 and KCC2 is associated with peripheral pain transmission in dorsal root ganglion neurons.To this aim,rats with persistent hyperalgesia were randomly divided into four groups.Rats in the control group received no treatment,and the rat sciatic nerve was only exposed in the sham group.Rats in the chronic constriction injury group were established into chronic constriction injury models by ligating sciatic nerve and rats were given bumetanide,an inhibitor of NKCC1,based on chronic constriction injury modeling in the chronic constriction injury + bumetanide group.In the experiment measuring thermal withdrawal latency,bumetanide (15 mg/kg) was intravenously administered.In the patch clamp experiment,bumetanide (10 μg/μL) and acutely isolated dorsal root ganglion neurons (on day 14) were incubated for 1 hour,or bumetanide (5 μg/μL) was intrathecally injected.The Hargreaves test was conducted to detect changes in thermal hyperalgesia in rats.We found that the thermal withdrawal latency of rats was significantly decreased on days 7,14,and 21 after model establishment.After intravenous injection of bumetanide,the reduction in thermal retraction latency caused by model establishment was significantly inhibited.Immunohistochemistry and western blot assay results revealed that the immune response and protein expression of NKCC1 in dorsal root ganglion neurons of the chronic constriction injury group increased significantly on days 7,14,and 21 after model establishment.No immune response or protein expression of KCC2 was observed in dorsal root ganglion neurons before and after model establishment.The Cl^– (chloride ion) fluorescent probe technique was used to evaluate the change of Cl^– concentration in dorsal root ganglion neurons of chronic constriction injury model rats.We found that the relative optical density of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (a Cl^– fluorescent probe whose fluorescence Cenintensity decreases as Cl– concentration increases) in the dorsal root ganglion neurons of the chronic constriction injury group was significantly decreased on days 7 and 14 after model establishment.The whole-cell patch clamp technique revealed that the resting potential and action potential frequency of dorsal root ganglion neurons increased,and the threshold and rheobase of action potentials decreased in the chronic constriction injury group on day 14 after model establishment.After bumetanide administration,the above indicators were significantly suppressed.These results confirm that CCI can induce abnormal overexpression of NKCC1,thereby increasing the Cl^– concentration in dorsal root ganglion neurons;this then enhances the excitability of dorsal root ganglion neurons and ultimately promotes hyperalgesia and allodynia.In addition,bumetanide can achieve analgesic effects.All experiments were approved by the Institutional Ethics Review Board at the First Affiliated Hospital,College of Medicine,Shihezi University,China on February 22,2017 (approval No.A2017-169-01).     

Global burden of thermal burns, 1990–2017: Unbalanced distributions and temporal trends assessed from the Global Burden of Disease Study 2017

BackgroundMany studies demonstrate that being burned has both physical and psychological sequelae that affect quality of life. Further, these effects may be more prevalent in some regions and populations. We sought to access the unbalanced distributions and temporal trends concerning the health burden of thermal burns.MethodsData were collected from the Global Burden of Disease Study 2017, and the disability-adjusted life year (DALY)¹ was used as a measure of health burden. Linear regression was used to evaluate the relationship between the age-standardized DALY rate and socio-demographic index.² Joinpoint regression analysis and comparison line charts were all applied to assess the temporal trends of burns.ResultsThe age-standardized DALY rate of global thermal burns decreased by 43.7%, from 197 (95% CI: 152–228) per 100,000 in 1990 to 111 (95% CI: 93–129) per 100,000 in 2017. The burden was borne mainly by children 1–4 years of age and people over 80 years. Socio-demographic index was negatively correlated with the age-standardized DALY rate. In low-middle and low socio-demographic index regions, the decreasing trends were slower than other regions with an average annual percentage change of ?2.1% (95% CI: ?2.2 to ?2.0) and ?2.1% (95% CI: ?2.1 to ?2.0), respectively. Among six geographical regions, Africa presented the highest age-standardized DALY rates of 352 (95% CI: 275–410) per 100,000 in 1990 and 208 (95% CI: 175–236) per 100,000 in 2017, and also the slowest average decreasing trend, with an average annual percentage change of ?1.9% (95% CI: ?2 to ?1.8).ConclusionsThe global burden of thermal burns shows a downward trend from 1990 to 2017, and regions with lower socio-demographic index and Africa show greater burdens and smaller downward trends.     

Challenging the challenge: A randomized controlled trial evaluating the inflammatory response and pain perception of healthy volunteers after single-dose LPS administration,as a potential model for inflammatory pain in early-phase drug development

Background and aimsFollowing an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.Methods and resultsThis was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1–3 h post-dose.ConclusionMild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.