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PURPOSE: Symptoms are important components in determining asthma control and in the adjustment of treatment levels. However, clinical relevance of cough in severe asthma is not well-understood. This study aimed to evaluate the severity and association of cough with patient-reported outcomes (PROs) in patients with severe asthma. METHODS: This study analyzed cross-sectional data from the Korean Severe Asthma Registry. The severity of coughing and wheezing symptoms was assessed using a Visual Analog Scale (VAS) ranging from 0 to 100 for each symptom. Additionally, PROs included the Asthma Control Test (ACT), the Severe Asthma Questionnaire (SAQ), and the EuroQoL 5-Dimension (EQ-5D) index. Multivariate linear regression analysis was employed to explore the relationship between cough severity and other PRO scores. RESULTS: A total of 498 patients with severe asthma (age: 57.9 ± 13.1 years, females: 60.2%) were analyzed. The cough VAS score was higher than the wheeze score (median 30, [interquartile range 10-50] vs. 20 [0-50]; P < 0.001). Additionally, 22.5% of patients ranked in a higher tertile for cough severity compared to wheezing, while 18.5% ranked higher for wheezing severity than cough. Significant correlations were observed between cough and wheeze VAS scores (r = 0.61, P < 0.05) and between each symptom's VAS score and the SAQ (cough: r = -0.41, P < 0.001; wheeze: r = -0.52, P < 0.001), ACT scores (cough: r = -0.50, P < 0.001; wheeze: r = -0.63, P < 0.001) and EQ-5D index (cough: r = -0.40, P < 0.001; wheeze: r = -0.45, P < 0.001). In univariate regression analysis, the cough VAS score had weaker descriptive power (R2) values than the wheeze VAS score in relation to the PRO measures. Nevertheless, cough severity remained significantly associated with ACT, SAQ scores and EQ-5D index in multivariate analyses adjusted for wheeze severity and other confounders. CONCLUSION: Cough frequently presents as a severe symptom in patients with severe asthma and could have distinct impact on asthma control and quality of life.
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Asma , Tos , Medición de Resultados Informados por el Paciente , Calidad de Vida , Ruidos Respiratorios , Índice de Severidad de la Enfermedad , Humanos , Tos/fisiopatología , Tos/psicología , Asma/complicaciones , Asma/fisiopatología , Asma/psicología , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Anciano , Ruidos Respiratorios/fisiopatología , Adulto , República de Corea/epidemiología , Sistema de Registros , Encuestas y CuestionariosRESUMEN
This study aimed to determine the effects of indoor environment (IE) and outdoor air pollutants (OAPs) in residential areas on acute exacerbation (AE) in patients with severe asthma. A total of 115 participants were recruited. To characterize IE, we used structured questionnaires and estimated OAP concentrations using a land-use regression model. Participants who were exposed to passive smoking and lived in houses where the kitchen and living room were not separated showed a significantly higher rate of AE (p = 0.014 and 0.0016, respectively). The mean concentration of PM2.5 in residential areas during the last 3 years was significantly higher in participants with AE than that in those without AE (19.8 ± 3.1 vs. 21.0 ± 2.5 µg/m3, p = 0.033). Moreover, the serum level of 8-hydroxy-2'-deoxyguanosine significantly increased in participants with AE compared to those without AE (56.9 ± 30.0 vs. 94.7 ± 44.5 ng/mL, p = 0.0047) suggesting enhanced oxidative stress in those with AE.
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BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin-tolerant asthma (ATA). OBJECTIVES: This study aimed to investigate the long-term clinical outcomes between AERD and ATA. METHODS: AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real-world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. RESULTS: Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p < .05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p < .01) than those with ATA. In a 10-year follow-up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. CONCLUSION AND CLINICAL RELEVANCE: We demonstrated that AERD patients presented poorer long-term clinical outcomes than ATA patients in real-world data analyses.
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Asma Inducida por Aspirina , Asma , Eosinofilia , Sinusitis , Humanos , Asma Inducida por Aspirina/diagnóstico , Asma/metabolismo , Sinusitis/metabolismo , Eosinófilos , Eosinofilia/inducido químicamente , Aspirina/efectos adversosRESUMEN
BACKGROUND: Blood eosinophil count (BEC), immunoglobulin (Ig) E, and fractional exhaled nitric oxide (FeNO) are key clinical indicators for identifying type 2 (T2) asthma. OBJECTIVE: To provide optimal cutoff points of T2 markers for assessing T2-high or uncontrolled asthma in real-world practice. METHODS: Various clinical and laboratory parameters were analyzed according to the result of T2 markers (BEC, serum-free IgE, and FeNO) in adults with asthma who had maintained antiasthmatic medications. The cutoff levels for representing uncontrolled asthma were determined using receiver operating characteristic analysis. Blood levels of periostin and eosinophil-derived neurotoxin were measured by enzyme-linked immunosorbent assay. Activation markers of circulating eosinophils (Siglec8+) and neutrophils (CD66+) were analyzed by flow cytometry. RESULTS: Of 133 patients with asthma, 23 (17.3%) had 3 T2 markers (BEC ≥ 300 cells/µL, serum-free IgE ≥ 120 ng/mL, and FeNO ≥ 25 parts per billion) and significantly higher levels of sputum eosinophils, blood eosinophil-derived neurotoxin, and Siglec8+ eosinophils but lower 1-second forced expiratory volume percentage, in addition to a higher rate of uncontrolled status (P < .05 for all). Furthermore, patients with uncontrolled asthma had significantly higher levels of FeNO and BEC with lower 1-second forced expiratory volume percentage (P < .05 for all). The optimal cutoff values for predicting uncontrolled asthma were found to be 22 parts per billion of FeNO levels, 161.4 cells/L of BECs, and 85.9 ng/mL of serum-free IgE levels. CONCLUSION: We suggest the optimal cutoff values of BEC, IgE, and FeNO for classifying T2-high or uncontrolled asthma, which could be applied as candidate biomarkers for targeting patients with asthma who require T2 biologics.
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Asma , Óxido Nítrico , Adulto , Humanos , Neurotoxina Derivada del Eosinófilo , Óxido Nítrico/análisis , Asma/diagnóstico , Asma/tratamiento farmacológico , Eosinófilos/fisiología , Inmunoglobulina E , BiomarcadoresRESUMEN
AIMS: To develop a deep learning model for pressure injury stages classification based on real-world photographs and compare its performance with that of clinical nurses to seek the opportunity of its application in clinical settings. DESIGN: This was a retrospective observational study using a deep learning model. REVIEW METHODS: A plastic surgeon and two wound care nurses labelled a set of pressure injury images. We applied several modern Convolutional Neural Networks architectures and compared the performances with those of clinical nurses. DATA SOURCES: We retrospectively analysed the electronic medical records of hospitalized patients between January 2019 and April 2021. RESULTS: A set of 2464 pressure injury images were compiled and analysed. Using EfficientNet, in classifying pressure injury images, the macro F1-score was calculated to be 0.8941, and the average performance of two experienced nurses was reported as 0.8781. CONCLUSION: A deep learning model for classifying pressure injury images by stages was successfully developed, and the performance of the model was compared with that of experienced nurses. The classification model developed in this study is expected to help less-experienced nurses or those working in under-resourced healthcare settings determine the stages of pressure injury. IMPACT: Our deep learning model can minimize discrepancies in nurses' assessment of classifying pressure injury stages. Follow-up studies on improving the performance of deep learning models using modern techniques and clinical usability will lead to improved quality of care among patients with pressure injury. NO PATIENT OR PUBLIC CONTRIBUTION: Patients or the public were not involved in our research's design, conduct, reporting or dissemination plans because this was a retrospective study that used electronic medical records.
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Aprendizaje Profundo , Enfermeras y Enfermeros , Úlcera por Presión , Humanos , Estudios Retrospectivos , Redes Neurales de la ComputaciónRESUMEN
Background Evaluation of interstitial lung disease (ILD) at CT is a challenging task that requires experience and is subject to substantial interreader variability. Purpose To investigate whether a proposed content-based image retrieval (CBIR) of similar chest CT images by using deep learning can aid in the diagnosis of ILD by readers with different levels of experience. Materials and Methods This retrospective study included patients with confirmed ILD after multidisciplinary discussion and available CT images identified between January 2000 and December 2015. Database was composed of four disease classes: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, and chronic hypersensitivity pneumonitis. Eighty patients were selected as queries from the database. The proposed CBIR retrieved the top three similar CT images with diagnosis from the database by comparing the extent and distribution of different regional disease patterns quantified by a deep learning algorithm. Eight readers with varying experience interpreted the query CT images and provided their most probable diagnosis in two reading sessions 2 weeks apart, before and after applying CBIR. Diagnostic accuracy was analyzed by using McNemar test and generalized estimating equation, and interreader agreement was analyzed by using Fleiss κ. Results A total of 288 patients were included (mean age, 58 years ± 11 [standard deviation]; 145 women). After applying CBIR, the overall diagnostic accuracy improved in all readers (before CBIR, 46.1% [95% CI: 37.1, 55.3]; after CBIR, 60.9% [95% CI: 51.8, 69.3]; P < .001). In terms of disease category, the diagnostic accuracy improved after applying CBIR in UIP (before vs after CBIR, 52.4% vs 72.8%, respectively; P < .001) and NSIP cases (before vs after CBIR, 42.9% vs 61.6%, respectively; P < .001). Interreader agreement improved after CBIR (before vs after CBIR Fleiss κ, 0.32 vs 0.47, respectively; P = .005). Conclusion The proposed content-based image retrieval system for chest CT images with deep learning improved the diagnostic accuracy of interstitial lung disease and interreader agreement in readers with different levels of experience. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wielpütz in this issue.
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Aprendizaje Profundo , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Diagnóstico Diferencial , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.
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Ataxia Cerebelosa/genética , Cerebelo/metabolismo , Metilación de ADN , ADN Polimerasa beta/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Encéfalo/embriología , Encéfalo/patología , Cerebelo/anomalías , Cerebelo/patología , Citosina/metabolismo , Daño del ADN , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Ratones , Ratones Noqueados , Neurogénesis/genéticaRESUMEN
In response to health concerns generated by increased sodium intake, many new approaches have been studied to reduce the sodium content in processed food. It has been suggested that reducing sodium in the food supply may be the most appropriate solution. The aim of this scoping review was to establish what sodium reduction strategies are effective in maintaining acceptable sensory qualities for various food industry applications. Studies that evaluate and report on the effectiveness of a sodium reduction strategy relevant to food and included outcomes detailing how the strategies were received by human subjects using sensory data are included, as well as book chapters, literature reviews, and patents focusing on sodium reduction strategies. Only those published in English and since 1970 were included. Literature was obtained through Scopus, PubMed, EBSCOhost, and ScienceDirect databases, whereas patents were obtained through US Patent Trademark Office, Google Patents, and PATENTSCOPE databases. Two-hundred and seventy-seven primary studies, 27 literature reviews, 10 book chapters, and 143 patents were selected for inclusion. Data extracted included details such as analytical methods, broad and specific treatment categories, significant outcomes, and limitations among other material. Sodium reduction methods were categorized as either salt removal, salt replacement, flavor modification, functional modification, or physical modification. Although salt removal and salt replacement were the majority of included studies, future research would benefit from combining methods from other categories while investigating the impact on sensory characteristics, technological aspects, and consumer perception of the strategy.
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Cloruro de Sodio Dietético , Sodio , Comida Rápida , Industria de Alimentos , Abastecimiento de Alimentos , HumanosRESUMEN
BACKGROUND: While the clinical characteristics and outcomes of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have been frequently compared with those of COPD or asthma, the prevalence and features of ACO in patients with severe asthma are unclear. OBJECTIVES: Evaluation of the prevalence and clinical features of ACO using the Korean severe asthma registry. METHODS: At the time of registration, ACO was determined in patients with severe asthma by attending specialists. Patients were classified into ACO and non-ACO groups, and the demographic and clinical characteristics of these two groups were compared. RESULTS: Of 482 patients with severe asthma, 23.7% had ACO. Patients in the ACO group were more likely to be male (P < .001), older (P < .001), and ex- or current smokers (P < .001) compared with those in the non-ACO group. Patients in the ACO group had lower mean forced expiratory volume in 1 second (P < .001) and blood eosinophil percentage (P = .006), but higher blood neutrophil percentage (P = .027) than those in the non-ACO group. The ACO group used more inhaled long-acting muscarinic antagonist (P < .001), methylxanthine (P = .001), or sustained systemic corticosteroid (P = .002). In addition, unscheduled emergency department visits due to exacerbation were more frequent in the ACO group (P = .006). CONCLUSION: Among patients with severe asthma, those with ACO were older, predominantly male, and were more likely to have a smoking history than those with asthma only. Patients with ACO used more systemic corticosteroid and had more frequent exacerbations related to emergency department visits than those with severe asthma only.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Asma/diagnóstico , Asma/epidemiología , Femenino , Humanos , Masculino , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Sistema de Registros , República de Corea/epidemiología , EspecializaciónRESUMEN
BACKGROUND: It has been known that a high serum total immunoglobulin E (IgE) level is a predisposing factor of allergic asthma; however, there are considerable limitations to apply it in clinical practice. OBJECTIVE: To determine the clinical significance of the serum-free IgE level in patients with adult asthma. METHODS: We measured free IgE levels using our homemade enzyme-linked immunosorbent assay by applying a novel IgE TRAP protein (GI innovation, Seoul, Republic of Korea) in sera of adults with asthma (n = 116) compared with healthy controls (n = 32); enzyme-linked immunosorbent assay inhibition test was performed to validate its binding specificity. Associations between asthma-related clinical and laboratory parameters were analyzed. The diagnostic value and cutoff point for detecting atopy and type 2 asthma were determined using receiver operating characteristic curve analysis. RESULTS: The serum-free IgE levels were significantly higher in adults with asthma than in healthy controls and were significantly associated with atopic status and type 2 asthma (all P < .001). In the receiver operating characteristic analysis, serum-free IgE had a significantly greater area under the curve (AUC) than serum total IgE for assessing asthma, especially type 2 asthma (AUC, 0.810 vs 0.743; P = .006 and AUC, 0.729 vs 0.572; P < .001). The optimal cutoff points for predicting atopy and type 2 asthma were 82.8 and 120.8 ng/mL, respectively. CONCLUSION: It is suggested that a higher serum-free IgE level may be a useful biomarker of atopy and type 2 asthma in adults with asthma.
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Asma/diagnóstico , Hipersensibilidad Inmediata/diagnóstico , Inmunoglobulina E/sangre , Adulto , Anciano , Alérgenos/inmunología , Área Bajo la Curva , Asma/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hipersensibilidad Inmediata/sangre , Masculino , Persona de Mediana Edad , Curva ROC , República de CoreaRESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells without affecting most normal cells. Despite being in clinical testing, novel strategies to induce TRAIL-mediated apoptosis are in need to overcome cancer cell unresponsiveness and resistance. Plasma-activated medium (PAM) markedly stimulates reactive oxygen/nitrogen species (ROS/RNS)-dependent apoptosis in cancer cells. We investigate the capability of PAM and TRAIL (PAM/TRAIL) combination therapy to overcome TRAIL resistance and improve the anticancer efficacy of TRAIL. The combinatorial treatment of PAM and TRAIL shows synergistic effects on growth inhibition in TRAIL-resistant cancer cells via augmented apoptosis by two attributes. DR5 (TRAIL-R2) transcription by CHOP is upregulated in a PAM-generated ROS/RNS-dependent manner, and PAM itself upregulates PTEN expression mediated by suppression of miR-425 which is involved in Akt inactivation, leading to increased apoptosis induction. Treatment of cancer cell lines with the antioxidant N-acetylcysteine reduces the extent of membrane dysfunction and the expression of both CHOP-DR5 and miR-425-PTEN axes, attenuating PAM/TRAIL-induced cancer cell apoptosis. These data suggest that PAM/TRAIL treatment is a novel approach to sensitizing cancer cells to TRAIL-induced apoptosis and overcoming TRAIL resistance. PAM is a promising candidate for further investigations as a chemotherapeutic sensitizer in the treatment of cancer.
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Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Gases em Plasma/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Regulación hacia Arriba/efectos de los fármacos , Células A549 , Apoptosis/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , MicroARNs/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , ARN Neoplásico/metabolismoRESUMEN
Defects in DNA damage response or repair mechanisms during neurogenesis result in genomic instability, which is causative for several neural defects. These include brain tumors, particularly medulloblastoma, which occurs in the cerebellum with a high incidence in children. We generated an animal model with defective base excision repair during brain development through selective inactivation of DNA polymerase ß (Polb) in neuroprogenitor cells. All of Polb conditional knockout mice developed medulloblastoma in a p53 null background, similar to the Xrcc1 and p53 double deficient animal model. XRCC1 is a scaffolding protein which is involved in DNA damage repair and binds to POLB. In both animal models, the histopathological characteristics of the medulloblastoma were similar to those of human classic medulloblastoma. Brain tumor development was slower in the Polb and p53 double null animals than in the Xrcc1 and p53 double knockout animals. Molecular marker analysis suggested that Polb- and Xrcc1-deficient medulloblastomas belonged to the SHHα subtype, underscoring the important role of genomic stability in preventing this devastating pediatric cerebellar tumor.
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Neoplasias Cerebelosas/genética , ADN Polimerasa beta/genética , Genes p53 , Meduloblastoma/genética , Animales , Carcinogénesis , Neoplasias Cerebelosas/patología , Cerebelo , Femenino , Expresión Génica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Masculino , Meduloblastoma/patología , Ratones , Ratones Noqueados , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genéticaRESUMEN
Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients.
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Pueblo Asiatico/genética , Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Metiltransferasas/genética , Proteínas Mitocondriales/genética , Mutación/genética , Factores de Transcripción/genética , Secuencia de Bases , Células Cultivadas , Preescolar , ADN Mitocondrial/genética , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Homocigoto , Humanos , Masculino , Metiltransferasas/química , Mitocondrias/metabolismo , Proteínas Mitocondriales/química , Modelos Moleculares , Linaje , Factores de Transcripción/químicaRESUMEN
Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis.
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Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Células-Madre Neurales/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Ratones , Ratones Noqueados , Proteína p53 Supresora de Tumor/deficienciaRESUMEN
BACKGROUND: The role of J-waves in the pathogenesis of ventricular fibrillation (VF) occurring in structurally normal hearts is important. METHODS: We evaluated 127 patients who received an implantable cardioverter-defibrillator (ICD) for Brugada syndrome (BS, n = 53), early repolarization syndrome (ERS, n = 24), and patients with unknown or deferred diagnosis (n = 50). Electrocardiography (ECG), clinical characteristics, and ICD data were analyzed. RESULTS: J-waves were found in 27/50 patients with VF of unknown/deferred diagnosis. The J-waves were reminiscent of those seen in BS or ERS, and this subgroup of patients was termed variants of ERS and BS (VEB). In 12 VEB patients, the J/ST/T-wave morphology was coved, although amplitudes were <0.2 mV. In 15 patients, noncoved-type J/ST/T-waves were present in the right precordial leads. In the remaining 23 patients, no J-waves were identified. VEB patients exhibited clinical characteristics similar to those of BS and ERS patients. Phenotypic transition and overlap were observed among patients with BS, ERS, and VEB. Twelve patients with BS had background inferolateral ER, while five ERS patients showed prominent right precordial J-waves. Patients with this transient phenotype overlap showed a significantly lower shock-free survival than the rest of the study patients. CONCLUSIONS: VEB patients demonstrate ECG phenotype similar to but distinct from those of BS and ERS. The spectral nature of J-wave morphology/distribution and phenotypic transition/overlap suggest a common pathophysiologic background in patients with VEB, BS, and ERS. Prognostic implication of these ECG variations requires further investigation.
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Síndrome de Brugada/clasificación , Síndrome de Brugada/diagnóstico , Electrocardiografía/métodos , Infarto del Miocardio con Elevación del ST/clasificación , Infarto del Miocardio con Elevación del ST/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
DNA replication and repair in mammalian cells involves three distinct DNA ligases: ligase I (Lig1), ligase III (Lig3) and ligase IV (Lig4). Lig3 is considered a key ligase during base excision repair because its stability depends upon its nuclear binding partner Xrcc1, a critical factor for this DNA repair pathway. Lig3 is also present in the mitochondria, where its role in mitochondrial DNA (mtDNA) maintenance is independent of Xrcc1 (ref. 4). However, the biological role of Lig3 is unclear as inactivation of murine Lig3 results in early embryonic lethality. Here we report that Lig3 is essential for mtDNA integrity but dispensable for nuclear DNA repair. Inactivation of Lig3 in the mouse nervous system resulted in mtDNA loss leading to profound mitochondrial dysfunction, disruption of cellular homeostasis and incapacitating ataxia. Similarly, inactivation of Lig3 in cardiac muscle resulted in mitochondrial dysfunction and defective heart-pump function leading to heart failure. However, Lig3 inactivation did not result in nuclear DNA repair deficiency, indicating essential DNA repair functions of Xrcc1 can occur in the absence of Lig3. Instead, we found that Lig1 was critical for DNA repair, but acted in a cooperative manner with Lig3. Additionally, Lig3 deficiency did not recapitulate the hallmark features of neural Xrcc1 inactivation such as DNA damage-induced cerebellar interneuron loss, further underscoring functional separation of these DNA repair factors. Therefore, our data reveal that the critical biological role of Lig3 is to maintain mtDNA integrity and not Xrcc1-dependent DNA repair.
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Núcleo Celular/genética , ADN Ligasas/metabolismo , Reparación del ADN , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/metabolismo , Animales , Ataxia/patología , Ataxia/fisiopatología , Biocatálisis , Supervivencia Celular , Células Cultivadas , Daño del ADN , ADN Ligasa (ATP) , ADN Ligasas/deficiencia , ADN Ligasas/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Genes Esenciales , Corazón/fisiología , Corazón/fisiopatología , Interneuronas/enzimología , Interneuronas/patología , Ratones , Mitocondrias/enzimología , Mitocondrias/genética , Mitocondrias/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Miocardio/enzimología , Miocardio/patología , Sistema Nervioso/enzimología , Sistema Nervioso/patología , Fenotipo , Proteínas de Unión a Poli-ADP-Ribosa , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Proteínas de XenopusRESUMEN
Objective We aimed to determine whether the extension of ablation could influence the ablation outcome for ventricular tachycardia (VT)/premature ventricular contractions (PVCs) from the right ventricular outflow tract (RVOT). Methods and results The radiofrequency catheter ablation results of 33 VT/6 frequent PVCs from the RVOT were analysed. The ablation extension was divided into 3 categories from the final successful ablation point with the earliest activation: (I) focal ablation (15 cases); ablation at 1 or 2 points; (II) focal with extended ablation (12 cases); focal and surrounding area ablation (maximum ≤1 cm) after elimination of clinical VT/PVCs; and (III) broad ablation (12 cases); continued broad ablation (maximum >1 cm) after elimination of clinical VT/PVCs. Acute termination was defined as the complete elimination and non-inducibility of clinical VT/PVCs during the procedure. For the mean follow-up of 12.8 months, the recurrence rate was not significantly different among the groups (P = 0.49). The mean procedure time was longer in group II, but ablation times and complication rates were not different among the groups. When acute termination was achieved, the overall recurrence rate was 7.6%. However, when confirming absence of the clinical VT/PVCs using 24-hour Holter monitoring immediately after the procedure, the recurrence rate was 2.7%. Conclusions Ablation extension did not affect ablation outcome of VT/PVCs from the RVOT. Confirmation of absence of clinical VT/PVCs using 24-hour Holter monitoring immediately after the procedure could guarantee long-term success.
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Ablación por Catéter/métodos , Sistema de Conducción Cardíaco/fisiopatología , Ventrículos Cardíacos/fisiopatología , Taquicardia Ventricular/cirugía , Función Ventricular Derecha/fisiología , Complejos Prematuros Ventriculares/cirugía , Electrocardiografía Ambulatoria , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Taquicardia Ventricular/fisiopatología , Resultado del Tratamiento , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.
Asunto(s)
Apoptosis , Ataxia Telangiectasia/fisiopatología , Daño del ADN/fisiología , Neuronas/fisiología , Síndrome de Nijmegen/fisiopatología , Transducción de Señal/genética , Animales , Apoptosis/efectos de la radiación , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Encéfalo/patología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Daño del ADN/genética , ADN Ligasa (ATP) , ADN Ligasas/metabolismo , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/fisiología , Femenino , Proteína Homóloga de MRE11 , Masculino , Ratones , Ratones Transgénicos , Microcefalia/patología , Mutación , Neuronas/citología , Neuronas/efectos de la radiación , Síndrome de Nijmegen/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Radiación Ionizante , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The ATR (ATM (ataxia telangiectasia mutated) and rad3-related) checkpoint kinase is considered critical for signalling DNA replication stress and its dysfunction can lead to the neurodevelopmental disorder, ATR-Seckel syndrome. To understand how ATR functions during neurogenesis, we conditionally deleted Atr broadly throughout the murine nervous system, or in a restricted manner in the dorsal telencephalon. Unexpectedly, in both scenarios, Atr loss impacted neurogenesis relatively late during neural development involving only certain progenitor populations. Whereas the Atr-deficient embryonic cerebellar external germinal layer underwent p53- (and p16(Ink4a/Arf))-independent proliferation arrest, other brain regions suffered apoptosis that was partially p53 dependent. In contrast to other organs, in the nervous system, p53 loss did not worsen the outcome of Atr inactivation. Coincident inactivation of Atm also did not affect the phenotype after Atr deletion, supporting non-overlapping physiological roles for these related DNA damage-response kinases in the brain. Rather than an essential general role in preventing replication stress, our data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis.
Asunto(s)
Encéfalo/embriología , Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Células Madre/fisiología , Animales , Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada , Encéfalo/patología , Proteínas de Ciclo Celular/deficiencia , Proliferación Celular , Histocitoquímica , Inmunohistoquímica , Ratones , Ratones Noqueados , Microscopía , Proteínas Serina-Treonina Quinasas/deficienciaRESUMEN
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.