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  • Collateral pial circulation relates to the degree of brain edema on CT 24 hours after ischemic stroke
    Publication . Galego, O; Jesus-Ribeiro, J; Baptista, M; Sargento-Freitas, J; Martins, AI; Silva, F; Santos, GC; Cunha, L; Nunes, C; Machado, E
    Background Cerebral edema is frequent in patients with acute ischemic stroke (AIS) who undergo reperfusion therapy and is associated with high mortality. The impact of collateral pial circulation (CPC) status on the development of edema has not yet been determined. Methods We studied consecutive patients with AIS and documented M1-middle cerebral artery (MCA) and/or distal internal carotid artery (ICA) occlusion who underwent reperfusion treatment. Edema was graded on the 24-hour non-contrast computed tomography (NCCT) scan. CPC was evaluated at the acute phase (≤6 hours) by transcranial color-coded Doppler, angiography and/or CT angiography. We performed an ordinal regression model for the effect of CPC on cerebral edema, adjusting for age, baseline National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on admission, NCCT, parenchymal hemorrhagic transformation at 24 hours and complete recanalization at six hours. Results Among the 108 patients included, 49.1% were male and mean age was 74.2 ± 11.6 years. Multivariable analysis showed a significant association between cerebral edema and CPC status (OR 0.22, 95% CI 0.08-0.59, p = 0.003), initial ASPECTS (OR 0.72, 95% CI 0.57-0.92, p = 0.007) and parenchymal hemorrhagic transformation (OR 23.67, 95% CI 4.56-122.8, p < 0.001). Conclusions Poor CPC is independently associated with greater cerebral edema 24 hours after AIS in patients who undergo reperfusion treatment.
    2018-10Journal article Open access Show more
  • Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA
    Publication . Borràs, N; Orriols, G; Batlle, J; Pérez-Rodríguez, A; Fidalgo, T; Martinho, P; López-Fernández, MF; Rodríguez-Trillo, Á; Lourés, E; Parra, R; Altisent, C; Cid, AR; Bonanad, S; Cabrera, N; Moret, A; Mingot-Castellano, ME; Navarro, N; Pérez-Montes, R; Marcellini, S; Moreto, A; Herrero, S; Soto, I; Fernández-Mosteirín, N; Jiménez-Yuste, V; Alonso, N; de Andrés-Jacob, A; Fontanes, E; Campos, R; Paloma, MJ; Bermejo, N; Berrueco, R; Mateo, J; Arribalzaga, K; Marco, P; Palomo, Á; Castro Quismondo, N; Iñigo, B; Nieto, MM; Vidal, R; Martínez, MP; Aguinaco, R; Tenorio, JM; Ferreiro, M; García-Frade, J; Rodríguez-Huerta, AM; Cuesta, J; Rodríguez-González, R; García-Candel, F; Dobón, M; Aguilar, C; Vidal, F; Corrales, I
    Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7473G>A (p.=) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of 3 mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that 4 of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease.
    2018-10-25Journal article Open access Show more