All-trans retinoic acid inhibits migration and invasiveness of rheumatoid fibroblast-like synoviocytes

[Abstract] Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT All-trans retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs.Instituto de Salud Carlos III; PI1701660Instituto de Salud Carlos III; PI1401153Instituto de Salud Carlos III (RETICS); RD16/0012/001

Exercise Capacity in Children and Adolescents With Congenital Heart Disease: A Systematic Review and Meta-Analysis

Congenital heart disease (CHD) entails structural defects in the morphogenesis of the heart or its main vessels. Analyzing exercise capacity of children and adolescents with CHD is important to improve their functional condition and quality of life, since it can allow timely intervention on poor prognostic factors associated with higher risk of morbidity and mortality.To describe exercise capacity in children and adolescents with CHD compared with healthy controls.A systematic review was carried out. Randomized clinical trials and observational studies were included assessing exercise capacity through direct and indirect methods in children and adolescents between 5 and 17 years-old. A sensitive analysis was performed including studies with CHD repaired participants. Additionally, it was sub-analyzed by age range (< and ? 12 years old). Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of the evidence.5619 articles were found and 21 were considered for the review. Eighteen articles used the direct exercise capacity measurement method by cardiopulmonary exercise test (CPET). The CHD group showed significant differences in peak oxygen consumption (VO2peak) with a value of -7.9 ml/Kg/min (95% CI: -9.9, -5.9, p = 0.00001), maximum workload (Wmax) -41.5 (95% CI: -57.9, -25.1 watts, p = 0.00001), ventilatory equivalent (VE/VCO2 ) slope 2.6 (95% CI: 0.3, 4.8), oxygen pulse (O2 pulse)-2.4 ml/beat (95% CI: -3.7, -1.1, p = 0.0003), and maximum heart rate (HRmax) -15 bpm (95% CI: -18, -12 bpm, p = 0.00001), compared with healthy controls. Adolescents (? 12 yrs) with CHD had a greater reduction in VO2peak (-10.0 ml/Kg/min (95% CI: -12.0, -5.3), p < 0.00001), Wmax (-45.5 watts (95% CI: -54.4, -36.7), p < 0.00001) and HRmax (-21 bpm (95% CI: -28, -14), p<0.00001).Suffering CHD in childhood and adolescence is associated with lower exercise capacity as shown by worse VO2peak, Wmax, VE/VCO2 slope, O2 pulse, and HRmax compared with matched healthy controls. The reduction in exercise capacity was greater in adolescents.www.crd.york.ac.uk/prospero/display_record.php?RecordID=208963, identifier: CRD42020208963.Copyright © 2022 Villaseca-Rojas, Varela-Melo, Torres-Castro, Vasconcello-Castillo, Mazzucco, Vilaró and Blanco

Cross-Comparison of Climate Change adaptation Strategies Across Large River Basins in Europe, Africa and Asia

A cross-comparison of climate change adaptation strategies across regions was performed, considering six large river basins as case study areas. Three of the basins, namely the Elbe, Guadiana, and Rhine, are located in Europe, the Nile Equatorial Lakes region and the Orange basin are in Africa, and the Amudarya basin is in Central Asia. The evaluation was based mainly on the opinions of policy makers and water management experts in the river basins. The adaptation strategies were evaluated considering the following issues: expected climate change, expected climate change impacts, drivers for development of adaptation strategy, barriers for adaptation, state of the implementation of a range of water management measures, and status of adaptation strategy implementation. The analysis of responses and cross-comparison were performed with rating the responses where possible. According to the expert opinions, there is an understanding in all six regions that climate change is happening. Different climate change impacts are expected in the basins, whereas decreasing annual water availability, and increasing frequency and intensity of droughts (and to a lesser extent floods) are expected in all of them. According to the responses, the two most important drivers for development of adaptation strategy are: climate-related disasters, and national and international policies. The following most important barriers for adaptation to climate change were identified by responders: spatial and temporal uncertainties in climate projections, lack of adequate financial resources, and lack of horizontal cooperation. The evaluated water resources management measures are on a relatively high level in the Elbe and Rhine basins, followed by the Orange and Guadiana. It is lower in the Amudarya basin, and the lowest in the NEL region, where many measures are only at the planning stage. Regarding the level of adaptation strategy implementation, it can be concluded that the adaptation to climate change has started in all basins, but progresses rather slowl

