Injection of acid into the gastrocnemius muscle results in a persistent, mechanical hyperalgesia of the hindpaw (Sluka et al., 2001). Here, the ability of neurotrophins to alter the development of this secondary hyperalgesia was assessed using transgenic mice and exogenous neurotrophin administration. Acid-induced hyperalgesia was measured in wild-type and transgenic mice that overexpress neurotrophin-3 (NT-3) in muscle (myo/NT-3 mice). Mechanical and thermal sensitivity of the hindpaws were assessed after injections of acidic saline, pH 4, into the right medial gastrocnemius. Wild-type mice exhibited mechanical but not thermal hyperalgesia in both paws 1 d after acid injection. In contrast, myo/NT-3 mice developed a transient mechanical hyperalgesia in both paws that disappeared by 2-3 d. The reversal of hyperalgesia in myo/NT-3 mice could be mimicked by intramuscular administration of exogenous NT-3 to acid-injected mice but not by other neurotrophins. The route of NT-3 administration appears critical, because intrathecal or intraperitoneal delivery were ineffective. The hyperalgesia could only be reversed by NT-3 treatment concurrent with acid injection and not after the emergence of hyperalgesia. The acid-induced hyperalgesia did not redevelop after the termination of NT-3 treatment, suggesting that NT-3 permanently reversed the hyperalgesia. Consistent with the behavioral data, paw palpation of acid-injected mice significantly increased Fos expression in the spinal cord of wild-type but not myo/NT-3 or NT-3-injected mice. The attenuation of hyperalgesia suggests that NT-3 may be a modulator of muscle-derived pain, and NT-3 may suppress events that lead to secondary hyperalgesia triggered by insult to muscle afferents.
BackgroundGiant Cell Arteritis (GCA) is a type of large vessel vasculitis that can cause blindness and aortic aneurysms. A significant unmet medical need remains in GCA, as current treatment options are limited, and relapse increases corticosteroid (CS) exposure and toxicity.The primary role of macrophages/dendritic cells (DCs) and TH1/TH17 lymphocytes in GCA pathogenesis has been highlighted previously. Granulocyte-macrophage colony stimulating factor (GM-CSF) may contribute to GCA pathogenesis by stimulating giant cell formation.1 GM-CSF produced by CD4+ T helper TH1 and TH17 cells can stimulate conventional DCs and promote differentiation of monocyte-derived DCs.2 GM-CSF may drive DCs to program naïve CD4+ cells to TH1, TH17, and T follicular helper phenotypes (IFNγ/IL-17/IL-21). Notably GM-CSF RNA has been reported in GCA lesions3 and in peripheral blood mononuclear cells of symptomatic patients.4 ObjectivesWe hypothesized elevation of the GM-CSF pathway signature in GCA vessels versus controls.MethodsTwo independent sources of temporal artery biopsies were utilized. First, GCA (n=17) and control (symptomatic patients suspected for GCA, but with a normal temporary artery biopsy; n=5) biopsies were analyzed for 15 mRNA transcripts representing TH1, TH17, and GM-CSF signaling (RNAscope; RS) and for mRNA transcripts representing the autoimmune panel (Nanostring; NS). Semi-quantitative scoring was performed on RS images, and fold-change of representative TH1, TH17 and GM-CSF related mRNA transcripts were calculated via NS nCounter analysis. Additional GCA and control biopsies were obtained and analyzed by RT-PCR for a subset of transcripts (n=10 each) and by confocal microscopy for GM-CSF and GM-CSF-Rα protein (n=2 each).ResultsThe GM-CSF signaling pathway molecular signature was confirmed to be upregulated by 4 independent analyses.GM-CSF-associated and TH1-associated genes were upregulated in GCA biopsies versus control (GMCSF: 3-4x RS; GM-CSF-Rα: 6.7x NS, 6x RS; and CD83: 3.9x NS, 6x RS; TNFα: 2x NS, 3x RS; IFNγ: 2x RS; IL-1β: 6x RS). TH17 associated genes were not elevated, potentially due to concomitant CS treatment.Upregulation of both GM-CSF (12x) and GM-CSF-Rα (3x) mRNA was confirmed in a separate cohort of biopsies from GCA patients vs. controls by RT-PCR (Figure). GM-CSF and GM-CSFRα proteins were detected in the luminal endothelium, neovessels and inflammatory cells of GCA patients. In normal temporal arteries, GM-CSF protein was not detected, and some GM-CSFRα expression was observed in the luminal endothelium.Pu.1, a transcription factor downstream of GM-CSF signaling, was increased 8x in GCA vs. controls (RS, NS) (Figure).ConclusionGM-CSF and TH1 pathway signatures were demonstrated in GCA patient temporal arteries by independent analytical techniques. Active GM-CSF signaling in diseased tissue is evidenced by increased expression of Pu.1 in the vessel wall. These data implicate the GM-CSF pathway in GCA pathophysiology and increase confidence in rationale for targeting GM-CSF in GCA.References[1] M-...
