Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate or advanced disease and inflammation was characterized through activation of pathways mediated by Interferon, NF-κB, glucocorticoid receptor and STAT-6. Inflammation signatures revealed expression of genes and proteins induced by Interferon and NF-κB in early stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease. The pro-resolving proteins FPR2/ALX and ChemR23 were increased in early stage disease compared to intermediate-advanced stage disease. Patients who were pain-free post-treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain post-treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and Interferon target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi Lipoxin A 4 , a stable lipoxin metabolite derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation. *Corresponding author Stephanie G Dakin, stephanie.dakin@ndorms.ox.ac.uk Corresponding author telephone +44 (0)1865 227374. Author contributions: SGD performed all experiments and wrote the manuscript with input from all co-authors. SGD, AJC and FOM designed the study. FOM, UO and GW provided qPCR reagents and FOM and UO performed array analysis. FOM and GW provided human macrophages for co-culture experiments. CY facilitated confocal image acquisition. BD, KW, BW, LR and AJC facilitated procurement and collection of healthy and diseased shoulder tendons from patients.

Objective To investigate whether placebo controls should be used in the evaluation of surgical interventions.Design Systematic review.Data sources We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013.Study selection Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques.Data extraction Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies.Results In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection.Conclusions Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged.

No abstract

Tendinopathy is a common clinical problem and has a significant disease burden attached, not only in terms of health care costs, but also for patients directly in terms of time off work and impact upon quality of life. Controversy surrounds the pathogenesis of tendinopathy, however the recent systematic analysis of the evidence has demonstrated that many of the claims of an absence of inflammation in tendinopathy were more based around belief than robust scientific data. This review is a summary of the emerging research in this topical area, with a particular focus on the role of neuronal regulation and inflammation in tendinopathy.

The existing evidence supports the hypothesis that increased numbers of inflammatory cells are present in pathological tendons. The lack of high-quality quantitative studies in this area demonstrates a clear need for future research to better understand the role of inflammation in tendinopathy.

IntroductionThe pathogenesis of rotator cuff disease (RCD) is complex and not fully understood. This systematic review set out to summarise the histological and molecular changes that occur throughout the spectrum of RCD.MethodsWe conducted a systematic review of the scientific literature with specific inclusion and exclusion criteria.ResultsA total of 101 studies met the inclusion criteria: 92 studies used human subjects exclusively, seven used animal overuse models, and the remaining two studies involved both humans and an animal overuse model. A total of 58 studies analysed supraspinatus tendon exclusively, 16 analysed subacromial bursal tissue exclusively, while the other studies analysed other tissue or varying combinations of tissue types including joint fluid and muscle. The molecular biomarkers that were altered in RCD included matrix substances, growth factors, enzymes and other proteins including certain neuropeptides.ConclusionsThe pathogenesis of RCD is being slowly unravelled as a result of the significant recent advances in molecular medicine. Future research aimed at further unlocking these key molecular processes will be pivotal in developing new surgical interventions both in terms of the diagnosis and treatment of RCD.

Solid-state heterojunction solar cells formed from binary blends of conjugated polymers and fullerenes provide a promising class of organic devices. We demonstrate that ternary blends incorporating porphyrins can be of similar morphology to the binary mixture and retain full device functionality. They allow, for the first time, the construction of efficient devices containing less than 10% polymer. By analyzing the absorption spectra as a function of concentration, we determine the proportion of light absorbed by each individual component in both binary and ternary mixtures. This analysis reveals that the majority of the light is absorbed by the fullerene in 1:4 polymer/C 60 -fullerene blends, with over 50% of the photocurrent produced under AM 1.5 conditions occurring subsequent to C 60 -fullerene absorption. This result provides for a consistent understanding of the origin of primary charge separation in general polymer/C 60 -fullerene blends, polymer/C 70 -fullerene blends, and polymer-fullerene dyad molecules. Porphyrins are demonstrated to add broad-band character to the device and may be used to tune for particular wavelengths; they also are shown to initiate primary charge separation through electron-transfer to the fullerene. Finally, addition of the porphyrin is shown to increase the internal quantum efficiency following polymer absorption from ca. 60 to 80%.

ObjectivesTo find evidence, either corroborating or refuting, for many persisting beliefs regarding the feasibility of carrying out surgical randomised controlled trials with a placebo arm, with emphasis on the challenges related to recruitment, funding, anaesthesia or blinding.DesignSystematic review.Data sources and study selectionThe analysis involved studies published between 1959 and 2014 that were identified during an earlier systematic review of benefits and harms of placebo-controlled surgical trials published in 2014.Results63 trials were included in the review. The main problem reported in many trials was a very slow recruitment rate, mainly due to the difficulty in finding eligible patients. Existing placebo trials were funded equally often from commercial and non-commercial sources. General anaesthesia or sedation was used in 41% of studies. Among the reviewed trials, 81% were double-blinded, and 19% were single-blinded. Across the reviewed trials, 96% (range 50–100%) of randomised patients completed the study. The withdrawal rate during the study was similar in the surgical and in the placebo groups.ConclusionsThis review demonstrated that placebo-controlled surgical trials are feasible, at least for procedures with a lower level of invasiveness, but also that recruitment is difficult. Many of the presumed challenges to undertaking such trials, for example, funding, anaesthesia or blinding of patients and assessors, were not reported as obstacles to completion in any of the reviewed trials.