Mitochondrial dysfunction in advanced liver disease: Emerging Concepts.

Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog's MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros' O2k-technology and Agilent Seahorse XF technology

Proresolving lipid mediators and liver disease.

Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions

Promover la inclusión educativa

Algunos centros que deciden emprender un proceso de cambio hacia la educación inclusiva se encuentran con algunas dificultades y la falta de guía para llevarlo a cabo. Este artículo nos aproxima a un conjunto de materiales prácticos y adaptables, expresamente diseñados para apoyar a las comunidades educativas

Anàlisi del temps d'infermeria dedicat als malalts amb ventilació mecànica invasiva a una unitat de monitoratge d'un servei d'urgències

Respiración artificial; Enfermería; Gestión del tiempoRespiració artificial; Infermeria; Gestió del tempsArtificial Respiration; Nursing; Time ManagementL'objectiu va ser descriure i analitzar el temps d'estada dels pacients que varen precisar ventilació mecànica invasiva (VMI) per la COVID-19 a una unitat de monitoratge (UMO) d'un servei d'urgències d'un hospital comarcal. Es van recollir les dades dels pacients que van precisar VMI a la UMO des de juliol de 2020 fins a l'actualitat. Les dades de l'estudi van ser utilitzades i recollides emprant l'eina electrònica de gestió de dades REDCap, localitzada al servidor intern de l'hospital. Es van incloure 117 pacients que van precisar VMI amb infecció per COVID-19, el 78,4% homes. La mediana de temps que van estar els pacients a la nostra UMO des de l'inici de la VMI fins al trasllat a l'UCI va ser de 195 minuts (RIQ=130). El 57,8% dels pacients es van traslladar a l'UCI de l'Hospital Josep Trueta, l'11,2% a la de l'Hospital Santa Caterina i la resta, 31% a les UCI d'hospitals fora de la província de Girona. Si tenim en compte la divisió territorial en clústers, el 22,4% es van traslladar fora. El temps d'estada a la UMO dels pacients que van precisar VMI va ser elevat, tractant-se d'un hospital comarcal. La majoria de pacients es van traslladar a les UCI de Girona o del clúster Nord Girona. Així i tot, hi ha un alt nombre de pacients que van haver de ser traslladats a altres centres, fet que reflecteix la manca de llits de crítics en el nostre entorn

Albumin Lipidomics Reveals Meaningful Compositional Changes in Advanced Cirrhosis and Its Potential to Promote Inflammation Resolution

Albumin infusions are therapeutically used to revert hypoalbuminemia and to replace the extensively oxidized albumin molecule circulating in patients with acutely decompensated (AD) cirrhosis. Because albumin has high affinity for lipids, here we characterized the albumin lipidome in patients with AD and explored the albumin effects on the release of fatty acid (FA)-derived lipid mediators by peripheral leukocytes. Lipids and lipid mediators were measured by liquid chromatography-tandem mass spectrometry in albumin-enriched and albumin-depleted plasma fractions separated by affinity chromatography and in leukocyte incubations from 18 patients with AD and 10 healthy subjects (HS). Lipid mediators were also measured in 41 patients with AD included in an albumin therapy trial. The plasma lipidome associated with AD cirrhosis was characterized by generalized suppression of all lipid classes except FAs. In contrast to HS, albumin from patients with AD had lower content of polyunsaturated FAs (PUFAs), especially of the omega-3-PUFA docosahexaenoic acid. Consistent with this, the PUFA-derived lipid mediator landscape of albumin from patients with AD was dominated by lower content of monohydroxy FA precursors of anti-inflammatory/pro-resolving lipid mediators (i.e., 15-hydroxyeicosatetraenoic acid [15-HETE]). In addition, albumin from patients with AD was depleted in prostaglandin (PG) E2 , suggesting that this proinflammatory PG primarily travels disassociated to albumin in these patients. Incubation of leukocytes with exogenous albumin reduced PG production while inducing 15-lipoxygenase expression and 15-HETE release. Similar effects were seen under lipopolysaccharide plus N-formylmethionyl-leucyl-phenylalanine-stimulated conditions. Finally, PG levels were lower in patients with AD receiving albumin therapy, whereas 15-HETE was increased after albumin treatment compared with baseline. Conclusion: Our findings indicate that the albumin lipid composition is severely disorganized in AD cirrhosis and that administration of exogenous albumin has the potential to redirect leukocyte biosynthesis from pro-inflammatory to pro-resolving lipid mediators

