A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol

© 2020, The Author(s). Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. Methods: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. Discussion: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. Trial registration: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020)

Options for agriculture at Marrakech climate talks: messages for SBSTA 45 agriculture negotiators

SBSTA 45 in Marrakech represents a unique opportunity for Parties to decide on the future of agriculture within the UNFCCC. The process of discussions on issues related to agriculture initiated at COP17 in Durban 2011 culminates at COP22 in Marrakech 2016. The explicit reference to food security in the preamble of the Paris Agreement and the Intended Nationally Determined Contributions which prioritize agriculture as a sector for adaptation and mitigation actions, provide a foundation for Parties to develop appropriate frameworks to support actions within the agricultural sector. SBSTA workshops on agriculture in 2015 and 2016 allowed Parties to share experiences, identify priorities, and propose ways of taking action within the agricultural sector and so provide the core knowledge base to work from. As Parties reach a decision on issues related to agriculture at SBSTA 45, a number of options are available. This report presents ten such options that might contribute to a decision, taking into consideration political priorities, implementation arrangements, timelines and level of ambition. Options outlined in this report are not mutually exclusive and can be combined in many different ways

Single-cell RNA sequencing analysis of cirrhotic patients reveals that Cathepsin D-expressing mononuclear phagocytes are involved in ECM remodelling

Resumen del trabajo presentado en el XXXIII Congrés de la Societat Catalana de Digestologia, celebrado en Lleida, del 25 al 27 de enero de 202

Treballs d'investigació en atenció primària: revisió dels treballs en llengües espanyoles publicats l'any 1986

Revisem 29 treballs elaborats per professionals d'atenció primària i publicats a: Atención Primaria, Medicina Clínica, Gaseta Sanitaria, Revista Clínica Española, Revista Española de Pediatría i Annals de Medicina. La majoria els trobem realitzats per especialistes o residents de Medicina Familiar i Comunitària, amb absència de pediatres. Entre els temes analitzats destaca l'anàlisi de la demanda, hipertensió arterial i vacunacions, que totalitzen quasi el 50% dels treballs. Cal ressaltar un 89% de dissenys descriptius, amb solament dos de tipus analític o experimental. Sobre 6 paràmetres d'adequació metodològica hi hagué un compliment mitjà de 4,38 (DE = 2,23). El 52% dels treballs no tenien tractament estadístic. Creiem que hi ha una extensa variabilitat en la qualitat deis treballs i que és necessari adaptar la temàtica d'interès deis investigadors i adaptar els dissenys a la demostració d'hipòtesis que suposin canvis en la pràctica assistencial

Protease-driven lysosomal activity is a core mechanism for macrophage driven collagen remodeling during liver and kidney fibrosis

Trabajo presentado en el 2nd International Workshop on Liver and Gut Fibrosis, celebrado en Valencia (España), los días 26 y 27 de octubre de 202

Unraveling the proteolytic network controlling collagen remodeling during liver fibrosis

Resumen del trabajo presentado en el 48 Congreso anual Asociación Española para el Estudio del Hígado, celebrado en Madrid (España), del 15 al 17 de marzo de 202

Novel insights on the contribution of collagen degradative macrophages to fibrosis resolution

Trabajo presentado en el EASL Congress 2023, celebrado en Viena (Austria), del 21 al 24 de junio de 2023Background and aims: Liver fibrosis is caused by an excessive accumulation of extracellular matrix (ECM) proteins. Macrophages are important effectors for ECM remodelling through recycling of the ECM within acidic compartments and can contribute to liver fibrosis resolution. Proteases, such as cathepsins, are essential for lysosomal proteolytic activity; however, their contribution to ECM remodelling within the macrophages is unknown. Thus, the aim of this study was to investigate the proteolytic and degradative signalling pathways associated to macrophages during liver fibrosis. Method: A novel macrophage-cathepsin D KO mouse strain (CtsDΔMyel) was generated by breeding LysMCre (macrophages) with CtsD-floxed mice. Fibrosis was established by chronic CCl4 administration and bile duct ligation in CtsDF/F or CtsDΔMyel mice and determined by hydroxyproline, Sirius Red, α-SMA, Col1A1 and TGF-β RT-PCR. Proteomic profile was determined by LC-MS/MS in fibrotic livers. Reversion was assessed 72 h post-challenge in a 4-week CCl4 model. Collagen degradation in liver was determined by R-CHP staining. Macrophage polarization and proteolytic secretome was assessed by RT-PCR and protease array, respectively. Collagen degradation and endocytosis was determined by FACS in Kupffer cells (KC). Single-cell RNA sequencing analysis was performed using GSE136103 dataset. Results: ScRNAseq analysis and CtsD IHP demonstrated high expression of CtsD in liver macrophages from cirrhotic patients. Next, CtsDΔMyel mouse was validated by FACS and WB in KC and dual IHP (F4/80-CtsD) in liver. CtsD deletion in macrophages enhanced liver fibrosis with enriched matrisome proteomic signatures in chronic CCl4 and BDL models. Analysis of KC isolated from 72hCCl4-treated livers demonstrated significantly lower expression of markers associated with resolutive macrophages (CD206, TREM-2 and TGF-β) and defective proteolytic secretome profile in CtsDΔMyel KC. In addition, CtsDΔMyel KC displayed defective proteolytic processing of collagen I without impairment of the Endo180 receptormediated endocytosis demonstrated by FACS. Analysis of CtsD macrophage subclusters in control and cirrhotic human livers, confirmed cirrhotic CtsD-expressing subclusters were differentially enriched in ECM degradation and organization signalling pathways. In addition, it revealed a decrease in the number of CtsD-expressing macrophage subclusters in cirrhotic livers, which could contribute to inadequate ECM recycling, perpetuating fibrosis and hampering resolution. Indeed, CtsDΔMyel mouse was unable to remodel collagen in vivo when subjected to a fibrosis reversion model determined by both percentage of HP and fluorescent intensity of collagen hybridizing peptide (CHP) binding to liver tissue. Conclusion: CtsD is essential in regulating the collagenolytic activity of macrophages during liver fibrosis and is part of a novel and currently unknown degradome landscape of restorative macrophages

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation

In vivo partial cellular reprogramming enhances liver plasticity and regeneration.

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration

Open access solutions for biodiversity journals : Do not replace one problem with another

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