© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email journals.permissions@oup.com.OBJECTIVES Although pain is a common complication of the hypermobile type of Ehlers-Danlos syndrome, its underlying mechanisms are still an issue of controversy. In this psychophysical study, we aimed at testing small-fiber function and the endogenous pain inhibitory control in patients with pain due to Ehlers-Danlos syndrome. METHODS In 22 patients with pain due to Ehlers-Danlos syndrome and 22 healthy participants, matched for age and sex, we tested small-fiber function using quantitative sensory testing and the endogenous pain inhibitory control using the conditioned pain modulation (CPM) protocol. As quantitative sensory testing methods, we included thermal pain and mechanical pain thresholds and the wind-up ratio.  https://www.selleckchem.com/products/sb297006.html  The CPM protocol consisted of two heat painful stimuli, that is, a test stimulus and a conditioning stimulus. RESULTS All patients complained of widespread pain. Quantitative sensory testing revealed no small-fiber deficit; in the area of maximum pain, we found an increased wind-up ratio. Whereas in the healthy participants the CPM protocol showed that the test stimulus rating was significantly reduced during conditioning, in patients with pain due to hEDS, the test stimulus rating increased during conditioning. CONCLUSIONS Our psychophysical study showing that patients with pain due to hEDS have an increased wind-up ratio in the area of maximum pain and abnormal CPM protocol suggests that in this condition, pain is associated with central sensitization, possibly due to deficit of the endogenous pain inhibitory control. These data might be relevant to pharmacological treatment. © 2020 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.OBJECTIVE To evaluate the effects of neuromodulation techniques in adults with phantom limb pain (PLP). METHODS A systematic search was performed, comprising randomized controlled trials (RCTs) and quasi-experimental (QE) studies that were published from database inception to February 2019 and that measured the effects of neuromodulation in adults with PLP. Hedge's g effect size (ES) and 95% confidence intervals were calculated, and random-effects meta-analyses were performed. RESULTS Fourteen studies (nine RCTs and five QE noncontrolled studies) were included. The meta-analysis of RCTs showed significant effects for i) excitatory primary motor cortex (M1) stimulation in reducing pain after stimulation (ES = -1.36, 95% confidence interval [CI] = -2.26 to -0.45); ii) anodal M1 transcranial direct current stimulation (tDCS) in lowering pain after stimulation (ES = -1.50, 95% CI = -2.05 to 0.95), and one-week follow-up (ES = -1.04, 95% CI = -1.64 to 0.45). The meta-analysis of noncontrolled QE studies demonstrated a high rate of pain reduction after stimulation with transcutaneous electrical nerve stimulation (rate = 67%, 95% CI = 60% to 73%) and at one-year follow-up with deep brain stimulation (rate = 73%, 95% CI = 63% to 82%). CONCLUSIONS The evidence from RCTs suggests that excitatory M1 stimulation-specifically, anodal M1 tDCS-has a significant short-term effect in reducing pain scale scores in PLP. Various neuromodulation techniques appear to have a significant and positive impact on PLP, but due to the limited amount of data, it is not possible to draw more definite conclusions. © 2020 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Chemical safety evaluation is in the midst of a transition from traditional whole-animal toxicity testing to molecular pathway-based in vitro assays and in silico modeling. However, to facilitate the shift in reliance on apical effects for risk assessment to predictive surrogate metrics having characterized linkages to chemical mechanisms of action, targeted in vivo testing is necessary to establish these predictive relationships. In this study, we demonstrate a means to predict thyroid-related metamorphic success in the model amphibian Xenopus laevis using relevant biochemical measurements during early pro-metamorphosis. The adverse outcome pathway for thyroperoxidase inhibition leading to altered amphibian metamorphosis was used to inform a pathway-based in vivo study design that generated response-response relationships. These causal relationships were used to develop Bayesian probabilistic network models that mathematically determine conditional dependencies between biochemical nodes and support the predictive capability of the biochemical profiles. Plasma thyroxine concentrations were the most predictive of metamorphic success with improved predictivity when thyroid gland sodium-iodide symporter gene expression levels (a compensatory response) were used in conjunction with plasma thyroxine as an additional regressor. Although thyroid-mediated amphibian metamorphosis has been studied for decades, this is the first time a predictive relationship has been characterized between plasma thyroxine and metamorphic success. Linking these types of biochemical surrogate metrics to apical outcomes is vital to facilitate the transition to the new paradigm of chemical safety assessments. Published by Oxford University Press 2020.OBJECTIVE Descending pain modulation can be experimentally assessed by way of testing conditioned pain modulation. The application of tonic heat as a test stimulus in such paradigms offers the possibility of observing dynamic pain responses, such as adaptation and temporal summation of pain. Here we investigated conditioned pain modulation effects on tonic heat employing participant-controlled temperature, an alternative tonic heat pain assessment. Changes in pain perception are thereby represented by temperature adjustments performed by the participant, uncoupling this approach from direct pain ratings. Participant-controlled temperature has emerged as a reliable and sex-independent measure of tonic heat. METHODS Thirty healthy subjects underwent a sequential conditioned pain modulation paradigm, in which a cold water bath was applied as the conditioning stimulus and tonic heat as a test stimulus. Subjects were instructed to change the temperature of the thermode in response to variations in perception to tonic heat in order to maintain their initial rating over a two-minute period.