RESUMO
Andersen-Tawil syndrome (ATS) is an inherited disease characterized by ventricular arrhythmias, periodic paralysis, and dysmorphic features. It results from a heterozygous mutation of KCNJ2, but little is known about mosaicism in ATS. We performed genetic analysis of KCNJ2 in 32 ATS probands and their family members and identified KCNJ2 mutations in 25 probands, 20 families who underwent extensive genetic testing. These tests revealed that seven probands carried de novo mutations while 13 carried inherited mutations from their parents. We then specifically assessed a single proband and the respective family. The proband was a 9 year old girl who fulfilled the ATS triad and carried an insertion mutation (p.75_76insThr). We determined that the proband's mother carried a somatic mosaicism and that the proband's younger brother also carried the ATS phenotype with the same insertion mutation. The mother, who exhibited mosaicism, was asymptomatic, although she exhibited Q(T)U prolongation. Mutant allele frequency was 11% as per TA cloning and 17.3% as per targeted deep sequencing. Our observations suggest that targeted deep sequencing is useful for the detection of mosaicism and that the detection of mosaic mutations in parents of apparently sporadic ATS patients can help in the process of genetic counseling.
Assuntos
Síndrome de Andersen/diagnóstico , Síndrome de Andersen/genética , Mosaicismo , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Alelos , Eletrocardiografia , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , FenótipoRESUMO
E2F is a family of transcription factors which regulates cell cycle and apoptosis of mammalian cells. E2F-1-3 localize in the nucleus, and preferentially bind pRb, while E2F-4 and 5 have no nuclear localization signal and preferentially bind p107/p130. E2F-6 suppresses the transcriptional activity of other E2F proteins. DP-1 and 2 are heterodimeric partners of each E2F protein. Using tetracycline-responsive promoters, here we compared the effects of ectopic expression of E2F-1, DP-1 and E2F-4 on cell cycle progression and apoptosis in Chinese hamster cell lines. We found that E2F-4, as well as DP-1 and E2F-1, induced growth arrest and caspase-dependent apoptosis. E2F-4 did not have a marked effect on cell cycle progression, while E2F-1 induced DNA synthesis of resting cells and DP-1 arrested cells in G1. Ectopic expression of E2F-4 did not activate E2F-dependent transcription. Our results suggest that expression of E2F-4 at elevated levels induces growth arrest and apoptosis of mammalian cells through a mechanism distinct from E2F-1 and DP-1.
Assuntos
Apoptose/fisiologia , Proteínas de Transporte , Caspases/fisiologia , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição/fisiologia , Animais , Células CHO , Ciclo Celular/fisiologia , Cricetinae , Cricetulus , Replicação do DNA/fisiologia , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Fator de Transcrição E2F4 , Fator de Transcrição E2F6 , Regulação da Expressão Gênica/efeitos dos fármacos , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/fisiologia , Proteína 1 de Ligação ao Retinoblastoma , Tetraciclina/farmacologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Ativação Transcricional , TransfecçãoRESUMO
BACKGROUND: The measurement of serum concentrations of cardiac troponin T (TnT) is a simple, useful method to detect myocyte injury that may be repeated multiple times to follow patients without interobserver variability. METHODS AND RESULTS: Multiple measurements of TnT with a second-generation assay were performed in 60 patients with dilated cardiomyopathy confirmed by coronary angiography and endomyocardial biopsy between April 1996 and December 1999. Three evolutionary patterns of TnT concentrations were identified. Thirty-three patients had concentrations of TnT <0.02 ng/mL throughout the follow-up period (group 1). The remaining 27 patients had high initial serum concentrations of TnT (>/=0.02 ng/mL). In 10 of these 27 patients, TnT decreased to <0.02 ng/mL during follow-up (group 2), whereas 17 had persistently high serum TnT concentrations despite being conventionally treated for chronic congestive heart failure (group 3). Although the initial echocardiographic left ventricular diastolic dimension (LVDd) and left ventricular ejection fraction (LVEF) were not significantly different among the 3 groups, follow-up echocardiography showed significantly decreased LVDd and increased LVEF in group 1 (each P:<0.01) and group 2 (each P:<0.05) compared with increased LVDd and decreased LVEF in group 3 (each P:<0.05). The cardiac event-free rate was significantly lower in group 3 than in groups 1 and 2 (each P:<0.001), and the survival rate was lower in group 3 than in group 1 (P:<0.05). CONCLUSIONS: Persistently increased TnT concentrations in dilated cardiomyopathy suggest ongoing subclinical myocyte degeneration associated with deterioration of the patients' clinical status.
Assuntos
Cardiomiopatia Dilatada/sangue , Troponina T/sangue , Biópsia , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/patologia , Angiografia Coronária , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
In order to elucidate the effect of supplying vessels on 5-FU distribution within a tumor, the correlation between 5-FU tissue concentration and tumor microangiography was examined in 31 patients with colorectal cancer after administration of 5-FU (500 mg/day for 3 days). The 5-FU concentration at the tumor margin was significantly higher than that in the other two tissue areas (p less than 0.05). A low 5-FU concentration was noted in the central region of ulcerative cancer showing vertical invasion with vascular disarray and/or histological necrotic foci. This type of tumor also showed a low RNA index by flow cytometry. The present study indicates that the vascular change and vascular pattern of a tumor may be a major contributing factor to 5-FU transfer from the blood circulation into a tumor.
Assuntos
Neoplasias do Colo/irrigação sanguínea , Fluoruracila/farmacocinética , Neoplasias Retais/irrigação sanguínea , Adulto , Idoso , Angiografia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , DNA de Neoplasias/análise , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , RNA Neoplásico/análise , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/metabolismoAssuntos
Osso e Ossos/análise , Cefotaxima/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/prevenção & controle , Cefotaxima/análogos & derivados , Cefotaxima/análise , Cefotaxima/uso terapêutico , Meia-Vida , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-IdadeAssuntos
Cardiomiopatia Dilatada/sangue , Síndrome Hipereosinofílica/sangue , Miocárdio/metabolismo , Troponina T/sangue , Biomarcadores , Biópsia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/etiologia , Diagnóstico Diferencial , Ecocardiografia , Humanos , Síndrome Hipereosinofílica/complicações , Miocárdio/patologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeAssuntos
Analgésicos/administração & dosagem , Dor/tratamento farmacológico , Tiamina/administração & dosagem , Adolescente , Adulto , Idoso , Dor nas Costas/tratamento farmacológico , Doenças Ósseas/tratamento farmacológico , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Matemática , Pessoa de Meia-IdadeRESUMO
A 14-year-old girl was admitted with a diagnosis of osteogenic sarcoma of the distal femur. Pre-operative chemotherapy was effective, and sclerosis of the lesion made clear the presence of a proximal femoral and pulmonary metastasis. Total femur and knee joint replacement with titanium alloy was made after a total resection of the femur. Her post-operative clinical course was excellent without local recurrence. Now, 14 months after the operation, she can walk without crutches. We wish to emphasize that the presence of a pulmonary metastasis is not absolutely a contraindication as long as the tumor appears surgically resectable and responsive to per-operative chemotherapy.