RESUMO
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Motivo Estéril alfa/genética , Adulto , Idade de Início , Autoantígenos/genética , Sequência de Bases , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/patologia , Feminino , Instabilidade Genômica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Íntrons , Masculino , Linhagem , Células de Purkinje/patologia , Proteínas de Ligação a RNA/genética , Análise de Sequência de DNARESUMO
OBJECTIVE: HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL-mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-ßII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-ßII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-ßII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction.
Assuntos
HDL-Colesterol/sangue , Derivação Gástrica , Estilo de Vida , Obesidade Infantil/cirurgia , Adolescente , Angiotensinogênio/metabolismo , Estudos de Casos e Controles , Criança , Células Endoteliais/metabolismo , Endotélio/metabolismo , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade Infantil/sangue , Fosforilação , Proteína Quinase C beta/genética , Proteína Quinase C beta/metabolismo , Proteoma/metabolismo , Adulto JovemRESUMO
Sarcomatoid carcinoma of the thymus is rare and responds poorly to treatment. Invasion of great vessels and metastasis are significant predictors for poor prognosis. Thymic tumors commonly cause superior vena cava (SVC) obstruction by extrinsic compression or invasion, but intraluminal permeation is the most uncommon cause. We report a rare, long-surviving case of sarcomatoid carcinoma with SVC syndrome developed by tumor thrombus. She underwent SVC replacement and extended thymectomy. The resection indicated intracaval extension without direct invasion of thymic tumor, histologically diagnosed as sarcomatoid carcinoma. After adjuvant chemotherapy, she continues to show no apparent recurrence for five years.
Assuntos
Células Neoplásicas Circulantes , Timoma/patologia , Neoplasias do Timo/secundário , Veia Cava Superior , Idoso , Feminino , Humanos , Sobreviventes , Fatores de TempoRESUMO
Patients with diastolic heart failure tend to have a poor outcome, similar to that for patients with systolic heart failure. The aim of this study was to explore the ability of MDCT to estimate the left ventricular diastolic function. Thirty patients with suspected coronary artery disease underwent MDCT and echocardiography. The early transmitral flow velocities (E) and the velocity of mitral annulus early diastolic motion (e') were measured in order to evaluate the diastolic function. The scanning delay of CT was determined using a test injection technique. The aortic enhancement was measured over the aortic-root lumen, and it was plotted over time to yield a time-enhancement-curve. A gamma variate function was then fit to the time-enhancement-curve and thereafter both the 'slope' of enhancement for each patient and the region of interest [ROI] were calculated. According to a univariate analysis, the slope of the time-enhancement-curve was found to correlate with the e' (r = 0.686, P = 0.000) and E/e' (r = -0.482, P = 0.007), however, no significant correlation was observed with the systolic parameters of the left ventricle. These results indicate that the slope of the time-enhancement-curve in the aorta significantly correlates with e', i.e. the diastolic parameters, which are independent of the systolic parameters. Based on these findings, we propose that the slope of the time-enhancement-curve may serve as a parameter for the left ventricular diastolic function on MDCT.
