Major determinants of prolonged remission in systemic lupus erythematosus: retrospective study over a 41+year period

OBJECTIVES: To investigate predictors of sustained complete remission (CR) for 3 and 5 years, minimum. METHODS: Retrospective observational study from January 1978-december 2019, including Systemic Lupus Erythematosus (SLE) patients who attended the Lupus Clinic in a tertiary hospital, for at least 3 years. We used the British Isles Lupus Assessment Group (BILAG) score and serological profile to classify patients into CR, serologically active clinically quiescent (SACQ) and serological remission (SR). Multivariable cox regression analysis was performed to investigate predictors of CR and Kaplan-Meier curves were obtained. RESULTS: We included 564 patients; 15% achieved CR, 7% SACQ, 15% SR. 63% attained no remission. In the CR group, 73% sustained the remission for 5 or more years. Patients who did not reach any kind of sustained remission died significantly earlier (p32-years), HR 1.92 [1.24-2.97] p= 0.003; absence of renal involvement, HR 2.55 [1.39-4.67] p= 0.002; and of antiphospholipid syndrome (APS), HR 4.92 [1.55-15.59] p= 0.007. CONCLUSION: Patients not achieving any kind of sustained remission have a higher risk of early mortality. White ethnicity, older age at diagnosis, absence of renal involvement and of APS were significantly associated with CR. Predictors for sustained CR do not change whether a 3-year or 5-year period is applied

Immunobiology of Atherosclerosis: A Complex Net of Interactions

Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis.The authors’ research is supported by grants from the Instituto de Salud Carlos III (ISCIII) (PI17/01395; CPII16/00022) and EuroCellNet COST Action CA15214 with co-funding from the European Regional Development Fund (ERDF), “A way to build Europe,” and the Miguel Servet Program. The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). J.M.G.-G. is supported by the ISCIII Miguel Servet Program, i+12 and Universidad Autónoma de Madrid (UAM); R.G.B. and B.S. by i+12 and ISCIII and B.H.F. by i+12, UAM and FPU programs from the MCNU.S

Manejo clínico de la infección viral del herpes simple y Candidiasis oral: Reporte de un caso clínico

La infección por herpes simple tipo I es una de las enfermedades más frecuentes que afecta a la cavidad bucal, se manifiesta en forma de vesículas que tienden a remitir después de 10 a 12 días y es altamente recidivante. El siguiente trabajo tiene como finalidad presentar el caso clínico de un paciente con herpes simple recidivante intrabucal, acompañado de dolor intenso, con síntomas y signos clínicos persistentes por un largo periodo de tiempo, que no remitía con el tratamiento. Se detectó infección de Cándida Albicans acompañando al cuadro. Se realizaron análisis de laboratorio, incluyendo el test de Elisa para confirmar presencia de HIV resultando negativo, PCR para detección de VHS tipo 1 y cultivo de Cándida Albicans. Se trató la virosis con Aciclovir en altas dosis, la infección sobreagregada con nistatina y se indicó polivitamínicos para reforzar el huésped. El paciente fue tratado multidisciplinariamente y derivado al psicólogo por presentar un cuadro de estrés, lo que permitió disminuir la ansiedad del mismo ejerciendo un rol importante en el tratamiento.Fil: Gonzalez, Maria Mercedes. Universidad Nacional del Nordeste. Facultad de Odontologia; ArgentinaFil: Rosende, Roque O.. Universidad Nacional del Nordeste. Facultad de Odontologia; ArgentinaFil: Krupp, Sebastian. Universidad Nacional del Nordeste. Facultad de Odontologia; ArgentinaFil: Rosales, Carlos A.. Universidad Nacional del Nordeste. Facultad de Odontologia; ArgentinaFil: Fernandez, Estefania Raquel. Universidad Nacional del Nordeste. Facultad de Odontologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentin

Impact of operatoŕs experience on peri-procedural outcomes with Watchman FLX: Insights from the FLX-SPA registry 2

Left atrial appendage; Occlusion; OutcomesApéndice auricular izquierdo; Oclusión; ResultadosApèndix auricular esquerre; Oclusió; ResultatsBackground The Watchman FLX is a device upgrade of the Watchman 2.5 that incorporates several design enhancements intended to simplify left atrial appendage occlusion (LAAO) and improve procedural outcomes. This study compares peri-procedural results of LAAO with Watchman FLX (Boston Scientific, Marlborough, Massachusetts) in centers with varying degrees of experience with the Watchman 2.5 and Watchman FLX. Methods Prospective, multicenter, “real-world” registry including consecutive patients undergoing LAAO with the Watchman FLX at 26 Spanish sites (FLX-SPA registry). Implanting centers were classified according to the center’s prior experience with the Watchman 2.5. A further division of centers according to whether or not they had performed ≤ 10 or > 10Watchman FLX implants was prespecified at the beginning of the study. Procedural outcomes of institutions stratified according to their experience with the Watchman 2.5 and FLX devices were compared. Results 359 patients [mean age 75.5 (SD8.1), CHA2DS2-VASc 4.4 (SD1.4), HAS-BLED 3.8(SD0.9)] were included. Global success rate was 98.6%, successful LAAO with the first selected device size was achieved in 95.5% patients and the device was implanted at first attempt in 78.6% cases. There were only 9(2.5%) major peri-procedural complications. No differences in efficacy or safety results according to the centeŕs previous experience with Watchman 2.5 and procedural volume with Watchman FLX existed. Conclusions The Watchman FLX attains high procedural success rates with complete LAA sealing in unselected, real-world patients, along with a low incidence of peri-procedural complications, regardless of operatoŕs experience with its previous device iteration or the number of Watchman FLX devices implanted

