Browsing by Author "Pinho Costa, Paulo"
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- Circulating cell-free DNA methylation mirrors alterations in cerebral patterns in epilepsyPublication . Martins-Ferreira, Ricardo; Leal, Bárbara; Chaves, João; Ciudad, Laura; Samões, Raquel; Martins da Silva, António; Pinho Costa, Paulo; Ballestar, EstebanBackground: DNA methylation profiling of circulating cell-free DNA (cfDNA) has rapidly become a promising strategy for biomarker identification and development. The cell-type-specific nature of DNA methylation patterns and the direct relationship between cfDNA and apoptosis can potentially be used non-invasively to predict local alterations. In addition, direct detection of altered DNA methylation patterns performs well as a biomarker. In a previous study, we demonstrated marked DNA methylation alterations in brain tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Results: We performed DNA methylation profiling in cfDNA isolated from the serum of MTLE patients and healthy controls using BeadChip arrays followed by systematic bioinformatic analysis including deconvolution analysis and integration with DNase accessibility data sets. Differential cfDNA methylation analysis showed an overrepresentation of gene ontology terms and transcription factors related to central nervous system function and regulation. Deconvolution analysis of the DNA methylation data sets ruled out the possibility that the observed differences were due to changes in the proportional contribution of cortical neurons in cfDNA. Moreover, we found no overrepresentation of neuron- or glia-specific patterns in the described cfDNA methylation patterns. However, the MTLE-HS cfDNA methylation patterns featured a significant overrepresentation of the epileptic DNA methylation alterations previously observed in the hippocampus. Conclusions: Our results support the use of cfDNA methylation profiling as a rational approach to seeking non-invasive and reproducible epilepsy biomarkers.
- Epilepsy progression is associated with cumulative DNA methylation changes in inflammatory genesPublication . Martins-Ferreira, Ricardo; Leal, Bárbara; Chaves, João; Li, Tianlu; Ciudad, Laura; Rangel, Rui; Santos, Agostinho; Martins da Silva, António; Pinho Costa, Paulo; Ballestar, EstebanMesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common focal epilepsy in adults. It is characterized by alarming rates of pharmacoresistance. Epileptogenesis is associated with the occurrence of epigenetic alterations, and the few epigenetic studies carried out in MTLE-HS have mainly focused on the hippocampus. In this study, we obtained the DNA methylation profiles from both the hippocampus and anterior temporal neocortex of MTLE-HS patients subjected to resective epilepsy surgery and autopsied non-epileptic controls. We assessed the progressive nature of DNA methylation changes in relation to epilepsy duration. We identified significantly altered hippocampal DNA methylation patterns encompassing multiple pathways known to be involved in epileptogenesis. DNA methylation changes were even more striking in the neocortex, wherein pathogenic pathways and genes were common to both tissues. Most importantly, DNA methylation changes at many genomic sites varied significantly with epilepsy duration. Such progressive changes were associated with inflammation-related genes in the hippocampus. Our results suggest that the neocortex, relatively spared of extensive histopathological damage, may also be involved in epilepsy development. These results also open the possibility that the observed neocortical impairment could represent a preliminary stage of epileptogenesis before the establishment of chronic lesions or a consequence of prolonged seizure exposure. Our two-tissue multi-level characterization of the MTLE-HS DNA methylome suggests the occurrence of a self-propagating inflammatory wave of epigenetic dysregulation.
- Haplotype analysis of newly diagnosed Portuguese and Brazilian families with fibrinogen amyloidosis caused by the FGA p.Glu545Val variantPublication . Tavares, Isabel; Oliveira, Márcia E.; Maia, Nuno; Moreira, Luciana; Castro Lacerda, Pedro; Santos, Josefina; Santos, Rosário; Pinho Costa, Paulo; Lobato, LuísaBackground: Fibrinogen A alpha-chain (AFib) amyloidosis is an autosomal dominant disease with an endemic foci in the district of Braga, northern Portugal [1]. Among the 16 amyloidogenic mutations identified in the fibrinogen A alpha-chain gene (FGA) [2,3], the c.1634A > T (p.Glu545Val) mutation (rs121909612) is the most common and, so far, the only one identified in Portugal. A first study using three common polymorphisms showed a single haplotype, associated with the FGA p.Glu545Val mutation in Irish–American and Polish–Canadian kindreds [4]. However, the origin of this amyloidogenic variant in diverse regions and its migration in the different populations are still unclear. Therefore, we proceeded to a preliminary study using two FGA haplotype markers in newly identified Portuguese and Brazilian carriers to investigate the possibility of a common ancestor.
- Psychological impact of life events in systemic lupus erythematosus patients - Differences between flares and remission.Publication . Faria, Raquel; Guimarães de Oliveira, Daniel; Alves, Rute; Farinha, Fátima; Pinho Costa, Paulo; Vasconcelos, Carlos; Figueiredo-Braga, MargaridaBackground: Stress has been linked to worsening symptoms and increased disease activity in patients with Systemic lupus erythematosus (SLE). Life-events are individual stress points, and there is conflicting evidence regarding their role in SLE activity and disease perception. Methods: Adult SLE patients were recruited for the study. Clinical and laboratory features of SLE were recorded, and previous diagnosis of anxiety or depression were retrieved from patients' electronic charts. Flares were defined by the Systemic Lupus Erythematosus Disease Activity (SLEDAI) flare Index, and flares during the previous year were documented. During a routine visit, they completed validated Portuguese translations of the 10-item Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS) and Life Experience Survey (LES) for the previous year. Results: A total of 47 female SLE patients were recruited. Ten patients (21.3%) had experienced recent flares. Patients with recent flares reported fewer life events, with lower positive, negative, and total weightings sums compared to those without recent flares. Although 42.2% of patients perceived pathological levels of stress in the previous month, 48.9% had anxiety symptoms, and 34% were at high risk for an anxiety disorder, these psychometric measures did not differ significantly between the recent flare and no-flare groups. Conclusions: There is a high prevalence of pathological levels of stress among SLE patients. SLE patients with recent flares report less psychological impact from life events, both positive and negative, independent of other psychological or pharmacological factors.