Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure

Extracellular heat-shock protein 72 (eHsp72) concentration increases during exercise-heat stress when conditions elicit physiological strain. Differences in severity of environmental and exercise stimuli have elicited varied response to stress. The present study aimed to quantify the extent of increased eHsp72 with increased exogenous heat stress, and determine related endogenous markers of strain in an exercise-heat model. Ten males cycled for 90 min at 50% O2peak in three conditions (TEMP, 20°C/63% RH; HOT, 30.2°C/51%RH; VHOT, 40.0°C/37%RH). Plasma was analysed for eHsp72 pre, immediately post and 24-h post each trial utilising a commercially available ELISA. Increased eHsp72 concentration was observed post VHOT trial (+172.4%) (P<0.05), but not TEMP (-1.9%) or HOT (+25.7%) conditions. eHsp72 returned to baseline values within 24hrs in all conditions. Changes were observed in rectal temperature (Trec), rate of Trec increase, area under the curve for Trec of 38.5°C and 39.0°C, duration Trec ≥ 38.5°C and ≥ 39.0°C, and change in muscle temperature, between VHOT, and TEMP and HOT, but not between TEMP and HOT. Each condition also elicited significantly increasing physiological strain, described by sweat rate, heart rate, physiological strain index, rating of perceived exertion and thermal sensation. Stepwise multiple regression reported rate of Trec increase and change in Trec to be predictors of increased eHsp72 concentration. Data suggests eHsp72 concentration increases once systemic temperature and sympathetic activity exceeds a minimum endogenous criteria elicited during VHOT conditions and is likely to be modulated by large, rapid changes in core temperature

Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis.</p> <p>Methods</p> <p>Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months.</p> <p>Results</p> <p>Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes.</p> <p>Conclusion</p> <p>Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.</p

Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

Examination of the efficacy of acute L-alanyl-L-glutamine ingestion during hydration stress in endurance exercise

<p>Abstract</p> <p>Background</p> <p>The effect of acute L-alanyl-L-glutamine (AG; Sustamine™) ingestion on performance changes and markers of fluid regulation, immune, inflammatory, oxidative stress, and recovery was examined in response to exhaustive endurance exercise, during and in the absence of dehydration.</p> <p>Methods</p> <p>Ten physically active males (20.8 ± 0.6 y; 176.8 ± 7.2 cm; 77.4 ± 10.5 kg; 12.3 ± 4.6% body fat) volunteered to participate in this study. During the first visit (T1) subjects reported to the laboratory in a euhydrated state to provide a baseline (BL) blood draw and perform a maximal exercise test. In the four subsequent randomly ordered trials, subjects dehydrated to -2.5% of their baseline body mass. For T2, subjects achieved their goal weight and were not rehydrated. During T3 - T5, subjects reached their goal weight and then rehydrated to 1.5% of their baseline body mass by drinking either water (T3) or two different doses (T4 and T5) of the AG supplement (0.05 g·kg^-1and 0.2 g·kg^-1, respectively). Subjects then exercised at a workload that elicited 75% of their VO₂max on a cycle ergometer. During T2 - T5 blood draws occurred once goal body mass was achieved (DHY), immediately prior to the exercise stress (RHY), and immediately following the exercise protocol (IP). Resting 24 hour (24P) blood samples were also obtained. Blood samples were analyzed for glutamine, potassium, sodium, aldosterone, arginine vasopressin (AVP), C-reactive protein (CRP), interleukin-6 (IL-6), malondialdehyde (MDA), testosterone, cortisol, ACTH, growth hormone and creatine kinase. Statistical evaluation of performance, hormonal and biochemical changes was accomplished using a repeated measures analysis of variance.</p> <p>Results</p> <p>Glutamine concentrations for T5 were significantly higher at RHY and IP than T2 - T4. When examining performance changes (difference between T2 - T5 and T1), significantly greater times to exhaustion occurred during T4 (130.2 ± 340.2 sec) and T5 (157.4 ± 263.1 sec) compared to T2 (455.6 ± 245.0 sec). Plasma sodium concentrations were greater (p < 0.05) at RHY and IP for T2 than all other trials. Aldosterone concentrations at RHY and IP were significantly lower than that at BL and DHY. AVP was significantly elevated at DHY, RHY and IP compared to BL measures. No significant differences were observed between trials in CRP, IL-6, MDA, or in any of the other hormonal or biochemical measures.</p> <p>Conclusion</p> <p>Results demonstrate that AG supplementation provided a significant ergogenic benefit by increasing time to exhaustion during a mild hydration stress. This ergogenic effect was likely mediated by an enhanced fluid and electrolyte uptake.</p

Wound healing after radiation therapy: Review of the literature

Radiation therapy is an established modality in the treatment of head and neck cancer patients. Compromised wound healing in irradiated tissues is a common and challenging clinical problem. The pathophysiology and underlying cellular mechanisms including the complex interaction of cytokines and growth factors are still not understood completely. In this review, the current state of research regarding the pathomechanisms of compromised wound healing in irradiated tissues is presented. Current and possible future treatment strategies are critically reviewed