A patchy particle model for C-S-H formation

The composition and structure of Calcium-Silicate-Hydrate (C-S-H) phases depends on various reaction parameters leading to its formation. Molecular Dynamic simulation studies probing the formation and structure of C-S-H are generally computationally expensive and can reach only very short time scales. Herein, we propose a coarse graining approach to model the formation of C-S-H, using patchy particles and a modified Patchy Brownian Cluster Dynamics algorithm. The simulations show that patchy particle systems can recover the qualitative kinetic evolution of C-S-H formation, and the obtained final structures were comparable to previously reported molecular dynamics studies and experiments. The model was extended to study the effect of water in the polymerization of tetraethoxysilane oligomers, the principal component of an impregnation treatment for deteriorated concrete surfaces. The intermediate system properties predicted by the simulations, such as viscosity and gel time, and structure were found to be well in accordance with the tailored experiments.The work described in this manuscript has been performed under InnovaConcrete EC project, supported by funding from the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement N◦760858. AP and JSD also acknowledge the support received from the BASKRETE initiative and the Joint Transborder Lab-oratory (LTC) “Aquitaine-Euskadi Network in Green Concrete and Cement-based Material

Evaluation of a lime-mediated sewage sludge stabilisation process. Product characterisation and technological validation for its use in the cement industry

This paper describes an industrial process for stabilising sewage sludge (SS) with lime and evaluates the viability of the stabilised product, denominated Neutral, as a raw material for the cement industry. Lime not only stabilised the sludge, raised the temperature of the mix to 80-100 °C, furthering water evaporation, portlandite formation and the partial oxidation of the organic matter present in the sludge. Process mass and energy balances were determined. Neutral, a white powder consisting of portlandite (49.8%), calcite (16.6%), inorganic oxides (13.4%) and organic matter and moisture (20.2%), proved to be technologically apt for inclusion as a component in cement raw mixes. In this study, it was used instead of limestone in raw mixes clinkerised at 1400, 1450 and 1500 °C. These raw meals exhibited greater reactivity at high temperatures than the limestone product and their calcination at 1500 °C yielded clinker containing over 75% calcium silicates, the key phases in Portland clinker. Finally, the two types of raw meal (Neutral and limestone) were observed to exhibit similar mineralogy and crystal size and distribution. © 2011.Peer Reviewe

RNA-Seq analysis of ileocecal valve and peripheral blood from Holstein cattle infected with Mycobacterium avium subsp. paratuberculosis revealed dysregulation of the CXCL8/IL8 signaling pathway

17 páginas, 5 tablas, 5 figuras.Paratuberculosis is chronic granulomatous enteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Whole RNA-sequencing (RNA-Seq) is a promising source of novel biomarkers for early MAP infection and disease progression in cattle. Since the blood transcriptome is widely used as a source of biomarkers, we analyzed whether it recapitulates, at least in part, the transcriptome of the ileocecal valve (ICV), the primary site of MAP colonization. Total RNA was prepared from peripheral blood (PB) and ICV samples, and RNA-Seq was used to compare gene expression between animals with focal or diffuse histopathological lesions in gut tissues versus control animals with no detectable signs of infection. Our results demonstrated both shared, and PB and ICV-specific gene expression in response to a natural MAP infection. As expected, the number of differentially expressed (DE) genes was larger in the ICV than in the PB samples. Among the DE genes in the PB and ICV samples, there were some common genes irrespective of the type of lesion including the C-X-C motif chemokine ligand 8 (CXCL8/IL8), apolipoprotein L (APOLD1), and the interferon inducible protein 27 (IF127). The biological processes (BP) enriched in the PB gene expression profiles from the cows with diffuse lesions included the killing of cells of other organism, defense response, immune response and the regulation of neutrophil chemotaxis. Two of these BP, the defense and immune response, were also enriched in the ICV from the cows with diffuse lesions. Metabolic analysis of the DE genes revealed that the N-glycan biosynthesis, bile secretion, one-carbon pool by folate and purine metabolism were significantly enriched in the ICV from the cows with focal lesions. In the ICV from cows with diffuse lesions; the valine, leucine and isoleucine degradation route, purine metabolism, vitamin digestion and absorption and the cholesterol routes were enriched. Some of the identified DE genes, BP and metabolic pathways will be studied further to develop novel diagnostic tools, vaccines and immunotherapeutics.This work was supported by grants from the Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria (INIA) and by European Funds for Regional Development (FEDER) (INIA RTA2014-00009-C02 and RTA2018-094192). The study is partially funded by the Principado de Asturias (PCTI 2018-2020, GRUPIN: IDI2018-000237). Maria Canive and Cristina Blanco-Vazquez are recipients of INIA fellowships. The authors thank ASTEGA Veterinary services for their assistance on sample collection. We are also grateful to Kyle Hearn for the careful editing of the manuscript

ME20-S as a Potential Biomarker for the Evaluation of Uveal Melanoma

PURPOSE: We previously identified the presence of the melanocyte-specific secreted (ME20-S) glycoprotein in secretomes of uveal melanoma (UM) cultures. The aim of this study was to test for the presence and levels of ME20-S in the serum of patients with choroidal nevi and UM and correlate these levels with individual clinical data. METHODS: Serum ME20-S levels were determined by ELISA in 111 patients distributed into four categories (53 choroidal nevi, 30 untreated UM, 11 10-year disease-free [DF] UM, 17 hepatic metastatic UM) and 32 age- and sex-matched controls. ME20-S levels were correlated with individual clinical data. RESULTS: The UM and the metastatic groups showed significantly higher levels of serum ME20-S than the other groups (P < 0.001). ME20-S levels in the DF patients did not differ from those in the control group. In addition, log-transformed serum ME20-S levels showed a positive correlation with the thickness of the lesion mass in UM patients (regression coefficient 0.0689, 95% confidence interval 0.0689-0.1123, R2 = 27.1%). CONCLUSIONS: Elevated ME20-S serum levels are associated with tumor size and advanced stages of UM while low levels are characteristic of DF patients. ME20-S might be a promising serum marker for UM and useful for monitoring metastatic disease

Prevalence of hospital PCR-confirmed COVID-19 cases in patients with chronic inflammatory and autoimmune rheumatic diseases

[Abstract] Background: The susceptibility of patients with rheumatic diseases and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown. Methods: We performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with severe acute respiratory syndrome coronavirus 2-positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups. Results: Patients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Patients with systemic autoimmune or immune-mediated disease (AI/IMID) showed a significant increase, whereas patients with inflammatory arthritis (IA) or systemic lupus erythematosus did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. Patients with IA on targeted-synthetic or biological disease-modifying antirheumatic drugs (DMARDs), but not those on conventional-synthetic DMARDs, had a greater prevalence despite a similar age distribution. Conclusion: Patients with AI/IMID show a variable risk of hospital-diagnosed COVID-19. Interplay of ageing, therapies and disease-specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyse the specific factors involved in COVID-19 susceptibility.Instituto de Salud Carlos III; RD16/0012 RETICS Progra

Propensity score matched comparison of transcatheter aortic valve implantation versus conventional surgery in intermediate and low risk aortic stenosis patients: A hint of real-world

Background: Recently, the use of transcatheter aortic valve implantation (TAVI) in inter­mediate-low risk patients has been evaluated in the PARTNER II randomized trial. However, in the last years, this therapy has been employed in this scenario with underreported results, as compared to surgical aortic valve replacement (SAVR). Methods: We enrolled 362 consecutive patients with severe symptomatic aortic stenosis and intermediate-low surgical risk (logEuroSCORE &lt; 20%), treated in our center with TAVI (103 patients) or single SAVR (259 patients) between 2009 and 2014. Patients were matched according to age, gender, logEuroSCORE, and use of bioprosthesis. Results: Mean age of the patients was 73 ± 10.4 years, and 40.3% were women. LogEuroSCORE and Society Thoracic Surgeons score were 7.0 ± 4.4% and 4.2 ± 2.5%, respectively, with mean left ventricular ejection fraction of 52 ± 9%. There were no differences regarding other comorbidities. The length-of-hospitalization was 11 ± 5 days after TAVI vs. 17 ± 9 days after SAVR (p = 0.003). After matched comparison, no differences in terms of in-hospital mortality (5.7% after TAVI vs. 2.9% after SAVR, p = 0.687) and 1-year mortality (11.4% vs. 7.1%, p = 0.381) were found. The combined endpoint of stroke and mortality at 1-year was also similar between both groups (15.7% in TAVI patients vs. 14.4% after SAVR, p = 0.136). Multivariate analysis determined that aortic regurgitation (AR) was an independent predictor of mortality (OR = 3.623, 95% CI: 1.267–10.358, p = 0.016). Although the rate of AR was higher after TAVI, none of the patients treated with the newest generation devices (10.7%) presented more than a mild degree of AR. Conclusions: TAVI is feasible and shows comparable results to surgery in terms of early, 1-year mortality, as well as cerebrovascular events in patients with severe aortic stenosis and intermediate-low operative risk. Better transvalvular gradients, yet higher rates of AR were found, however, newer devices presented comparable rate of AR.