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Arch Bronconeumol ; 2019 Nov 26.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31784347


INTRODUCTION: It is unclear whether low-risk patients with acute symptomatic pulmonary embolism (PE) should undergo echocardiogram. METHODS: We performed a meta-analysis of studies that enrolled patients with acute low-risk PE to assess the prognostic value of echocardiographic diagnosis of right ventricular (RV) dysfunction for the primary outcome of short-term all-cause mortality, and the secondary outcome of short-term PE-related mortality. We used a random-effects model to pool study results, a Begg rank correlation method to evaluate for publication bias, and I2 testing to assess heterogeneity. RESULTS: The meta-analysis included a total of 11 studies 1,868 patients with low-risk PE. Ten of the 447 (2.2%; 1.1%-4.1%) low-risk patients with echocardiographic RV dysfunction died soon after the diagnosis of PE compared with 10 of 1,421 (0.7%; 0.3-1.3%) patients without RV dysfunction. RV dysfunction was not significantly associated with short-term all-cause mortality (odds ratio 2.0; 95% confidence interval, 0.8-5.1, p=.14; I2=8%). RV dysfunction was significantly associated with short-term PE-related mortality (odds ratio 5.2; 95% confidence interval, 1.7-16, p <.01; I2=0%). CONCLUSIONS: In patients with low-risk PE, echocardiographic RV dysfunction is not associated with all-cause mortality, but identifies patients with an increased risk for short-term PE-related mortality.

Genet Med ; 21(9): 2092-2102, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30733599


PURPOSE: To demonstrate the utility of an amplification-free long-read sequencing method to characterize the Fuchs endothelial corneal dystrophy (FECD)-associated intronic TCF4 triplet repeat (CTG18.1). METHODS: We applied an amplification-free method, utilizing the CRISPR/Cas9 system, in combination with PacBio single-molecule real-time (SMRT) long-read sequencing, to study CTG18.1. FECD patient samples displaying a diverse range of CTG18.1 allele lengths and zygosity status (n = 11) were analyzed. A robust data analysis pipeline was developed to effectively filter, align, and interrogate CTG18.1-specific reads. All results were compared with conventional polymerase chain reaction (PCR)-based fragment analysis. RESULTS: CRISPR-guided SMRT sequencing of CTG18.1 provided accurate genotyping information for all samples and phasing was possible for 18/22 alleles sequenced. Repeat length instability was observed for all expanded (≥50 repeats) phased CTG18.1 alleles analyzed. Furthermore, higher levels of repeat instability were associated with increased CTG18.1 allele length (mode length ≥91 repeats) indicating that expanded alleles behave dynamically. CONCLUSION: CRISPR-guided SMRT sequencing of CTG18.1 has revealed novel insights into CTG18.1 length instability. Furthermore, this study provides a framework to improve the molecular diagnostic accuracy for CTG18.1-mediated FECD, which we anticipate will become increasingly important as gene-directed therapies are developed for this common age-related and sight threatening disease.

Am J Hum Genet ; 102(4): 528-539, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29526280


Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.

Distrofia Endotelial de Fuchs/genética , Predisposição Genética para Doença , Oligonucleotídeos Antissenso/farmacologia , Fator de Transcrição 4/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Estudos de Coortes , Células Endoteliais/metabolismo , Epitélio Posterior/patologia , Feminino , Distrofia Endotelial de Fuchs/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/metabolismo , Fatores de Risco