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.This project was funded by Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, Asociación Pablo Ugarte, grant numbers TRPV205/18; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17. Enrique Fernández-Tabanera is supported by Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, Saint T. Cervera is supported by Asociación Pablo Ugarte and Raquel M. Melero is supported by a CIBERER contract.S

Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation

BACKGROUND: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1β, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. OBJECTIVE: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis. METHODS: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) and mammalian target of rapamycin (mTOR [rapamycin]). RESULTS: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1β, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1β stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1β-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling. CONCLUSION: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1β/IL-17 axis.Funding This manuscript has been funded by grants SAF 2017-82886-R (FS-M) and SAF 2013-42850-R (MF) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (FS-M); CIBERCV, BIOIMID PIE13/041 from Instituto de Salud Carlos III and Fundación La Marató TV3 (20152330 31). The project leading to these results has also received funding from FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACIÓN CIENTÍFICA 2018 and from “la Caixa” Banking Foundation under the project code HR17-00016 (FS-M), and from Agencia Estatal de Investigación, Fondo Europeo de Desarrollo Regional PI17/01972 (E.D).S

Inactive disease in patients with lupus is linked to autoantibodies to type I interferons that normalize blood IFNα and B cell subsets

Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNα protein levels, inhibition of IFN-I downstream gene signatures, and inactive global disease score. Hallmarks of SLE pathogenesis, including increased immature, double-negative plasmablast B cell populations and reduction in regulatory B cell (Breg) frequencies, were normalized in patients with neutralizing anti-IFN-Abs compared with other patient groups. Immunoglobulin G (IgG) purified from sera of patients with SLE with neutralizing anti-IFN-Abs impedes CpGC-driven IFNα-dependent differentiation of B cells into immature B cells and plasmablasts, thus recapitulating the neutralizing effect of anti-IFN-Abs on B cell differentiation in vitro. Our findings highlight a role for neutralizing anti-IFN-Abs in controlling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutralizing-anti-IFN-Abs

Microtubule stabilization reduces amyloid pathology and improves synaptic/memory deficits in APP/PS1 mice

Aims: Cognitive decline in Alzheimer's disease (AD) is highly related to synaptic/neuronal loss. Tau hyperphosphorylation destabilizes microtubules leading to axonal transport failure and generation of dystrophic neurites, thus contributing to synaptic dysfunction. The effect of microtubule stabilization on amyloid-beta pathology has not been assessed in vivo yet. This study evaluated the effect of the microtubule-stabilizing agent, Epothilone D (EpoD) in the pathology of an amyloidogenic mouse model. Methods: APP751SL/PS1M146L mice (3-month-old) were treated weekly with intraperitoneal injections of EpoD (2 mg/kg) or vehicle for 3 months. For memory performance, animals were tested on the objectrecognition, Y-maze and Morris water maze. Hippocampal proteinopathies were quantified by image analysis after immunostaining. Somatostatin (SOM)-numerical density was calculated by stereology. APPswe-N2a cells were treated with EpoD 100nM for 12/24 hours. Protein levels were analysed by Western/dot-blot. Results: EpoD-treated mice improved their performance of cognitive tests, while hippocampal phospho-tau and Ab (especially oligomers) accumulation decreased, together with synaptic/neuritic pathology. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Conclusions: EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Ab accumulation and promoting neuronal and cognitive protection, underlining the cross-talk between cytoskeleton pathology and proteinopathy. Therefore, microtubule-stabilizing drugs could be candidates for slowing AD at both tau and Ab pathologies.Supported by PI18/01557 (to AG) and PI18/01556 (to JV) grants from ISCiii of Spain, co-financed by FEDER funds (European Union), CIBERNED collaborative grant (to AG and JV), and by PPIT.UMA.B1.2017/26 grant (to RSV). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Tecnologías de materiales con aplicaciones en fusión y su desarrollo en la instalación TechnoFusión

El futuro Centro Nacional de Tecnologías para la Fusión, TechnoFusión, tiene como objetivo desarrollar aquellas tecnologías, relacionadas con materiales, metales líquidos, manipulación remota y simulación, que permitan avanzar en los actuales retos que supone el uso de la fusión nuclear. Sus instalaciones, abiertas al servicio de la comunidad científica externa, garantizarán una destacada participación de empresas y grupos de investigación españoles. En esta contribución se describirán y analizarán las instalaciones que TechnoFusión construirá con capacidad para abordar: la fabricación y procesado de nuevas aleaciones a escala semiindustrial; el comportamiento de materiales, simulando las condiciones durante operación mediante una instalación de triple irradiación (iones pesados, hidrógeno y helio), generadores de plasma lineal (continuo y pulsado) y un circuito de litio líquido; y la caracterización del efecto que las severas condiciones de experimentación producen en las propiedades, en la composición y en la microestructura de materiales estructurales y funcionales (técnicas convencionales e in-situ)

EFFICHRONIC study protocol: A non-controlled, multicentre European prospective study to measure the efficiency of a chronic disease self-management programme in socioeconomically vulnerable populations

Introduction More than 70% of world mortality is due to chronic conditions. Furthermore, it has been proven that social determinants have an enormous impact on both health-related behaviour and on the received attention from healthcare services. These determinants cause h