Tissue specific in-vivosilencing of ALS mendelian genes to identify the primary trigger of neurodegeneration in the disease

[ES] La esclerosis lateral amiotrófica (ELA) es un síndrome neurodegenerativo raro de etiología incierta con desenlace fatal, en el cual un 10% de los casos son formas familiares causadas principalmente por 4 genes, entre ellos TARDBP y FUS. El objetivo ha sido conseguir un modelo de Drosophila melanogaster con silenciamiento tejido específico de los genes ortólogos de TARDBP y FUS. Concretamente el silenciamiento se ha inducido en glía y en músculo, tipos celulares que junto con la motoneurona integran la unión neuromuscular, y complementariamente se han realizado ensayos experimentales para detectar diferencias en el fenotipo locomotor de las moscas con silenciamiento de estos genes en músculo. El propósito final sería identificar si estos tejidos podrían desencadenar la degeneración de la motoneurona, consolidando la hipótesis de la ELA como enfermedad periférica primariamente metabólica. Este trabajo fin de grado aborda las primeras fases de este ambicioso proyecto.[EN] Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative syndrome that has an unknown aetiology with a tragic ending, in which 10% of all cases are familiar forms caused fundamentally by 4 genes, TARDBP and FUS among them. The aim has been to generate a model of Drosophila melanogaster with tissue-specific silencing of orthologous genes of TARDBP and FUS. We have chosen glial and muscular tissues for the silencing because they take part of the neuromuscular junction and additionally, some experimental trials have been made in order to detect differences in the locomotor phenotype which had these genes silenced in muscle. The final goal will be to identify if these tissues could trigger neurodegeneration, supporting the theory of ELA being a peripheral primarily metabolic disease. This final degree project is focused on the first phase of this ambitious project

Tissue specific in-vivosilencing of ALS mendelian genes to identify the primary trigger of neurodegeneration in the disease

[ES] La esclerosis lateral amiotrófica (ELA) es un síndrome neurodegenerativo raro de etiología incierta con desenlace fatal, en el cual un 10% de los casos son formas familiares causadas principalmente por 4 genes, entre ellos TARDBP y FUS. El objetivo ha sido conseguir un modelo de Drosophila melanogaster con silenciamiento tejido específico de los genes ortólogos de TARDBP y FUS. Concretamente el silenciamiento se ha inducido en glía y en músculo, tipos celulares que junto con la motoneurona integran la unión neuromuscular, y complementariamente se han realizado ensayos experimentales para detectar diferencias en el fenotipo locomotor de las moscas con silenciamiento de estos genes en músculo. El propósito final sería identificar si estos tejidos podrían desencadenar la degeneración de la motoneurona, consolidando la hipótesis de la ELA como enfermedad periférica primariamente metabólica. Este trabajo fin de grado aborda las primeras fases de este ambicioso proyecto.[EN] Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative syndrome that has an unknown aetiology with a tragic ending, in which 10% of all cases are familiar forms caused fundamentally by 4 genes, TARDBP and FUS among them. The aim has been to generate a model of Drosophila melanogaster with tissue-specific silencing of orthologous genes of TARDBP and FUS. We have chosen glial and muscular tissues for the silencing because they take part of the neuromuscular junction and additionally, some experimental trials have been made in order to detect differences in the locomotor phenotype which had these genes silenced in muscle. The final goal will be to identify if these tissues could trigger neurodegeneration, supporting the theory of ELA being a peripheral primarily metabolic disease. This final degree project is focused on the first phase of this ambitious project

Tissue specific in-vivosilencing of ALS mendelian genes to identify the primary trigger of neurodegeneration in the disease

[ES] La esclerosis lateral amiotrófica (ELA) es un síndrome neurodegenerativo raro de etiología incierta con desenlace fatal, en el cual un 10% de los casos son formas familiares causadas principalmente por 4 genes, entre ellos TARDBP y FUS. El objetivo ha sido conseguir un modelo de Drosophila melanogaster con silenciamiento tejido específico de los genes ortólogos de TARDBP y FUS. Concretamente el silenciamiento se ha inducido en glía y en músculo, tipos celulares que junto con la motoneurona integran la unión neuromuscular, y complementariamente se han realizado ensayos experimentales para detectar diferencias en el fenotipo locomotor de las moscas con silenciamiento de estos genes en músculo. El propósito final sería identificar si estos tejidos podrían desencadenar la degeneración de la motoneurona, consolidando la hipótesis de la ELA como enfermedad periférica primariamente metabólica. Este trabajo fin de grado aborda las primeras fases de este ambicioso proyecto.[EN] Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative syndrome that has an unknown aetiology with a tragic ending, in which 10% of all cases are familiar forms caused fundamentally by 4 genes, TARDBP and FUS among them. The aim has been to generate a model of Drosophila melanogaster with tissue-specific silencing of orthologous genes of TARDBP and FUS. We have chosen glial and muscular tissues for the silencing because they take part of the neuromuscular junction and additionally, some experimental trials have been made in order to detect differences in the locomotor phenotype which had these genes silenced in muscle. The final goal will be to identify if these tissues could trigger neurodegeneration, supporting the theory of ELA being a peripheral primarily metabolic disease. This final degree project is focused on the first phase of this ambitious project

Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort

Objectives: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). Methods: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. Results: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P <0.01) and previous renal failure (57.9%, P <0.01). Patients treated with cloxacillin presented higher rates of septic shock (25%, P = 0.033) and new-onset or worsening renal failure (47.3%, P = 0.024) with significantly higher rates of in-hospital mortality (38.5%, P = 0.017). One-year IE-related mortality and rate of relapses were similar between treatment groups. None of the treatments were identified as risk or protective factors. Conclusion: Our results suggest that cefazolin is a valuable option for the treatment of MSSA IE, without differences in 1-year mortality or relapses compared with cloxacillin, and might be considered equally effective