Esplenomegalia como signo de enfermedad lisosomal

La estructura sana del bazo funciona como función hematopoyética para el período fetal; después, se convierte en un gran órgano linfoide, y también, es del sistema de filtro de células sanguíneas. La enfermedad de Gaucher es un extraño trastorno de almacenamiento lisosomal, muchos de ellos son hereditarios y multisistémicos. Hoy en día, setenta LSD han sido adoptados

Esplenomegalia como signo de enfermedad lisosomal

Healthy spleen structure works as hematopoietic function for the fetal period; after, it becomes a big lymphoid organ, and also, it´s from the blood cells filter System. Gaucher illness is a strange lysosomal storage disorder, most of them are inherited and multisystemic. Nowadays, seventy LSDs have been embracedLa estructura sana del bazo funciona como función hematopoyética para el período fetal; después, se convierte en un gran órgano linfoide, y también, es del sistema de filtro de células sanguíneas. La enfermedad de Gaucher es un extraño trastorno de almacenamiento lisosomal, muchos de ellos son hereditarios y multisistémicos. Hoy en día, setenta LSD han sido adoptados

El género Amanita Pers. ex Hooker en la provincia de León

Se citan 23 taxa del género Amanita en la provincia de León (Noroeste de España).Se acompaña una clave para su determinación, su distribución provincial, ecología, así como su relación con las series de vegetación.Twenty three taxa of genus Amanita in León province (NW Spain) are quoted.An identification key of all these taxa is provided, as well as their provincial distribution, ecology and their relation with the vegetation serie

Serum amyloid a1/toll-like receptor-4 Axis, an important link between inflammation and outcome of TBI patients

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability world-wide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patientsThis work was supported by grants from Fundación Mutua Madrileña and Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet CP14/00008; CPII19/00005; PI16/00735; PI19/00082) to JE, RYC2019-026870-I to JMR and PI18/01387 to A

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7473G>A (p.=) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of 3 mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that 4 of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease.info:eu-repo/semantics/publishedVersio

Growth hormone remodels the 3D-structure of the mitochondria of inflammatory macrophages and promotes metabolic reprogramming

IntroductionMacrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming.MethodsHere we use biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy.ResultsWe demonstrate that growth hormone (GH) reprograms inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ) by functioning as a metabolic modulator. We found that exogenous treatment of GM-MØ with recombinant human GH reduced glycolysis and lactate production to levels similar to those found in anti-inflammatory M-MØ. Moreover, GH treatment of GM-MØ augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae.ConclusionsOur data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered as a new target to intervene in inflammatory diseases

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. clinicaltrials.gov identifier:02869074

Estudio prospectivo, de seguimiento en pacientes con enfermedad de Gaucher Tipo 1 que reciben tratamiento con CERDELGA®. Proyecto TRAZELGA

Poster [PC-303] Introducción: La enfermedad de Gaucher tipo 1 (EG1), secundaria al déficit en la enzima glucocerebrosidasa lisosomal, provoca el acúmulo de glucocerebrósido principalmente en macrófagos, causando deterioro de los órganos en los que se deposita. El nuevo inhibidor de substrato Eliglustat (ELG), aprobado por la EMEA en 2015 y disponible desde enero 2017, inhibe de forma selectiva y potente la enzima glucosilceramida sintasa, disminuyendo el acúmulo de substrato, está indicado en EG1 metabolizadores rápidos, intermedios o lentos para el citocromo CYP2D6. Los ensayos clínicos de fase 2 y 3 demostraron mejora y estabilización de los parámetros tanto en los pacientes naïve, como en los de tratamiento enzimático sustitutivo. En este trabajo se expone el estudio de trazabilidad del tratamiento con eliglustat en pacientes con GD1 en España (TRAZELGA). Material y Métodos: El estudio nacional, multicéntrico TRAZELGA, ha sido diseñado como herramienta para evaluar de forma uniforme la respuesta al tratamiento durante un año, analizando los cambios en parámetros clínicos y biomarcadores habituales, registro de medicamentos concomitantes y efectos adversos a ELG, estudio de calidad de vida e incorporando un estudio exploratorio de marcadores de activación del sistema inmune (perfil de citoquinas, ferritina, lipocalina, gammaglobulinas, marcadores de estrés oxidativo), así como cambios en la infiltración medular cuantificados por RM y DEXA. Previo al inicio de ELG se realizó una evaluación de función cardíaca, hepática y renal. Resultados: 35 pacientes han iniciado tratamiento oral con Eliglustat. En esta presentación aportamos resultados preliminares de 21 pacientes (mediana de edad: 43, 8 años(23-75), 47% varones), genotipo de EG N370S/N370S: (29, 4%), N370S/L444P (41, 2%), otros dobles heterocigotos con N370S (29, 4%), metabolismo del CYP2D6 (12% metabolizadores lentos, 64, 5% intermedios y 33, 5% rápidos, ningún paciente recibió el tratamiento en prímera línea y sus características basales (tabla1), son de pacientes estabilizados con TES (15 casos) o miglustat (6). Un paciente esplenectomizado. 3 pacientes esplenomegalia palpable al momento de inclusión. 6 pacientes con multimorbilidades y polimedicaciones y 5 pacientes aquejaban astenia como síntoma principal antes de su inclusión en este estudio. El seguimiento medio actual es de 6 meses. Conclusiones: Se espera incluir un total de 30 pacientes en el estudio y analizar la influencia de Eliglustat sobre los biomarcadores, marcadores de inflamación, densidad mineral ósea. Tener información sobre adherencia, efectos adversos en práctica clínica habitual y grado de satisfacción. Aunque escasos, hasta ahora no hay publicada información de la respuesta al tratamiento en pacientes provenientes de tratamiento con miglustat. En caso de aceptación se presentará un análisis exhaustivo, invitando a todos los interesados a unirse al proyecto

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic