MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only ...hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
Abstract MicroRNAs have emerged as important modulators of gene expression. Both during development and disease, regulation by miRNAs controls the choice between self-renewal and differentiation, ...survival and apoptosis and dictates how cells respond to external stimuli. In mouse pluripotent embryonic stem cells, a surprisingly small set of miRNAs, encoded by four polycistronic genes is at the center of such decisions. miR-290–295, miR-302–367, miR-17–92 and miR-106b–25 encode for miRNAs with highly related sequences that seem to control largely overlapping gene sets. Recent studies have highlighted the importance of these miRNAs in the maintenance of ‘stemness’ and regulation of normal development and have linked the deregulation of their expression to a variety of human diseases.
MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only ...hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-1792 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-1792 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-1792 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-1792 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
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Although non-ischemic troponin elevation is frequently seen in patients admitted to the emergency department (ED), consensus regarding its management is lacking.
This study aimed to characterize ...patients admitted to the ED with non-ischemic troponin elevation and to identify potential mortality predictors in this population.
This retrospective observational study included ED patients with a positive troponin test result between June and July of 2015. Patients with a clinical diagnosis of acute coronary syndrome (ACS) were excluded. Data on patient demographics and clinical and laboratory variables were extracted from medical records. Follow-up data were obtained for 16 months or until death occurred. The statistical significance level was 5%.
Troponin elevation without ACS was found in 153 ED patients. The median (IQR) patient age was 78 (19) years, 80 (52.3%) were female and 59(38.6%) died during follow-up. The median (IQR) follow-up period was 477(316) days. Survivors were significantly younger 76 (24) vs. 84 (13) years; p=0.004) and featured a higher proportion of isolated troponin elevation (without creatine kinase or myoglobin elevation) in two consecutive evaluations: 48 (53.9%) vs. 8 (17.4%), p<0.001. Survivors also presented a lower rate of antiplatelet treatment and same-day hospitalization. In the multivariate logistic regression with adjustment for significant variables in the univariate analysis, isolated troponin elevation in two consecutive evaluations showed a hazard ratio= 0.43 (95%CI 0.17-0.96, p=0.039); hospitalization, previous antiplatelet treatment and age remained independently associated with mortality.
Isolated troponin elevation in two consecutive measurements was a strong predictor of survival in ED patients with troponin elevation but without ACS.
Resumo Fundamento: Embora a elevação não isquêmica da troponina seja frequentemente observada em pacientes admitidos no pronto-socorro (PS), não há consenso quanto ao seu manejo. Objetivos: Este ...estudo teve como objetivo caracterizar os pacientes admitidos no PS com elevação da troponina não-isquêmica e identificar potenciais preditores de mortalidade nessa população. Métodos: Este estudo observacional retrospectivo incluiu pacientes do PS com resultado positivo no teste da troponina entre junho e julho de 2015. Pacientes com diagnóstico clínico de síndrome coronariana aguda (SCA) foram excluídos. Os dados demográficos dos pacientes e as variáveis clínicas e laboratoriais foram extraídos dos prontuários médicos. Os dados do seguimento foram obtidos por 16 meses ou até a ocorrência de morte. O nível de significância estatística foi de 5%. Resultados: A elevação da troponina sem SCA foi encontrada em 153 pacientes no PS. A mediana (IIQ) de idade dos pacientes foi de 78 (19) anos, 80 (52,3%) eram do sexo feminino e 59 (38,6%) morreram durante o seguimento. A mediana do período de seguimento (IIQ) foi de 477 (316) dias. Os sobreviventes eram significativamente mais jovens 76 (24) vs. 84 (13) anos; p=0,004) e apresentaram uma maior proporção de elevação da troponina isolada (sem elevação da creatina quinase ou mioglobina) em duas avaliações consecutivas: 48 (53,9%) vs. 8 (17,4%), p<0,001. Os sobreviventes também apresentaram menor taxa de tratamento antiplaquetário e internação no mesmo dia. Na regressão logística multivariada com ajuste para variáveis significativas na análise univariada, a elevação isolada da troponina em duas avaliações consecutivas mostrou hazard ratio = 0,43 (IC95% 0,17–0,96, p=0,039); hospitalização, tratamento antiplaquetário anterior e idade permaneceram independentemente associados à mortalidade. Conclusões: A elevação isolada da troponina em duas medidas consecutivas foi um forte preditor de sobrevida em pacientes no PS com elevação da troponina, mas sem SCA.
Resumo: Introdução: A ressonância magnética cardíaca (RMC) tem vindo a adquirir grande relevância na avaliação diagnóstica de um espectro cada vez mais amplo de cardiomiopatias, incluindo as que ...apresentam potencial arritmogénico. Objetivo: Avaliação do valor acrescentado da RMC no diagnóstico etiológico de arritmias ventriculares, quando a investigação convencional inicial com outros métodos complementares de diagnóstico não é conclusiva. Métodos: Estudaram-se retrospetivamente os doentes que realizaram RMC para esclarecimento da etiologia de arritmias ventriculares, entre 2005-2011 (n = 113). Foram incluídos apenas doentes com arritmias ventriculares documentadas. Constituíram critérios de exclusão a obtenção de diagnóstico definitivo por exame complementar, de diagnóstico realizado previamente e a presença de história prévia sugestiva de doença coronária (antecedentes de síndrome coronária aguda ou história de angor típico, de elevação de biomarcadores de necrose miocárdica ou teste de isquemia positivo, quando realizado). Os resultados da RMC foram considerados relevantes quando sugeriram um diagnóstico provável. Resultados: Dos 113 doentes incluídos, 57,5% eram homens. A idade média foi 41,7 ± 16,2 anos. Quanto à arritmia documentada, 38,1% dos doentes foram referenciados por taquicardia ventricular/fibrilhação ventricular (FV/TV mantida) e 61,9% por extrassistolia ventricular com menor complexidade (ESV). A RMC mostrou alterações sugestivas de um diagnóstico específico em 42,5% dos doentes, foi totalmente normal em 36,3% e mostrou alterações inespecíficas nos restantes. Nos casos de referenciação por FV/TV mantida a RMC foi diagnóstica em 60,4% dos casos, enquanto nos casos de ESV foi-o em 31,4%.Os diagnósticos prováveis mais frequentes foram displasia arritmogénica do ventrículo direito, não compactação ventricular e miopericardite. Assinala-se que, apesar da ausência de evidências clínicas sugestivas pelos critérios atrás referidos, 6,2% dos doentes apresentaram áreas de realce tardio com distribuição e características atribuíveis a doença coronária obstrutiva. Conclusão: A RMC proporciona valor acrescentado no diagnóstico etiológico de arritmias ventriculares quando exames mais acessíveis ou realizados previamente não são conclusivos. A percentagem de doentes em que foi conclusiva foi de 42,5% (60,4% nos casos de referenciação por FV/TV mantida) e em que foi totalmente normal foi de 36,3%. Abstract: Introduction: Cardiac magnetic resonance (CMR) imaging is increasingly important in the diagnostic work-up of a wide range of heart diseases, including those with arrhythmogenic potential. Objective: To assess the added value of CMR in etiological diagnosis of ventricular arrhythmias after an inconclusive conventional investigation. Methods: Patients undergoing CMR between 2005 and 2011 for investigation of ventricular arrhythmias were included (n=113). All had documented arrhythmias. Those with a definite diagnosis from a previous investigation and those with evidence of coronary artery disease (acute coronary syndrome, typical angina symptoms, increase in biomarkers or positive stress test) were excluded. CMR results were considered relevant when they fulfilled diagnostic criteria. Results: Of the 113 patients, 57.5% were male and mean age was 41.7±16.2 years. Regarding the initial arrhythmia, 38.1% had ventricular fibrillation/sustained ventricular tachycardia (VF/VT) and 61.9% had less complex ventricular ectopy. CMR imaging showed criteria of a specific diagnosis in 42.5% of patients, was totally normal in 36.3%, and showed non-specific alterations in the remainder. In VF/VT patients, specific criteria were found in 60.4%, and in 31.4% of those with less complex ectopy.The most frequent diagnoses were arrhythmogenic right ventricular dysplasia, ventricular non-compaction and myopericarditis. It is worth noting that, although there was no evidence of previous coronary artery disease, 6.2% of patients had a late gadolinium enhancement distribution pattern compatible with myocardial infarction. Conclusion: CMR gives additional and important information in the diagnostic work-up of ventricular arrhythmias after an inconclusive initial investigation. The proportion of patients with diagnostic criteria was 42.5% (60.0% in those with VF/VT), and CMR was completely normal in 36.6%. Palavras-chave: Ressonância magnética cardíaca, Etiologia de arritmias ventriculares, Substrato arritmogénico, Keywords: Cardiac magnetic resonance, Diagnosis of ventricular arrhythmias, Arrhythmogenic substrate
Cardiac magnetic resonance (CMR) imaging is increasingly important in the diagnostic work-up of a wide range of heart diseases, including those with arrhythmogenic potential.
To assess the added ...value of CMR in etiological diagnosis of ventricular arrhythmias after an inconclusive conventional investigation.
Patients undergoing CMR between 2005 and 2011 for investigation of ventricular arrhythmias were included (n=113). All had documented arrhythmias. Those with a definite diagnosis from a previous investigation and those with evidence of coronary artery disease (acute coronary syndrome, typical angina symptoms, increase in biomarkers or positive stress test) were excluded. CMR results were considered relevant when they fulfilled diagnostic criteria.
Of the 113 patients, 57.5% were male and mean age was 41.7 ± 16.2 years. Regarding the initial arrhythmia, 38.1% had ventricular fibrillation/sustained ventricular tachycardia (VF/VT) and 61.9% had less complex ventricular ectopy. CMR imaging showed criteria of a specific diagnosis in 42.5% of patients, was totally normal in 36.3%, and showed non-specific alterations in the remainder. In VF/VT patients, specific criteria were found in 60.4%, and in 31.4% of those with less complex ectopy. The most frequent diagnoses were arrhythmogenic right ventricular dysplasia, ventricular non-compaction and myopericarditis. It is worth noting that, although there was no evidence of previous coronary artery disease, 6.2% of patients had a late gadolinium enhancement distribution pattern compatible with myocardial infarction.
CMR gives additional and important information in the diagnostic work-up of ventricular arrhythmias after an inconclusive initial investigation. The proportion of patients with diagnostic criteria was 42.5% (60.0% in those with VF/VT), and CMR was completely normal in 36.6%.
A ressonância magnética cardíaca (RMC) tem vindo a adquirir grande relevância na avaliação diagnóstica de um espectro cada vez mais amplo de cardiomiopatias, incluindo as que apresentam potencial ...arritmogénico.
Avaliação do valor acrescentado da RMC no diagnóstico etiológico de arritmias ventriculares, quando a investigação convencional inicial com outros métodos complementares de diagnóstico não é conclusiva.
Estudaram-se retrospetivamente os doentes que realizaram RMC para esclarecimento da etiologia de arritmias ventriculares, entre 2005-2011 (n=113). Foram incluídos apenas doentes com arritmias ventriculares documentadas. Constituíram critérios de exclusão a obtenção de diagnóstico definitivo por exame complementar, de diagnóstico realizado previamente e a presença de história prévia sugestiva de doença coronária (antecedentes de síndrome coronária aguda ou história de angor típico, de elevação de biomarcadores de necrose miocárdica ou teste de isquemia positivo, quando realizado). Os resultados da RMC foram considerados relevantes quando sugeriram um diagnóstico provável.
Dos 113 doentes incluídos, 57,5% eram homens. A idade média foi 41,7±16,2 anos. Quanto à arritmia documentada, 38,1% dos doentes foram referenciados por taquicardia ventricular/fibrilhação ventricular (FV/TV mantida) e 61,9% por extrassistolia ventricular com menor complexidade (ESV). A RMC mostrou alterações sugestivas de um diagnóstico específico em 42,5% dos doentes, foi totalmente normal em 36,3% e mostrou alterações inespecíficas nos restantes. Nos casos de referenciação por FV/TV mantida a RMC foi diagnóstica em 60,4% dos casos, enquanto nos casos de ESV foi-o em 31,4%.
Os diagnósticos prováveis mais frequentes foram displasia arritmogénica do ventrículo direito, não compactação ventricular e miopericardite. Assinala-se que, apesar da ausência de evidências clínicas sugestivas pelos critérios atrás referidos, 6,2% dos doentes apresentaram áreas de realce tardio com distribuição e características atribuíveis a doença coronária obstrutiva.
A RMC proporciona valor acrescentado no diagnóstico etiológico de arritmias ventriculares quando exames mais acessíveis ou realizados previamente não são conclusivos. A percentagem de doentes em que foi conclusiva foi de 42,5% (60,4% nos casos de referenciação por FV/TV mantida) e em que foi totalmente normal foi de 36,3%.
Cardiac magnetic resonance (CMR) imaging is increasingly important in the diagnostic work-up of a wide range of heart diseases, including those with arrhythmogenic potential.
To assess the added value of CMR in etiological diagnosis of ventricular arrhythmias after an inconclusive conventional investigation.
Patients undergoing CMR between 2005 and 2011 for investigation of ventricular arrhythmias were included (n=113). All had documented arrhythmias. Those with a definite diagnosis from a previous investigation and those with evidence of coronary artery disease (acute coronary syndrome, typical angina symptoms, increase in biomarkers or positive stress test) were excluded. CMR results were considered relevant when they fulfilled diagnostic criteria.
Of the 113 patients, 57.5% were male and mean age was 41.7±16.2 years. Regarding the initial arrhythmia, 38.1% had ventricular fibrillation/sustained ventricular tachycardia (VF/VT) and 61.9% had less complex ventricular ectopy. CMR imaging showed criteria of a specific diagnosis in 42.5% of patients, was totally normal in 36.3%, and showed non-specific alterations in the remainder. In VF/VT patients, specific criteria were found in 60.4%, and in 31.4% of those with less complex ectopy.
The most frequent diagnoses were arrhythmogenic right ventricular dysplasia, ventricular non-compaction and myopericarditis. It is worth noting that, although there was no evidence of previous coronary artery disease, 6.2% of patients had a late gadolinium enhancement distribution pattern compatible with myocardial infarction.
CMR gives additional and important information in the diagnostic work-up of ventricular arrhythmias after an inconclusive initial investigation. The proportion of patients with diagnostic criteria was 42.5% (60.0% in those with VF/VT), and CMR was completely normal in 36.6%.
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