Identificación y caracterización de microRNAs hepáticos como biomarcadores de esteatosis y colestasis por fármacos

La lesión hepática inducida por fármacos (DILI) es un problema de salud prioritario y la razón principal de la retirada del mercado de muchos medicamentos. Debido a su patogénesis multifactorial, el DILI puede presentar diversas manifestaciones. Una de ellas, la esteatosis, es la acumulación de triglicéridos en el hígado que, si se cronifica, da lugar a la enfermedad del hígado graso no alcohólico (EHGNA). Los fármacos pueden tener un papel etiológico directo o indirecto, aunque la EHGNA más prevalente es la asociada al síndrome metabólico. Otra manifestación del DILI, la colestasis, se define como la detención del flujo de bilis hacia el duodeno, con la acumulación de ácidos biliares en hepatocitos y torrente sanguíneo. El 42-52% de los pacientes con DILI cursan con colestasis. El diagnóstico actual del DILI se basa en parámetros bioquímicos tradicionales (alanino aminotransferasa, ALT; fosfatasa alcalina, FA…) poco específicos y sensibles. Además, la gravedad de la EHGNA sólo se puede estimar fiablemente en la biopsia hepática. Por ello, es necesaria la identificación y validación de nuevos biomarcadores no invasivos. Los miRNAs, por su papel esencial en multitud de procesos fisiológicos y patológicos y por su estabilidad en los fluidos biológicos, son considerados biomarcadores emergentes de numerosas enfermedades. Sin embargo, los estudios de miRNAs en DILI se han centrado en la hepatotoxicidad intrínseca por paracetamol, y sólo el miR-122 se acepta como biomarcador de diagnóstico y pronóstico en la EHGNA. En la presente tesis, pretendemos profundizar en el estudio de los miRNAs como herramientas no invasivas y predictivas del DILI y sus distintas manifestaciones. Para ello, tratamos células hepáticas humanas 28 en cultivo con fármacos esteatósicos o colestásicos modelo, analizamos su miRNoma para identificar biofirmas singulares, y buscamos su reflejo en el suero de pacientes con EHGNA y DILI colestásico. Los resultados demuestran que, en hepatocitos en cultivo, los fármacos esteatósicos y colestásicos modelo producen alteraciones significativas en el perfil de miRNAs, que son trasladadas al medio de cultivo. Algunos fármacos comunes en pacientes con síndrome metabólico también inducen los miRNAs biomarcadores de esteatosis iatrogénica y podrían estar propiciando la EHGNA. Algunos de estos miRNAs, y otros postulados en trabajos previos, han podido ser validados como biomarcadores no invasivos para la predicción de la gravedad en la EHGNA (esteatohepatitits y fibrosis avanzada). Por otro lado, 4 miRNAs identificados in vitro se encontraron alterados en el suero de pacientes con DILI colestásico, y otros 4 fueron inducidos en pacientes con DILI hepatocelular. En general, estos nuevos biomarcadores no invasivos demostraron mejor rendimiento diagnóstico que los marcadores bioquímicos tradicionales, o permitieron mejorar algoritmos diagnósticos previos, pudiendo así ser postulados por primera vez como biomarcadores para el diagnóstico y clasificación de la hepatotoxicidad idiosincrásica

Characterization of Ionic Exchange and Macroporous Resins for Their Application on the Separation and Recovery of Chlorogenic Acid from the Wastewater of Artichoke Blanching

[EN] Food wastes have traditionally been considered as dead-end materials; however, recent international, national, and regional policies strongly promote the use of these wastes as potential resources. This change of perception considers the need for sustainable exploitation of natural resources. In this context, artichoke processing produces high amounts of wastewaters, and specifically, wastewaters from the artichoke blanching step present a high content of valuable biocomponents such as carbohydrates and phenolic compounds (e.g., chlorogenic acid, 1700 ppm). In this work, the recovery of chlorogenic acid by applying sorption processes was studied. Five resins were tested, and it was found that the resin XAD 7 HP presented the best total adsorption-desorption yield (72.8%) at 20 degrees C. It was also found that there was a strong variation of the adsorption ratio depending on solution pH (3-7). Four models of isotherms were applied to the adsorption processes, and the Langmuir isotherm better explained the adsorption behavior. The kinetic study showed that the adsorption and desorption of chlorogenic acid followed a pseudo-second order model where the kinetic constant depended on the adsorbate concentration. In addition, it was found that the sorption process was controlled by more than just the intraparticle diffusion mechanism.Rodríguez López, AD.; Reig Riera, MM.; Mayor, L.; Ortiz-Climent, M.; Garcia-Castello, EM. (2021). Characterization of Ionic Exchange and Macroporous Resins for Their Application on the Separation and Recovery of Chlorogenic Acid from the Wastewater of Artichoke Blanching. Sustainability. 13(16):1-15. https://doi.org/10.3390/su13168928S115131

New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease

Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis

Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: Altered energetic efficiency?

