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OBJECTIVES: This study aimed to evaluate the effectiveness of dalbavancin as sequential therapy in patients with infective endocarditis (IE) due to gram positive bacteria (GPB) in a real-life heterogenous cohort with comorbid patients. METHODS: A single center retrospective cohort study including all patients with definite IE treated with dalbavancin between January 2017 and February 2022 was developed. A 6-month follow-up was performed. The main outcomes were clinical cure rate, clinical and microbiological relapse, 6-month mortality, and adverse effects (AEs) rate. RESULTS: The study included 61 IE episodes. The median age was 78.5 years (interquartile range [IQR] 63.2-85.2), 78.7% were male, with a median Charlson comorbidity index of 7 (IQR 4-9) points. Overall, 49.2% suffered native valve IE. The most common microorganism was Staphylococcus aureus (26.3%) followed by Enterococcus faecalis (21.3%). The median duration of initial antimicrobial therapy and dalbavancin therapy were 27 (IQR 20-34) and 14 days (IQR 14-28) respectively. The total reduction of hospitalization was 1090 days. The most frequent dosage was 1500mg of dalbavancin every 14 days (96.7%). An AE was detected in 8.2% of patients, only one (1.6%) was attributed to dalbavancin (infusion reaction). Clinical cure was achieved in 86.9% of patients. One patient (1.6%) with Enterococcus faecalis IE suffered relapse. The 6-month mortality was 11.5%, with only one IE-related death (1.6%). CONCLUSION: This study shows a high efficacy of dalbavancin in a heterogeneous real-world cohort of IE patients, with an excellent safety profile. Dalbavancin allowed a substantial reduction of in-hospital length of stay.
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BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. METHODS: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. RESULTS: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. CONCLUSIONS: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
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Aneurisma Aórtico/fisiopatologia , Síndrome de Marfan/genética , Mitocôndrias/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Síndrome de Marfan/fisiopatologia , CamundongosRESUMO
Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.
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Proteínas de Ligação ao Cálcio/deficiência , Deleção de Genes , Imunidade Celular , Nefropatias/imunologia , Rim/imunologia , Células Th17/imunologia , Animais , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Camundongos , Células Th17/patologia , Obstrução Ureteral/genética , Obstrução Ureteral/imunologia , Obstrução Ureteral/patologiaRESUMO
The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.
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Senilidade Prematura/imunologia , Proteínas de Ligação a DNA/deficiência , Mitocôndrias/metabolismo , Proteínas Mitocondriais/deficiência , Multimorbidade , Linfócitos T/metabolismo , Fatores de Transcrição/deficiência , Senilidade Prematura/genética , Senilidade Prematura/prevenção & controle , Animais , Síndrome da Liberação de Citocina/imunologia , Proteínas de Ligação a DNA/genética , Feminino , Deleção de Genes , Inflamação/genética , Inflamação/imunologia , Longevidade , Masculino , Camundongos , Camundongos Mutantes , Proteínas Mitocondriais/genética , NAD/administração & dosagem , NAD/farmacologia , Aptidão Física , Linfócitos T/ultraestrutura , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
No disponible
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Humanos , Endocardite Bacteriana/epidemiologia , Endocardite Bacteriana/cirurgia , Idoso Fragilizado , Endocardite/complicações , Endocardite/epidemiologia , Tomada de DecisõesRESUMO
Antecedentes y Objetivos. Presentamos 3 casos de dermatofibrosarcoma protuberans (DFSP) en pacientes pediátricos para documentar la presentación clínica poco frecuente de esta patología. Pacientes y Método. Realizamos un análisis descriptivo retrospectivo de los 3 últimos casos de DFSP en nuestro centro durante los años 2010 - 2013. Resultados. Una niña de 12 años remitida desde otra institución por DFSP en parte distal del muslo, en la que ampliamos bordes quirúrgicos de resección en 3 cm y practicamos cobertura con dermis artificial e injerto autólogo; tras 1 año de observación sin recidiva, realizamos reconstrucción del defecto mediante injertos autólogos de grasa. Otra niña de 12 años diagnosticada de Síndrome de Hamartomatosis Múltiple asociado al gen PTEN, que presentó DFSP en labio mayor derecho y en mama derecha, recidivante en esta última localización. Por último, un DFSP congénito en una paciente remitida a los 3 meses de vida con tumoración gigante de pared abdominal. El diagnóstico orientativo inicial con resonancia magnética con gadolino, solo se confirmó finalmente por los hallazgos histopatológicos de la pieza de resección; ni la punción aspiración ni la biopsia cutánea lograron confirmar el diagnóstico. Conclusiones. El DFSP es un tipo de sarcoma raro de la piel del niño y del adulto, localmente agresivo y con una alta tasa de recidiva. La escisión local amplia puede provocar mutilaciones y desfigurar al paciente; por ello la cirugía micrográfica de Mohs permite reducir los márgenes quirúrgicos (AU)
Background and Objectives. We present 3 cases of dermato fibro sarcoma protuberans (DFSP) to document the unusual clinical presentation of this condition in pediatric patients. Patients and Methods. We conduct a retrospective descriptive analysis of the last 3 cases of DFSP treated in our institution during years 2010-2013. Results. A 12-year-old girl referred from another institution for DFSP in distal thigh; we practised surgical margins extended 3 cm resection and cover with artificial dermis and autologous graft; after 1 year follow up without recurrence, reconstruction of the defect was performed using autologous fat grafts. Another 12-year-old girl diagnosed of Multiple Hamartoma Syndrome associated with PTEN gene, who presented DFSP at the right labia major and at the right breast, being recurrent in this last location. Finally, a congenital DFSP in a patient referred at 3 months with giant tumour of abdominal wall. The initial diagnosis was made by MRI with gadolinium. The final diagnosis of DFSP was made based on histopathological findings of the piece following surgical resection, because percutaneous biopsy or skin biopsy couldn´t confirm the diagnostic. Conclusions. DFSP is a rare type of sarcoma of the skin in children and adults, locally aggressive, with a high rate of recurrence. Wide local excision may cause maiming and disfiguring to the patient, thereby Mohs micrographic surgery (CMM) enables to reduce surgical margins (AU)
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Humanos , Feminino , Lactente , Criança , Dermatofibrossarcoma/cirurgia , Cirurgia de Mohs/métodos , Neoplasias Cutâneas/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Síndrome do Hamartoma Múltiplo/complicaçõesRESUMO
OBJECTIVE: To investigate whether running influences smoking habits. DESIGN: Study of cases and controls, with 1:1 pairing. Retrospective longitudinal observational study. SETTING: Primary care. City of Toledo, Spain. CASES: 48 healthy volunteer runners of 47+/-7.8 years of age. CONTROLS: 48 healthy subjects, paired by gender and year of birth, chosen at random from the medical list assigned to the medical researcher. PRINCIPAL MEASUREMENTS: Smoking habits and alcohol consumption in grams per week using a questionnaire, weight, height, blood pressure, and heart rate at rest. The odds ratio (OR) was obtained on the proportion of subjects who smoked or smoked at some time, those who continued smoking and the probabilities of giving up tobacco in each group. RESULTS: The OR of the proportion of subjects who smoked or had smoked between the groups of runners (54.2%) and controls (70.9%) was 0.486 (95% confidence interval [CI], 0.205-1.149; chi(2)=2.8; P=.093). The OR for continuing the habit between groups of runners (8.4%) and controls (41.7%) was 0.127 (95% CI, 0.035-0.456; chi(2)=14.0; P=.0002). In the group of runners, 45.8% had stopped smoking, as well as 31.2% of the controls (OR=7.85; 95% CI, 1.89-32.52; chi(2)=11.8; P=.0007); 50% of the runners who smoked had given it up since starting to run and 76.9% of these had given it up just at the time of starting to run. CONCLUSIONS: There is a negative association between running and tobacco. If a smoker decides to run regularly he/she has high probabilities of giving up smoking and continue to do so.
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Corrida/estatística & dados numéricos , Fumar/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Objetivo. Investigar si la carrera a pie influye sobre el hábito tabáquico. Diseño. Estudio de casos y controles, con emparejamiento 1:1. Observación longitudinal retrospectiva. Emplazamiento. Atención primaria. Ciudad de Toledo. Participantes. Casos: 48 corredores voluntarios sanos de 47± 7,8 años de edad. Controles: 48 sujetos sanos, emparejados por sexo y año de nacimiento, elegidos al azar entre la población adscrita al médico investigador. Mediciones principales. Hábito tabáquico y gramos semanales de alcohol mediante cuestionario, peso, talla, presión arterial y frecuencia cardíaca de reposo. Se obtuvieron las odds ratio (OR) de las proporciones de sujetos que fumaban o habían fumado aguna vez, de los que seguían fumando y de las probabilidades de abandono do tabaco en cada grupo. Resultados. La OR de la proporción de sujetos que fumaban o habían fumado entre los grupos de corredores (54,2 por ciento) y controles (70,9 por ciento) era de 0,486 (intervalo de confianza [IC] del 95 por ciento, 0,205-1,149; x² = 2,8; p = 0,093). La OR para continuación del hábito entre los grupos de corredores (8,4 por ciento) y de controles (41,7 por ciento) era de 0,127 (IC del 95 por ciento, 0,035-0,456; x = 14,0; p = 0,0002). En el grupo de corredores había abandonado el tabaco el tabaco el 45,8 por ciento y en el de controles, el 31,2 por ciento (OR = 7,85; IC del 95 por ciento, 1,89-32,52; x = 11,8; p = 0,0007). El 50 por ciento de los corredores que fumaban lo había dejado desde que comenzó a correr y el 76,9 por ciento de estos lo había dejado justo en el momento de comenzar a correr. Conclusiones. Hay una asociasión negativa entre carrera a pie y tabaco. Si un fumador decide comenzar a correr regularmente, tiene muchas probabilidades de dejar de fumar y mantenerse así.(AU)
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Corrida , Tabagismo , Estudos de Casos e ControlesRESUMO
Objetivo. Investigar si la carrera a pie influye sobre el hábito tabáquico. Diseño. Estudio de casos y controles, con emparejamiento 1:1. Observación longitudinal retrospectiva. Emplazamiento. Atención primaria. Ciudad de Toledo. Participantes. Casos: 48 corredores voluntarios sanos de 47 ± 7,8 años de edad. Controles: 48 sujetos sanos, emparejados por sexo y año de nacimiento, elegidos al azar entre la población adscrita al médico investigador. Mediciones principales. Hábito tabáquico y gramos semanales de alcohol mediante cuestionario, peso, talla, presión arterial y frecuencia cardíaca de reposo. Se obtuvieron las odds ratio (OR) de las proporciones de sujetos que fumaban o habían fumado alguna vez, de los que seguían fumando y de las probabilidades de abandono del tabaco de cada grupo. Resultados. La OR de la proporción de sujetos que fumaban o habían fumado entre los grupos de corredores (54,2%) y controles (70,9%) era de 0,486 (intervalo de confianza [IC] del 95%, 0,205-1,149; *2 = 2,8; p = 0,093). La OR para continuación del hábito entre los grupos de corredores (8,4%) y controles (41,7%) era de 0,127 (IC del 95%, 0,035-0,456; *2 = 14,0; p = 0,0002). En el grupo de corredores había abandonado el tabaco el 45,8% y en el de controles, el 31,2% (OR = 7,85; IC del 95%, 1,89-32,52; *2 = 11,8; p = 0,0007). El 50% de los corredores que fumaban lo había dejado desde que comenzó a correr y el 76,9% de éstos lo había dejado justo en el momento de comenzar a correr. Conclusiones. Hay una asociación negativa entre carrera a pie y tabaco. Si un fumador decide comenzar a correr regularmente, tiene muchas probabilidades de dejar de fumar y mantenerse así
Objective. To investigate whether running influences smoking habits. Design. Study of cases and controls, with 1:1 pairing. Retrospective longitudinal observational study. Setting. Primary care. City of Toledo, Spain. Participants. Cases: 48 healthy volunteer runners of 47±7.8 years of age. Controls: 48 healthy subjects, paired by gender and year of birth, chosen at random from the medical list assigned to the medical researcher. Principal measurements. Smoking habits and alcohol consumption in grams per week using a questionnaire, weight, height, blood pressure, and heart rate at rest. The odds ratio (OR) was obtained on the proportion of subjects who smoked or smoked at some time, those who continued smoking and the probabilities of giving up tobacco in each group. Results. The OR of the proportion of subjects who smoked or had smoked between the groups of runners (54.2%) and controls (70.9%) was 0.486 (95% confidence interval [CI], 0.205-1.149; *2=2.8; P=.093). The OR for continuing the habit between groups of runners (8.4%) and controls (41.7%) was 0.127 (95% CI, 0.035-0.456; *2=14.0; P=.0002). In the group of runners, 45.8% had stopped smoking, as well as 31.2% of the controls (OR=7.85; 95% CI, 1.89-32.52; *2=11.8; P=.0007); 50% of the runners who smoked had given it up since starting to run and 76.9% of these had given it up just at the time of starting to run. Conclusions. There is a negative association between running and tobacco. If a smoker decides to run regularly he/she has high probabilities of giving up smoking and continue to do so