Efectividad del tratamiento anti-TNFa en pacientes con enfermedad de crohn que no han alcanzado la remisión con un primer anti-TNFa

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 6-07-2016Los fármacos anti-TNFα son efectivos para inducir y mantener la remisión clínica en los pacientes con enfermedad de Crohn. Desafortunadamente, un porcentaje importante de enfermos no logra alcanzar dicha remisión, por obtener sólo respuesta parcial al tratamiento o por no presentar ningún tipo de respuesta a éste. El uso consecutivo de diferentes fármacos anti-TNFα parece ser efectivo si el motivo de suspensión inicial fue la pérdida de respuesta o la intolerancia. Pero disponemos de pocos datos sobre la evolución de aquellos pacientes que reciben un anti-TNFα tras no haber alcanzado la remisión con el primero. Según diferentes estudios, el porcentaje de pacientes que no alcanzan la remisión clínica con un anti-TNFα podrían oscilar entre el 50 y el 80%. A pesar de ser un porcentaje relevante, son pocos los trabajos que hasta la fecha han evaluado la efectividad del tratamiento secuencial en este grupo de pacientes. El objetivo principal del presente estudio fue evaluar la efectividad de un tratamiento anti-TNFα en pacientes con enfermedad de Crohn que no habían alcanzado la remisión previamente con otro fármaco del mismo grupo terapéutico. Con este fin se incluyeron un total de 118 pacientes procedentes de 24 hospitales españoles con diagnóstico previo de enfermedad de Crohn y que hubieran recibido un segundo tratamiento anti-TNFα habiendo tenido falta de remisión con el previo. El primer anti-TNFα se había suspendido por ausencia de respuesta en el 54% de los casos y por respuesta parcial en el 46%. El 51% de los pacientes alcanzó la remisión clínica a corto plazo con el segundo tratamiento anti-TNFα. El porcentaje de remisión alcanzado con el segundo fármaco fue menor en aquellos pacientes en los que el tratamiento biológico se indicó por enfermedad perianal (OR = 0,3, IC 95% = 0,1-0,7, p = 0,005). La probabilidad de mantener la remisión fue del 76%, 68% y 64% a los 12, 18 y 24 meses, respectivamente. Durante el seguimiento, el 33% de los pacientes requirió intensificación del segundo anti-TNFα y, de ellos, el 37% logró alcanzar la remisión clínica. A la luz de estos resultados, podemos concluir que el tratamiento con un segundo fármaco anti-TNFα tras no haber alcanzado la remisión con el anterior es una estrategia efectiva en aproximadamente la mitad de los pacientes, teniendo menos probabilidades de responder aquellos pacientes con enfermedad perianal. No obstante, una proporción relevante de pacientes pierde la respuesta a lo largo del tiempo y, en estos casos, la intensificación del tratamiento es una opción terapéutica válida

Reduction of net sulfide production rate by nitrate in wastewater bioreactors. Kinetics and changes in the microbial community

15 páginas, 7 figuras, 5 tablas, 44 referencias.-- [email protected] addition stimulated sulfide oxidation by increasing the activity of nitrate-reducing sulfide-oxidizing bacteria (NR-SOB), decreasing the concentration of dissolved H2S in the water phase and, consequently, its release to the atmosphere of a pilot-scale anaerobic bioreactor. The effect of four different concentrations of nitrate (0.12, 0.24, 0.50, and 1.00 mM) was investigated for a period of 3 days in relation to sulfide concentration in two bioreactors set up at Guadalete wastewater treatment plant (Jerez de la Frontera, Spain). Physicochemical variables were measured in water and air, and the activity of bacteria implicated in the sulfur and nitrogen cycles was analyzed in the biofilms and in the water phase of the bioreactors. Biofilms were a net source of sulfide for the water and gas phases (7.22±5.3 μmol s−1) in the absence of nitrate dosing. Addition of nitrate resulted in a quick (within 3 h) decrease of sulfide both in the water and atmospheric phases. Sulfide elimination efficiency in the water phase increased with nitrate concentrations following the Michaelis–Menten kinetics (Ks=0.63 mM NO3 −). The end of nitrate addition resulted in a recovery or increase of initial net sulfide production in about 3 h. Addition of nitrate increased the activity of NR-SOB and decreased the activity of sulfate-reducing bacteria. Results confirmed the role of NR-SOB on hydrogen sulfide consumption coupled with nitrate reduction and sulfate recycling, revealing Sulfurimonas denitrificans and Paracoccus denitrificans as NR-SOB of great importance in this process.We acknowledge the support of the grants P06-RNM-01787, P11-RNM-7199, the PAI groups RNM-214 and BIO-288 from Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain and CTM2009-10736 from the Ministerio de Innovación y Ciencia, Spain, which include cofinancing from FEDER funds. S. Papaspyrou was funded by a JAE-Doc fellowship (Programa JAE, JAE-Doc109, Spanish National Research Council) and a Marie Curie ERG action (NITRICOS, 235005, European Union).Peer reviewe

