Er a plausible explanation to these differences but emphasize that ourEr a plausible explanation to

Er a plausible explanation to these differences but emphasize that our
Er a plausible explanation to these differences but emphasize that our study had a larger number of patients (66 in our study vs. 27 by Mabilleau and 26 by Uccioli) and used a significantly more sensitive technique to analyze biomarkers having with a dynamic range of PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/25112874 106 as compared to 103 for colorimetric ELISA [31, 32]. It may appear paradoxical that proinflammatory cytokines in Charcot patients at presentation are below or at the level of diabetic controls when considering that the acute Charcot foot presents itself with soft tissue, cartilage andbone pathology and the classical features of a local inflammatory reaction, i.e. a red, hot and swollen foot [5]. A plausible explanation could be that proinflammatory cytokines such as TNF- and IL-1, although important for the initiation of tissue inflammation following trauma [1, 3], only last a few days and constitute a small portion of the great basin of mediators (e.g. bradykinin, histamine, prostaglandins, substance P) involved in the local regulation of blood flow (flare and heat reaction) and vascular permeability (swelling) [33] with the ability to entertain the complex neuroinflammatory cascade until optimal healing conditions are met. Another explanation for the low levels of proinflammatory cytokines at Charcot presentation is the counterregulatory buy JWH-133 activation of anti-inflammatory cytokines, such as IL-4, IL-10 and IL-13, in order to down-regulate potentially harmful levels of proinflammatory cytokines [34, 35]. The latter mechanism is supported by the current results showing high levels of IL-1RA, the circulating natural antagonist of the potent proinflammatory cytokine IL-1. IL-RA acts as a counter-regulatory positive feed-back loopFolestad et al. Journal of Foot and Ankle Research (2015) 8:Page 11 ofwith direct inhibitory effect on IL-1 thereby protecting the bone from excessive osteoclastic activity [36]. However, as we also showed high IL-1RA level in diabetic control patients, it could be inferred that its activity is linked to the diabetic disease per se as high inflammasome activity and excessive release of ROS, typical of diabetes [37], have been shown to induce high levels of IL-1RA [38]. Diabetes as the sole PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28667899 explanation is however contradicted by the IL-1RA/IL-1 ratio being significantly higher in Charcot patients due to lower IL-1 being lower than in diabetic controls. A high ratio at presentation and further increase during offloading suggest that IL-1 had reached a harmful level in the diseased foot thus prompting a counter-regulatory inhibition and a shift of the ratio in an anti-inflammatory direction. This inhibition of IL-1 may also explain the contained levels of IL-6 and TNF-, as most proinflammatory cytokines which are present at high levels in the blood of diabetic patients are IL-1-driven and reduced by blocking its activity [39]. This inhibition appear however to extend beyond the Th1/Th2 subset of proinflammatory cytokines as we were recently able to show a similar containment of IL-17 cytokines belonging to the Th17 subset in Charcot patients exerting full weight-bearing at presentation [12]. Although minor movements in a fracture have been proven beneficial for bone healing, instability and excessive motion has been shown to cause predominantly catabolic activity, suppress ingrowth of new blood vessels, trigger excessive formation of cartilage and inhibit its subsequent replacement with bone thus hindering bone from bridging the fracture gap [3]. Stabili.