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

Adsorption of (Poly)vanadate onto Ferrihydrite and Hematite: An In Situ ATR–FTIR Study

Copyright © 2020 American Chemical SocietyFunding was provided by the Natural Sciences and Engineering Council of Canada (NSERC) through the Discovery Grants program (Grant no. RGPIN-2014-06589). Additional support awarded to C.J.V. was through the NSERC-Canada Graduate Scholarship-Master’s (NSERC CGS-M) Program. M.P.S. would like to acknowledge the Natural Sciences and Engineering Research Council Collaborative Research and Training Experience Sustainable Applied Fertilizer and Environmental Remediation (NSERC CREATE SAFER) program, as well as the NSERC Research and Development grant supported by Federated Cooperatives Limited for financial support.Peer ReviewedVanadium (V) has been a useful trace metal in describing Earth’s biogeochemical cycling and development of industrial processes; however, V has recently been recognized as a potential contaminant of concern. Although Fe (oxyhydr)oxides are important sinks for aqueous V in soils and sediments, our understanding of adsorption mechanisms is currently limited to mononuclear species (i.e., HxVO4(3–x)–). Here we use in situ attenuated total reflectance – Fourier transform infrared spectroscopy to examine sorption mechanisms and capacity for (poly)vanadate attenuation by ferrihydrite and hematite from pH 3 to 6. Adsorption isotherms illustrate the low affinity of polyvanadate species for ferrihydrite surfaces compared to hematite. Mononuclear V species (i.e., [HxVO4](3−x)− and VO2+) were present at all experimental conditions. At low surface loadings and pH 5 and 6, H2VO4− adsorption onto ferrihydrite and hematite surfaces results from formation of inner sphere complexes. At [V]T above 250 µM, adsorbed polynuclear V species in this study include H2V2O72− and V4O124−. Whereas, HV10O286−, H3V10O285−, and NaHV10O284− are the predominant adsorbed species at pH 3 and 4 and elevated [V]T. Surface polymers were identified on hematite at all experimental pH values, whereas polymeric adsorption onto ferrihydrite was limited to pH 3 and 4. These results suggest that hematite offers a more suitable substrate for polymer complexation compared to ferrihydrite. Our results demonstrate the pH and concentration dependant removal of (poly)vanadate species by Fe(III) (oxyhydr)oxides, which has implications for understanding V mobility, behaviour, and fate in the environment

The Unusually Long Duration Gamma-ray Burst GRB 000911: Discovery of the afterglow and host galaxy

Of all the well-localized gamma-ray bursts, GRB 000911 has the longest duration (T90 = 500 s) and ranks in the top 1% of BATSE bursts for fluence. Here we report the discovery of the afterglow of this unique burst. In order to simultaneously fit our radio and optical observations, we are required to invoke a model involving a hard electron distribution, p ∼ 1.5, and a jet-break time less than 1.5 days. A spectrum of the host galaxy taken 111 days after the burst reveals a single emission line, interpreted as [011] at a redshift z = 1.0585, and a continuum break that we interpret as the Balmer limit at this redshift. Despite the long 790, the afterglow of GRB 000911 is not unusual in any other way when compared to the set of afterglows studied to date. We conclude that the duration of the GRB plays little part in determining the physics of the afterglow.P. A. P. gratefully acknowledges an Alex Rodgers Travelling Scholarship. J. S. B. gratefully acknowledges the fellowship support from the Fannie and John Hertz Foundation. K. H. is grateful for Ulysses support under JPL contract 958056, and for IPN support under the NEAR Participating Scientist program, NAG 5-9503, and under the LTSA, NAG 5-3500. The Konus/Wind experiment was supported by RFBR grant 99-02-017031 and CRDF grant RPI-2260

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Chronic exposure to outdoor air pollution and diagnosed cardiovascular disease: meta-analysis of three large cross-sectional surveys

BACKGROUND: Higher exposure to outdoor air pollution is associated with increased cardiopulmonary deaths, but there is limited evidence about the association between outdoor air pollution and diagnosed cardiovascular disease. Our study aimed to estimate the size of the association between long term exposure to outdoor air pollution and prevalent cardiovascular disease. METHODS: We carried out a cross-sectional analysis of data on more than 19,000 white adults aged 45 and older who participated in three representative surveys of the English population in 1994, 1998 and 2003, examining the relationship between self-reported doctor-diagnosed cardiovascular disease and exposure to outdoor air pollutants using multilevel regression techniques and meta-analysis. RESULTS: The combined estimates suggested that an increase of 1 microg m-3 in concentration of particulate matter less than 10 microns in diameter was associated with an increase of 2.9% (95% CI -0.6% to 6.5%) in prevalence of cardiovascular disease in men, and an increase of 1.6% (95%CI -2.1% to 5.5%) in women. The year-specific analyses showed strongly positive associations in 2003 between odds of cardiovascular disease in both men and women and exposure to particulate matter but not in 1994 or 1998. We found no consistent associations between exposure to gaseous air pollutants and doctor-diagnosed cardiovascular disease. CONCLUSION: The associations of prevalent cardiovascular disease with concentration of particulate matter less than 10 microns in diameter, while only weakly positive, were consistent with the effects reported in cohort studies. The results provide evidence of the size of the association between particulate air pollution and the prevalence of cardiovascular disease but no evidence for an association with gaseous pollutants. We found strongly positive associations between particulate matter and cardiovascular disease in 2003 only, which highlights the importance of replicating findings in more than one population

Bridge to the future: Important lessons from 20 years of ecosystem observations made by the OzFlux network

In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on global change biology. OzFlux is a network not only for ecosystem researchers, but also for those ‘next users’ of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem\u27s carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under-represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long-term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists, geologists, remote sensors and modellers

Bridge to the future: Important lessons from 20 years of ecosystem observations made by the OzFlux network

In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on global change biology. OzFlux is a network not only for ecosystem researchers, but also for those ‘next users’ of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem's carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under-represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long-term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists, geologists, remote sensors and modellers.</p

A consensus-based transparency checklist

We present a consensus-based checklist to improve and document the transparency of research reports in social and behavioural research. An accompanying online application allows users to complete the form and generate a report that they can submit with their manuscript or post to a public repository

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common