Background: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. Objectives: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. Design: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period. Setting: Forty-two sites in 11 countries. Participants: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization. Intervention: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. Measurements: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. Results: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. Conclusion: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.
To evaluate cellular response to oncostatin M (OSM) in comparison to interleukin (IL)-31, we analyzed monocyte chemoattractant protein 1 (MCP-1) as a read-out for OSM responses with and without IL-4, IL-13, anti-OSM receptor β monoclonal antibody KPL-716, and anti–IL-31 receptor α antibody in human epidermal keratinocytes and human dermal fibroblasts in vitro . In human epidermal keratinocytes, OSM significantly induced STAT3 or STAT1 phosphorylation and synergized with IL-13 or IL-4 in elevating MCP-1. In human dermal fibroblasts, OSM results were similar, and leukemia inhibitory factor or IL-31 minimally activated STAT3 but not MCP-1. OSM significantly stimulated mRNA for type II IL-4 receptor and type II OSM receptor. KPL-716, not anti–IL-31Rα, significantly attenuated MCP-1 response to OSM and OSM + IL-4 in human epidermal keratinocytes and human dermal fibroblasts. OSM, not leukemia inhibitory factor or IL-31, synergized with IL-4 and IL-13 in human epidermal keratinocytes and human dermal fibroblasts, suggesting therapeutic potential of KPL-716 in inflammatory dermatologic diseases distinct from IL-31 inhibition.
Treatment with ruxolitinib cream (INCB18424; RUX) is associated with significant therapeutic benefit in mild to moderate atopic dermatitis patients. In comparison with vehicle and triamcinolone 0.1%, skin disease severity was improved to a greater degree following treatment with 1.5% RUX BID in a Phase 2b (NCT03011892) placebo-controlled clinical trial. This study investigated the effects of treatment with vehicle, triamcinolone 0.1%, 1.5% RUX QD, 1.5% RUX BID on inflammatory mediator expression in circulation. Sera from 65 subjects in the ITT population (n¼17 Vehicle, n¼19 Triamcinolone (4 weeks followed by vehicle), n¼13 1.5% RUX QD, n¼16 1.5% RUX BID) that had both baseline and week 8 serum samples were analyzed for broad proteomic changes following treatment. Paired t-tests were used to establish significant changes within treatment groups at a cutoff of p<0.05. Expression of 1012 proteins was evaluated for each subject. From week 1 to week 8, 183 proteins were modulated in the 1.5% RUX BID, 26 proteins in 1.5% RUX QD, 50 proteins in Triamcinolone, and 17 proteins in the vehicle cohort (p<0.05). The majority (n¼175) were down-regulated in 1.5% RUX BID, while slightly over 50% (n¼15) were down-regulated in 1.5% RUX QD. In comparison, 17 proteins were modulated in the Vehicle cohort and 50 in the Triamcinolone cohort. Using pathway analysis tools, the Th1 and Th2 activation, inflammatory response, and immune cell trafficking pathways were modulated by treatment with RUX. Topical treatment with RUX has the potential to modulate disease pathogenesis by reducing disease-related inflammatory markers during the course of treatment.
Background: Constipation is traditionally defined as infrequent bowel movements or hard faeces. Patients report a variety of symptoms, including decreased bowel motion frequency, straining, hard stools, the sensation of incomplete emptying, the sensation of anal blockage, or the use of digitation or positioning to aid defecation. Physical health, mental health, and social functioning are all compromised in affected individuals. Despite this, only one-fifth of constipated people seek medical attention. Constipation symptoms are reported by 10% to 20% of adults worldwide. This study investigated the effects of aerobic exercise along with core muscle strengthening on young individuals with constipation. Methods: The study included 50 participants having constipation. The participants were randomly allocated in two groups. The intervention period was of 4 weeks. The exercises were explained to all individuals and pre and post treatment PAC SYM (patient assessment of constipation symptoms) and PAC-QOL (patient assessment of constipation quality of life) questionnaire scoring along with Rome IV criteria was taken. Results: In group A, post-treatment values of PAC SYM and PAC QOL were significantly lower than pre-treatment values. The post-treatment comparison of two groups revealed a significant difference in PAC SYM and PAC QOL, with group B showing a significant reduction in PAC SYM and PAC QOL compared to group A. Conclusions: The present study concluded that individuals who underwent both aerobic and core strengthening training showed more improvement than individuals who performed aerobic training alone.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.