TGF-β antagonist attenuates fibrosis but not luminal narrowing in experimental tracheal stenosis.

Introduction/Objective: Acquired tracheal stenosis (ATS) is an unusual disease often secondary to prolonged mechanical trauma. ATS pathogenesis involves inflammation and subsequent fibrosis with narrowing of the tracheal lumen. TGF-β represents a pivotal factor in most fibrotic processes and therefore, a potential target in this context. The aim of this study is to analyze the role of TGF-β as a target for anti-fibrotic interventions in tracheal stenosis. Methods: Human stenotic tracheobronchial tissues from patients with benign airway stenosis and normal controls from pneumonectomy specimens were analyzed. Tracheal stenosis was induced in adult NZ rabbits by a circumferential thermal injury to the mucosa during open surgery and re-anastomosis. Rabbits were treated postoperatively with a peritracheal collagen sponge containing a TGF-β peptide antagonist (p17) or vehicle. Fibrosis was determined by Masson’s trichrome staining, and α-SMA+ Results: Human and rabbit stenotic tissues showed extensive submucosal fibrosis, characterized by significantly increased α-SMA myofibroblasts, CTGF and p-Smad2/3 expression by immunohistochemistry. + myofibroblasts and CTGF expression. In human stenotic lesions, increased p-Smad2/3+ nuclei were also observed. p17 treatment significantly reduced the fibrotic thickness as well as the density of α-SMA+ myofibroblasts and CTGF+ Conclusion: ATS is characterized by a TGF-β dependent fibrotic process but reduction of the fibrotic component by TGF-β1 antagonist therapy was not sufficient to improve tracheal narrowing, suggesting that fibrosis may not be the main contributor to luminal stenosis. cells in rabbit stenotic lesions but failed to improve the luminal area.pre-print1304 K

Finanzas sostenibles: Entre todos y para todos

Proyecto en el que participan dos universidades: Universidad Complutense de Madrid y Universidad Rey Juan Carlos, y un Instituto de Enseñanza Secundario: Gerardo DiegoDepto. de Economía Aplicada, Pública y PolíticaFac. de Ciencias Económicas y EmpresarialesFALSEUniversidad Complutense de Madridsubmitte

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect

Altres ajuts: This work was funded by Instituto de Salud Carlos III; Ministerio de Educación, Cultura y Deporte; Spanish Foundation per Amor a l'Art (FPAA) grant ; Fundació la Marató de TV3 grants 20143130; and 20143131; Generalitat Valenciana grants OP ERDF of Comunitat Valenciana 2014-2020; and PROMETEO/2018/135.FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders

SARS-CoV-2 infection elicits a rapid neutralizing antibody response that correlates with disease severity

The protective effect of neutralizing antibodies in SARS-CoV-2 infected individuals is not yet well defined. To address this issue, we have analyzed the kinetics of neutralizing antibody responses and their association with disease severity. Between March and May 2020, the prospective KING study enrolled 72 COVID-19+ participants grouped according to disease severity. SARS-CoV-2 infection was diagnosed by serological and virological tests. Plasma neutralizing responses were assessed against replicative virus and pseudoviral particles. Multiple regression and non-parametric tests were used to analyze dependence of parameters. The magnitude of neutralizing titers significantly increased with disease severity. Hospitalized individuals developed higher titers compared to mild-symptomatic and asymptomatic individuals, which together showed titers below the detection limit in 50% of cases. Longitudinal analysis confirmed the strong differences in neutralizing titers between non-hospitalized and hospitalized participants and showed rapid kinetics of appearance of neutralizing antibodies (50% and 80% of maximal activity reached after 11 and 17 days after symptoms onset, respectively) in hospitalized patients. No significant impact of age, gender or treatment on the neutralizing titers was observed in this limited cohort. These data identify a clear association of humoral immunity with disease severity and point to immune mechanisms other than antibodies as relevant players in COVID-19 protection.info:eu-repo/semantics/publishedVersio

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Programas de optimización del uso de antimicrobianos en hospitales: guía de recomendaciones de expertos para actividades en poblaciones específicas, síndromes y otros aspectos (PROA-2) de la SEIMC, SEFH, SEMPSPGS, SEMICYUC y SEIP

[EN] In 2012, The Spanish Societies of Infectious Diseases and Clinical Microbiology (SEIMC), Hospital Pharmacy (SEFH), and Preventive Medicine, Public Health and Healthcare Management (SEMPSGS) lead a consensus document including recommendations for the implementation of antimicrobial stewardship (AMS) programs (AMSP; PROA in Spanish) in acute care hospitals in Spain. While these recommendations were critical for the development of these programs in many centres, there is a need for guidance in the development of AMS activities for specific patient populations, syndromes or other specific aspects which were not included in the previous document or have developed significantly since then. The objective of this expert recommendation guidance document is to review the available information about these activities in these patient populations or circumstances, and to provide guidance recommendations about them. With this objective the SEIMC, SEFH, SEMPSPGS, the Spanish Society of Intensive Care Medicine (SEMICYUC) and the Spanish Pediatric Infectious Disease Society (SEIP) selected a panel of experts who chose the different aspects to include in the document. Because of the lack of high-level evidence in the implementation of the activities, the panel opted to perform a narrative review of the literature for the different topics for which recommendations were agreed by consensus. The document was open to public consultation for the members of these societies for their comments and suggestions, which were reviewed and considered by the panel.[ES] En 2012, las Sociedades Españolas de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), Farmacia Hospitalaria (SEFH) y Medicina Preventiva, Salud Pública y Gestión Sanitaria (SEMPSPGS) lideraron un documento de consenso que incluía recomendaciones para la implementación de Programas de optimización del uso de antimicrobianos (PROA) en hospitales de agudos en España. Si bien estas recomendaciones fueron críticas para el desarrollo de estos programas en muchos centros, actualmente es necesario establecer unas guías para la implementación de las actividades de los PROA en determinadas poblaciones de pacientes, síndromes clínicos y otros aspectos específicos que no se incluyeron en el documento previo o que desde entonces se han desarrollado significativamente. El objetivo de esta guía de recomendaciones de expertos es revisar la información disponible acerca de esas actividades en estas poblaciones o circunstancias de pacientes y proporcionar unas recomendaciones que sirvan de guía sobre ellas. Con este objetivo, la SEIMC, la SEFH y la SEMPSPGS, así como la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) y la Sociedad Española de Infectología Pediátrica (SEIP), seleccionaron un panel de expertos que eligieron los diferentes aspectos a incluir en el documento. Debido a la ausencia de evidencia de alto nivel en la implementación de las diferentes actividades, el panel optó por realizar una revisión narrativa de la literatura de los diferentes aspectos, en los que las recomendaciones se acordaron por consenso. El documento se abrió para consulta pública a los miembros de estas sociedades para sus comentarios y sugerencias, que fueron revisadas y consideradas por el panel.Peer reviewe