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Serum levels of Calcitonin Gene-Related Peptide (CGRP)-like immunoreactivity (CGRP-LI) in migraine patients before and after starting treatment with erenumab were measured to evaluate the association with clinical treatment response.
Learn More >Moderate to severe levels of persistent knee pain have been estimated to affect up to 25% of people 3-months or more after a total knee replacement. It is unknown whether the type of rehabilitation pathway is associated with persistent high pain after surgery. Using a prospectively followed Australian cohort who underwent total knee replacement for knee osteoarthritis, this study aimed to i) report the incidence of high-intensity knee pain (defined as a score ≤ 15 on the Oxford Knee Score pain subscale) across time and ii) identify whether referral to inpatient rehabilitation was one of the predictors of persistent pain at 3-months post-surgery.
Learn More >We aimed at investigating whether functional and morphometric tests assessing small-fibre damage, ie quantitative sensory testing, Sudoscan and skin biopsy, reliably reflect neuropathic pain and autonomic symptoms in patients with late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).
Learn More >Hyperalgesia is attributed to peripheral and central sensitization in knee osteoarthritis (OA). Pressure pain threshold (PPT) is a relevant method for evaluating pain sensitivity in knee OA. The effect of end-range and not end-range Maitland mobilization for certain time-period on pain sensitivity has not been investigated in knee OA.
Learn More >Placebo effects substantially contribute to analgesic treatment outcomes and might be leveraged to enhance gold-standard treatments. The taste of oral medications has been proposed to boost placebo effects. Here, we aimed at estimating in how far the taste of an oral medication enhances placebo analgesia. We conducted a randomized, double-blind, between-group, single-visit study, with pre-treatment baseline. Over the course of three sub-studies, 318 healthy volunteers (297 included) were tested in a clinical-trial setting. Participants were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste-neutral (water), or bitter (quinine), or sweet (saccharine), or no placebo drops. Pre- vs post-treatment changes in area under the pain rating curve, the main outcome, indicated that placebo treatment showed a small analgesic effect vs no treatment. Added taste induced placebo enhancement in the very small effect size range, but accounted for a substantial portion of the overall placebo effect. No noteworthy advantage of sweet over bitter placebo was observed. An exploration of heart rate recordings indicated that placebo treatments were associated with an increase in peak heart rate response to cold water, but these were not associated with placebo analgesia at an individual level. Placebo treatments were associated with minimal side effects. These results indicate that added taste may be an easy-to-implement, cost-effective, and safe way to optimize treatment outcomes and that taste-neutral preparations may reduce placebo-related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.
Learn More >Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used drugs due to their values in attenuating pain, fever and inflammation. Unfortunately, conspicuous adverse effects, such as gastrointestinal (GI) damage and/or cardiovascular events have impeded their application in clinic. M378 is a novel hydrogen sulfide-releasing NSAIDs with uncompromised potency and negligible toxicity compared to the existing NSAIDs. However, its anti-inflammatory activity and mechanism are still an enigma. Here we investigated the effect of M378 on the NLRP3 inflammasome signaling pathway and addressed the underlying molecular mechanism. Our data in vitro showed that M378 dose-dependently inhibited the cleavage of Caspase-1 and the secretion of active IL-1β and blocked NLRP3-dependent pyroptosis in LPS-primed J774A.1 macrophages. Furthermore, M378 remarkably inhibited upstream ASC oligomerization and ROS production regarding the process of NLRP3 inflammasome assembly. Our data in vivo demonstrated that M378 protected mice from acute liver injury, reducing the levels of ALT/AST and IL-1β and improving hepatic pathological damages. Immunoblot analysis revealed that M378 inhibited the expressions of Caspase-1 and IL-1β in liver tissues of ALI mice. We also showed that M378 alleviated IL-1β secretion and peritoneal neutrophils infiltration in MSU-elicited acute peritonitis mice. In conclusion, M378 exerted its anti-inflammatory effect both in vitro and in vivo and its mechanisms are at least connected to its inhibitory performance on the generation of ASC oligomers and ROS production. These findings give an insight. into the molecular mechanism of hydrogen sulfide-releasing NSAIDs and support a potent therapeutic role of M378 in the treatment of NLRP3-driven inflammatory diseases.
Learn More >Neuropathic pain is amongst the most common non-communicable disorders and the poor effectiveness of current treatment is an unmet need. Although pain is a universal experience, there are significant inter-individual phenotypic differences. Developing models that can accurately recapitulate the clinical pain features is crucial to better understand underlying pathophysiological mechanisms and find innovative treatments. Current data from heterologous expression systems that investigate properties of specific molecules involved in pain signaling, and from animal models, show limited success with their translation into the development of novel treatments for pain. This is in part because they do not recapitulate the native environment in which a particular molecule functions, and due to species-specific differences in the properties of several key molecules that are involved in pain signaling. The limited availability of post-mortem tissue, in particular dorsal root ganglia (DRG), has hampered research using human cells in pre-clinical studies. Human induced-pluripotent stem cells (iPSCs) have emerged as an exciting alternative platform to study patient-specific diseases. Sensory neurons that are derived from iPSCs (iPSC-SNs) have provided new avenues towards elucidating peripheral pathophysiological mechanisms, the potential for development of personalized treatments, and as a cell-based system for high-throughput screening for discovering novel analgesics. Nevertheless, reprogramming and differentiation protocols to obtain nociceptors have mostly yielded immature homogenous cell populations that do not recapitulate the heterogeneity of native sensory neurons. To close the gap between native human tissue and iPSCs, alternative strategies have been developed. We will review here recent developments in differentiating iPSC-SNs and their use in pre-clinical translational studies. Direct conversion of stem cells into the cells of interest has provided a more cost- and time-saving method to improve reproducibility and diversity of sensory cell types. Furthermore, multi-cellular strategies that mimic in vivo microenvironments for cell maturation, by improving cell contact and communication (co-cultures), reproducing the organ complexity and architecture (three-dimensional organoid), and providing iPSCs with the full spatiotemporal context and nutrients needed for acquiring a mature phenotype (xenotransplantation), have led to functional sensory neuron-like systems. Finally, this review touches on novel prospective strategies, including fluorescent-tracking to select the differentiated neurons of relevance, and dynamic clamp, an electrophysiological method that allows direct manipulation of ionic conductances that are missing in iPSC-SNs.
Learn More >We studied the effects of inflammatory pain on working memory and correlated the pain effects with changes in dendritic spine density and glutamate signaling in the medial prefrontal cortex (mPFC) of male and female mice. Injection of Complete Freund's Adjuvant (CFA) into the hind paw modeled inflammatory pain. The CFA equally decreased the mechanical thresholds in both sexes. The density of dendritic spines, as a marker for neuronal input, increased on the dendrites of both, pyramidal cells and interneurons in males but only on the dendrites of interneurons in CFA injected females. Next, we injected virus with glutamate sensor (pAAV.hSyn.iGluSnFr) into the mPFC and used fiber photometry to record glutamate signaling during Y-maze spontaneous alternations test, which is a test for working memory in rodents. The detected fluorescent signal was higher during correct alternations when compared to incorrect alternations in both sexes. The CFA injection did not change the pattern of glutamate fluorescence during the test but the female mice made fewer incorrect alternations than their male counterparts. Furthermore, while the CFA injection decreased the expression of the glutamate transporter VGlut1 on the soma of mPFC neurons in both sexes, the decrease was sex dependent. We concluded that inflammatory pain, which increases sensory input into the mPFC neurons, may impair working memory by altering the glutamate signaling. The glutamate deficit that develops as a result of the pain is more pronounced in male mice in comparison to female mice.
Learn More >Primary Sjögren's syndrome (pSS) is a chronic, systemic, autoimmune disorder characterized by lymphocytic infiltrates of the exocrine organs, leading to sicca symptoms and parotid enlargement. pSS has been linked to various neurological manifestations, including peripheral neuropathy (PN). We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related PN.
Learn More >There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children.
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