Background Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass. Methods The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques. Results Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei. Analyzing the expression of some factors related to proteolytic and thermogenic processes, we observed in tumor-bearing animals an increased expression of genes involved in proteolysis such as ubiquitin ligases Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box protein (MAFBx). Moreover, an overexpression of both sarco/endoplasmic Ca2 +-ATPase (SERCA1) and adenine nucleotide translocator (ANT1), both factors related to cellular energetic efficiency, was observed. Tumor burden also leads to a marked decreased in muscle ATP content. Conclusions In addition to muscle proteolysis, other ATP-related pathways may have a key role in muscle wasting, both directly by increasing energetic inefficiency, and indirectly, by affecting the sarcoplasmic reticulum-mitochondrial assembly that is essential for muscle function and homeostasis. General significance The present study reports profound morphological changes in cancer cachectic muscle, which are visualized mainly in alterations in sarcoplasmic reticulum and mitochondria. These alterations are linked to pathways that can account for energy inefficiency associated with cancer cachexia. Highlights ► Skeletal muscle from cachectic animals showed fiber morphologic alterations. ► These alterations are mitochondrial disruption and dilatation of sarcoplasmic reticulum. ► An overexpression of both sarco/endoplasmic Ca2 +-ATPase (SERCA1) and adenine nucleotide translocator (ANT1) was reported. ► Tumor burden also leads to a marked decreased in muscle ATP content. Previous article in issu

A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19

Background: current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. Methods: we conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. Results: the analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. Conclusions: postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)

Monografies del Montseny - 37

Antoni Pladevall Font va fer possible el naixement de la col.lecció completa de les Monografies del Montseny, n’ha estat el director durant molts anys, ha publicat més de seixanta treballs d’investigació històrica, i ha estat el mestre que ha mostrat el camí a seguir en la tasca d’aprofundiment de la història del Montseny i el seu entorn més proper. En el pròleg del volum 37 de les Monografies del Montseny es glosa la figura d’Antoni Pladevall Font, qui l’any 1966 inicià la col·laboració en el Servei de Conservació i Catalogació de Monuments Històrics a la Diputació de Barcelona; dos anys més tard, passà a exercir com a professor d’història medieval a la Facultat de Teologia de Barcelona. Obtingué el títol d’Arxiver Municipal de Vic l’any 1979, mentre treballa a la Diputació, i al 1981començà a treballar en el Departament de Cultura de la Generalitat fins a la seva jubilació l’any 1999. L’aleshores conseller de Cultura de la Generalitat Max Cahner li va encarregar d’organitzar el Servei de Conservació i Restauració de Monuments Arquitectònics on se li va assignar la secció d’inventari i la de cap de servei en funcions. Dos anys després hi va exercir com a director general del Patrimoni Arquitectònic. En aquesta etapa va col·laborar amb la Fundació i Editorial de la Gran Enciclopèdia Catalana, en la qual va exercir la direcció d’obres tan importants com la “Catalunya Romànica” i “L’Art Gòtic de Catalunya”, i va assessorar la “Gran Geografia Comarcal de Catalunya”.Objectius de Desenvolupament Sostenible::11 - Ciutats i Comunitats SosteniblesObjectius de Desenvolupament Sostenible::4 - Educació de QualitatPostprint (published version

TFG 2012/2013

Amb aquesta publicació, EINA, Centre universitari de Disseny i Art adscrit a la Universitat Autònoma de Barcelona, dóna a conèixer el recull dels Treballs de Fi de Grau presentats durant el curs 2012-2013. Voldríem que un recull com aquest donés una idea més precisa de la tasca que es realitza a EINA per tal de formar nous dissenyadors amb capacitat de respondre professionalment i intel·lectualment a les necessitats i exigències de la nostra societat. El treball formatiu s’orienta a oferir resultats que responguin tant a paràmetres de rigor acadèmic i capacitat d’anàlisi del context com a l’experimentació i la creació de nous llenguatges, tot fomentant el potencial innovador del disseny.Con esta publicación, EINA, Centro universitario de diseño y arte adscrito a la Universidad Autónoma de Barcelona, da a conocer la recopilación de los Trabajos de Fin de Grado presentados durante el curso 2012-2013. Querríamos que una recopilación como ésta diera una idea más precisa del trabajo que se realiza en EINA para formar nuevos diseñadores con capacidad de responder profesional e intelectualmente a las necesidades y exigencias de nuestra sociedad. El trabajo formativo se orienta a ofrecer resultados que respondan tanto a parámetros de rigor académico y capacidad de análisis, como a la experimentación y la creación de nuevos lenguajes, al tiempo que se fomenta el potencial innovador del diseño.With this publication, EINA, University School of Design and Art, ascribed to the Autonomous University of Barcelona, brings to the public eye the Final Degree Projects presented during the 2012-2013 academic year. Our hope is that this volume might offer a more precise idea of the task performed by EINA in training new designers, able to speak both professionally and intellectually to the needs and demands of our society. The educational task is oriented towards results that might respond to the parameters of academic rigour and the capacity for contextual analysis, as well as to considerations of experimentation and the creation of new languages, all the while reinforcing design’s innovative potential

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics