Vitamin E protects against the mitochondrial damage caused by cyclosporin A in LLC-PK1 cells

27 p.Cyclosporin A (CsA) has nephrotoxic effects known to involve reactive oxygen species (ROS), since antioxidants prevent the kidney damage induced by this drug. Given that mitochondria are among the main sources of intracellular ROS, the aims of our study were to examine the mitochondrial effects of CsA in the porcine renal endothelial cell line LLC-PK1 and the influence of the antioxidant Vitamin E (Vit E). Following the treatment of LLC-PK1 cells with CsA, we assessed the mitochondrial synthesis of superoxide anion, permeability transition pore opening, mitochondrial membrane potential, cardiolipin peroxidation, cytochrome c release and cellular apoptosis, using flow cytometry and confocal microscopy procedures. Similar experiments were done after Vit E preincubation of cells. CsA treatment increased superoxide anion in a dose-dependent way. CsA opened the permeability transition pores, caused Bax migration to mitochondria, and decreased mitochondrial membrane potential and cardiolipin content. Also CsA released cytochrome c into cytosol and provoked cellular apoptosis. Vit E pretreatment inhibited the effects that CsA induced on mitochondrial structure and function in LLC-PK1 cells and avoided apoptosis. CsA modifies mitochondrial LLC-PK1 cell physiology with loss of negative electrochemical gradient across the inner mitochondrial membrane and increased lipid peroxidation. These features are related to apoptosis and can explain the cellular damage that CsA induces. As Vit E inhibited these effects, our results suggest that they were mediated by an increase in ROS production by mitochondriaJunta de Comunidades de Castilla-La Manch

A deletion at Adamts9-magi1 Locus is associated with psoriatic arthritis risk

Objective: Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. Methods: A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ2 test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). Results: A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). Conclusions: The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice

Innovación del Diseño para el Desarrollo Social

Una labor de síntesis alrededor de la gran temática de este libro que surge a partir de una serie de reflexiones y propuestas encaminadas desde la innovación del diseño para el desarrollo social, refleja una invitación al lector para enunciar a partir de su lectura nuevas discusiones sobre el quehacer del diseño con una perspectiva de innovación para este tipo de desarrollo, es pues este texto una invitación a enunciar nuevos retos y diálogos partiendo de reconocer al desarrollo social como uno de los pilares fundamentales desde la Organización de las Naciones Unidas (ONU) como parte fundamental para garantizar el mejoramiento de la vida de las personas. Desde la disciplina del diseño y retomado como eje para su discusión se pretendería establecer una serie de reflexiones y acciones que permitan atender situaciones para grupos minoritarios y vulnerables, así como apoyar esfuerzos encaminados a mejorar la calidad de vida de los integrantes de grupos y sociedades establecidas y recuperar el patrimonio cultural como parte fundamental de las identidades culturales y por tanto de la historia de la humanidad.A lo largo de la historia, el diseño, en cualquiera de sus manifestaciones, ha estado presente en todos los ámbitos. Se ha convertido en una disciplina que evoluciona al ritmo de las sociedades, que se pone al servicio de las necesidades de mercado pero también de las que requieren un abordaje distinto, observadas desde una mirada que concierne a lo social, entendido éste como lo que se reproduce o se instaura en el colectivo, en el grupo, en las comunidades, en las sociedades como parte significativa de sus cotidianeidades. El Diseño desde esta perspectiva acompaña al ser humano produciendo una significación de los objetos como parte fundamental de sus vidas, que transforma una realidad deseada en una realidad concreta, de aquí la importancia de crear una conciencia social para la praxis laboral de esta disciplina. En este sentido el campo profesional, académico y de investigación del diseño debe ocuparse de crear, difundir y divulgar el quehacer de la misma, manifestando un equilibrio entre conciencia, racionalidad y la realidad. Desde el contexto planteado, la Universidad Autónoma del Estado de México, a través de su Facultad de Arquitectura y Diseño presenta en esta obra una serie de reflexiones en torno al papel que desempeña el diseño humanístico, científico y tecnológico desde un enfoque de vanguardia e innovación para el desarrollo social, como resultado de la experiencia vertida en el Coloquio Internacional de Diseño que organiza éste año este espacio académico, en donde cada una de las aportaciones refleja la experiencia de cada uno de sus participantes; con base en ello, el presente libro integrado por una compilación de trabajos ofrece descripciones, análisis y propuestas que contribuyen a la solución de problemas procurando un desarrollo social

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Extracción a nivel de documento de reacciones adversas a medicamentos en informes médicos electrónicos en español

Presentamos un sistema de extracción de Reacciones Adversas a Medicamentos (RAMs) para Informes Médicos Electrónicos escritos en español. El objetivo del sistema es asistir a expertos en farmacia cuando tienen que decidir si un paciente padece o no una o más RAMs. El núcleo del sistema es un modelo predictivo inferido de un corpus etiquetado manualmente, que cuenta con características semánticas y sintácticas. Este modelo es capaz de extraer RAMs de parejas enfermedad-medicamento en un informe dado. Finalmente, las RAMs extraídas automáticamente son post-procesadas usando un heurístico para presentar la información de una forma compacta. Esta fase ofrece los medicamentos y enfermedades del documento con su frecuencia, y también une las parejas relacionadas como RAMs. En resumen, el sistema no sólo presenta las RAMs en el texto sino que también da información concisa a petición de los expertos en farmacia (los usuarios potenciales del sistema).We outline an Adverse Drug Reaction (ADRs) extraction system for Electronic Health Records (EHRs) written in Spanish. The goal of the system is to assist experts on pharmacy in making the decision of whether a patient suffers from one or more ADRs. The core of the system is a predictive model inferred from a manually tagged corpus that counts on both semantic and syntactically features. This model is able to extract ADRs from disease-drug pairs in a given EHR. Finally, the ADRs automatically extracted are post-processed using a heuristic to present the information in a compact way. This stage reports the drugs and diseases of the document together with their frequency, and it also links the pairs related as ADRs. In brief, the system not only presents the ADRs in the text but also provides concise information on request by experts in pharmacy (the potential users of the system).This work was partially supported by the Spanish Ministry of Science and Innovation (EXTRECM: TIN2013-46616-C2-1-R) and the Basque Government (DETEAMI: Ministry of Health 2014111003, IXA Research Group of type A (2010-2015), Ber2Tek: IE12-333, Predoctoral Grant: PRE 2015 1 0211)

Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma

AIM: To evaluate the efficacy and the safety of azathioprine (AZA) and buthionine sulfoximine (BSO) by localized application into HepG2 tumor in vivo