Nanoparticles in Endodontics Disinfection: State of the Art

Endodontic-related diseases constitute the fourth most expensive pathologies in industrialized countries. Specifically, endodontics is the part of dentistry focused on treating disorders of the dental pulp and its consequences. In order to treat these problems, especially endodontic infections, dental barriers and complex root canal anatomy should be overcome. This constitutes an unmet medical need since the rate of successful disinfection with the currently marketed drugs is around 85%. Therefore, nanoparticles constitute a suitable alternative in order to deliver active compounds effectively to the target site, increasing their therapeutic efficacy. Therefore, in the present review, an overview of dental anatomy and the barriers that should be overcome for effective disinfection will be summarized. In addition, the versatility of nanoparticles for drug delivery and their specific uses in dentistry are comprehensively discussed. Finally, the latest findings, potential applications and state of the art nanoparticles with special emphasis on biodegradable nanoparticles used for endodontic disinfection are also reviewed. Keywords: PLGA; dentistry; endodontics; metal nanoparticles; nanoparticles

The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of nonalcoholic fatty liver disease (NAFLD), which is the hepatic manifestation of the metabolic syndrome associated with obesity. The specialized proresolving lipid mediator maresin 1 (MaR1) preserves tissue homeostasis by exerting cytoprotective actions, dampening inflammation, and expediting its timely resolution. Here, we explored whether MaR1 protects liver cells from lipotoxic and hypoxia-induced ER stress. Mice were rendered obese by high-fat diet feeding, and experiments were performed in primary hepatocytes, Kupffer cells, and precision-cut liver slices (PCLSs). Palmitate-induced lipotoxicity increased ER stress and altered autophagy in hepatocytes, effects that were prevented by MaR1. MaR1 protected hepatocytes against lipotoxicity-induced apoptosis by activating the UPR prosurvival mechanisms and preventing the excessive up-regulation of proapoptotic pathways. Protective MaR1 effects were also seen in hepatocytes challenged with hypoxia and TNF-α-induced cell death. High-throughput microRNA (miRNA) sequencing revealed that MaR1 actions were associated with specific miRNA signatures targeting both protein folding and apoptosis. MaR1 also prevented lipotoxic-triggered ER stress and hypoxia-induced inflammation in PCLSs and enhanced Kupffer cell phagocytic capacity. Together, these findings describe the ability of MaR1 to oppose ER stress in liver cells under conditions frequently encountered in NAFLD.-Rius, B., Duran-Güell, M., Flores-Costa, R., López-Vicario, C., Lopategi, A., Alcaraz-Quiles, J., Casulleras, M., Lozano, J. J., Titos, E., Clària, J. The specialized proresolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress

Valoració de la técnica del sondatge vesical en un servei d'urgències

Control d'infeccions nosocomials; Antisèpsia; Catèter urinariNosocomial infection control; Antisepsis; Urinary catheterControl de infecciones nosocomiales; Antisepsia; Sonda vesicalL'objectiu va ser conèixer el compliment del procediment del sondatge vesical per part dels infermeres/es d’un servei d’urgències, i identificar si són similar a les recomanacions del Proyecto ITU-Zero. Es va realitzar un estudi descriptiu i transversal sobre la tècnica del sondatge vesical realitzada pels infermers/es d’un servei d’urgències. Les dades analitzades varen ser sociodemogràfiques (edat, sexe, anys d’experiència com a infermer/a i torn) i variables sobre tècnica del sondatge vesical. L’estudi va ser aprovat per la Comissió de Recerca del centre. Es van analitzar 40 participants, 80% eren dones. La mitjana d’edat era de 39,20 anys (DE=8,57). La mitjana d’anys d’experiència com a infermer/a era de 16,43 anys (DE=9,04). Un 62,5% dels participants no utilitzaven antisèptic, i un 25% n’utilitzaven a vegades. Referent al tipus d’antisèptic, un 57,5% no n’utilitzaven, i un 40% utilitzaven povidona iodada. En la tècnica del sondatge vesical, un 90% d’infermers/es realitzaven higiene de mans i un 97,5% preparaven camp estèril. Conclusions: Pràcticament tots els participants en l’estudi realitzaven higiene de mans abans de la tècnica i preparaven camp estèril, tal com indiquen les recomanacions del Proyecto ITU-Zero. Un elevat percentatge d’infermers/es no utilitzaven antisèptic en la tècnica del sondatge vesical, i els que utilitzaven antisèptic, la solució d’elecció era povidona iodada

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3',5'-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit