IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury

Alarmins in frozen shoulder: a molecular association between inflammation and pain

Background: The pathophysiological mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Alarmins (also known as danger signals) are endogenous molecules that are released into the extracellular milieu after infection or tissue injury and that signal cell and tissue damage. Purpose: To investigate whether the presence of alarmins is higher in patients with idiopathic frozen shoulder than in control subjects. Study Design: Controlled laboratory study. Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients with unstable shoulders (control). The samples were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry using antibodies against alarmin molecules including high-mobility group protein B1 (HMGB1), interleukin 33, S100A8, S100A9, and the peripheral nerve marker PGP9.5. Immunoreactivities were rated in a blinded fashion from “none” to “strong.” Immunohistochemical distribution within the capsule was noted. Before surgery, patient-ranked pain frequency, severity, stiffness, and the range of passive shoulder motion were recorded and statistically analyzed. Results: Compared with control patients, patients with frozen shoulder had greater frequency and severity of self-reported pain (P = .02) and more restricted range of motion in all planes (P < .05). H&E-stained capsular tissue from frozen shoulder showed fibroblastic hypercellularity and increased subsynovial vascularity. Immunoreactivity of alarmins was significantly stronger in frozen shoulder capsules compared with control capsules (P < .05). Furthermore, the expression of the alarmin molecule HMGB1 significantly correlated (r > 0.9, P < .05) with the severity of patient-reported pain. Conclusion: This study demonstrates a potential role for key molecular danger signals in frozen shoulder and suggests an association between the expression of danger molecules and the pain experienced by patients

Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis

Objectives: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy. Methods: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining. Results: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes. Conclusion: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders

Measuring Black Hole Spin using X-ray Reflection Spectroscopy

I review the current status of X-ray reflection (a.k.a. broad iron line) based black hole spin measurements. This is a powerful technique that allows us to measure robust black hole spins across the mass range, from the stellar-mass black holes in X-ray binaries to the supermassive black holes in active galactic nuclei. After describing the basic assumptions of this approach, I lay out the detailed methodology focusing on "best practices" that have been found necessary to obtain robust results. Reflecting my own biases, this review is slanted towards a discussion of supermassive black hole (SMBH) spin in active galactic nuclei (AGN). Pulling together all of the available XMM-Newton and Suzaku results from the literature that satisfy objective quality control criteria, it is clear that a large fraction of SMBHs are rapidly-spinning, although there are tentative hints of a more slowly spinning population at high (M>5*10^7Msun) and low (M<2*10^6Msun) mass. I also engage in a brief review of the spins of stellar-mass black holes in X-ray binaries. In general, reflection-based and continuum-fitting based spin measures are in agreement, although there remain two objects (GROJ1655-40 and 4U1543-475) for which that is not true. I end this review by discussing the exciting frontier of relativistic reverberation, particularly the discovery of broad iron line reverberation in XMM-Newton data for the Seyfert galaxies NGC4151, NGC7314 and MCG-5-23-16. As well as confirming the basic paradigm of relativistic disk reflection, this detection of reverberation demonstrates that future large-area X-ray observatories such as LOFT will make tremendous progress in studies of strong gravity using relativistic reverberation in AGN.Comment: 19 pages. To appear in proceedings of the ISSI-Bern workshop on "The Physics of Accretion onto Black Holes" (8-12 Oct 2012). Revised version adds a missing source to Table 1 and Fig.6 (IRAS13224-3809) and corrects the referencing of the discovery of soft lags in 1H0707-495 (which were in fact first reported in Fabian et al. 2009

Evaluacija inovativno digitalno kontroliranog Er:YAG lasera u liječenju leukoplakije - probno istraživanje

The use of lasers for treatment of oral leukoplakia has gained a lot of interest in the past years, however, data on the use of Er:YAG laser are scarce. The aim of this study was to compare the efficacy of Er:YAG laser and 1% topical isotretinoin in the treatment of 27 oral leukoplakia patients. Er:YAG laser (LightWalker AT, Fotona, Slovenia) was used in 27 patients with 27 leukoplakia lesions. Postoperative pain was assessed by use of visual analog scale (VAS), and the impact of laser treatment on the quality of life was assessed by the OHIP-14 questionnaire (Croatian version). Control group consisted of the same 27 patients previously treated with 1% topical isotretionin three times a day during the period of one year. No improvement in the size of leukoplakia lesions was observed after treatment with topical isotretinoin. There were significant differences between men and women according to leukoplakia localization, number of laser sessions and VAS (p<0.05). At follow-up after six months and one year, there was no recurrence of lesions. Er:YAG laser is a successful treatment for oral leukoplakia. Topical isotretionin treatment is unsuccessful in patients with oral leukoplakia.Posljednjih godina postoji veliko zanimanje za upotrebu lasera u liječenju oralne leukoplakije, ali su podatci o upotrebi Er:YAG lasera malobrojni. Cilj ovoga istraživanja bio je usporediti učinak Er:YAG lasera i 1%-tnog topikalnog izotretinoina u liječenju 27 bolesnika s oralnom leukoplakijom. Er:YAG laser (LightWalker AT, Fotona, Slovenia) je korišten u 27 bolesnika s 27 leukoplakičnih lezija. Poslijeoperacijska bol je određena uz pomoć vizualne analogne ljestvice (visual analog scale, VAS), a utjecaj na kvalitetu života mjeren je pomoću upitnika OHIP-14 (hrvatska verzija). Kontrolna skupina se sastojala od istih 27 bolesnika koji su prije toga liječeni 1%-tnim topikalnim izotretioninom tri puta na dan tijekom tri mjeseca. Nije bilo poboljšanja u veličini lezija leukoplakije nakon topikalno primijenjenog izotretinoina. Utvrđene su značajne razlike između muškaraca i žena s obzirom na lokalizaciju leukoplakije, broj laserskih zahvata i rezultata VAS (p<0,05). Šest mjeseci i godinu dana od laserskog zahvata nije bilo recidiva oralne leukoplakije. Er:YAG laser je uspješna terapija u liječenju oralne leukoplakije. Topikalna primjena izotretionina nije uspješna u liječenju oralne leukoplakije

Why decision support systems are important for medical education

During the last decades the inclusion of digital tools in health education has rapidly lead to a continuously enlarging digital era. All the online interactions between learners and tutors, the description, creation, reuse and sharing of educational digital resources and the interlinkage between them in conjunction with cheap storage technology has led to an enormous amount of educational data. Medical education is a unique type of education due to accuracy of information needed, continuous changing competences required and alternative methods of education used. Nowadays medical education standards provide the ground for organizing the educational data and the paradata. Analysis of such education data through education data mining techniques is in its infancy, but decision support systems for medical education need further research. To the best of our knowledge, there is a gap and a clear need for identifying the challenges for decision support systems in medical education in the era of medical education standards. Thus, in this paper the role and the attributes of such a decision support system for medical education are delineated and the challenges and vision for future actions are identified

The first decade of web-based sports injury surveillance: Descriptive epidemiology of injuries in US high school boys' wrestling (2005-2006 through 2013-2014) and National Collegiate Athletic Association Men's Wrestling (2004-2005 through 2013-2014)

Context: The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided the acquisition of wrestling injury data. Objective: To describe the epidemiology of injuries sustained in high school boys' wrestling in the 2005-2006 through 2013-2014 academic years and collegiate men's wrestling in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. Design: Descriptive epidemiology study. Setting: Online injury surveillance from wrestling teams of high school boys (annual average ¼ 100) and collegiate men (annual average ¼ 11). Patients or Other Participants: Male wrestlers who participated in practices and competitions during the 2005-2006 through 2013-2014 academic years in high school or the 2004-2005 through 2013-2014 academic years in college. Main Outcome Measure(s): Athletic trainers collected time-loss (24 hours) injuries and exposure data during this time period. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios with 95% confidence intervals, and injury proportions by body site and diagnosis were calculated. Results: The High School Reporting Information Online documented 3376 time-loss injuries during 1 416 314 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 2387 time-loss injuries during 257 297 AEs. The total injury rate was higher in college than in high school (9.28 versus 2.38/1000 AEs; injury rate ratio ¼ 3.89; 95% confidence interval ¼ 3.69, 4.10). In high school, the most commonly injured body parts for both practices and competitions were the head/face (practices ¼ 19.9%, competitions ¼ 21.4%) and shoulder/clavicle (practices ¼ 14.1%, competitions ¼ 21.0%). In college, the most frequently injured body parts for both practices and competitions were the knee (practices ¼ 16.7%, competitions ¼ 30.4%) and head/face (practices ¼ 12.1%, competitions ¼ 14.6%). Conclusions: Injury rates were higher in collegiate than in high school players, and the types of injuries sustained most often differed. Based on these results, continued study of primary and secondary prevention of injury in wrestlers across levels of competition is warranted