Browsing by Author "Gomes, R"
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- Anatomical and Physiological Basis of Continuous Spike-Wave of Sleep Syndrome after Early Thalamic LesionsPublication . Leal, A; Calado, E; Vieira, JP; Mendonça, C; Ferreira, JC; Ferreira, H; Carvalho, D; Furtado, F; Gomes, R; Monteiro, JPOBJECTIVE: Early neonatal thalamic lesions account for about 14% of continuous spike-wave of sleep (CSWS) syndrome, representing the most common etiology in this epileptic encephalopathy in children, and promise useful insights into the pathophysiology of the disease. METHODS: We describe nine patients with unilateral neonatal thalamic lesions which progressed to CSWS. Longitudinal whole-night and high-density electroencephalograms (EEGs) were performed, as well as detailed imaging and clinical evaluation. Visual evoked potentials were used to probe cortical excitability. RESULTS: Thalamic volume loss ranged from 19% to 94%, predominantly on medial and dorsal nuclei and sparing the ventral thalamus. Lesions produced white matter loss and ventricle enlargement on the same hemisphere, which in four patients was associated with selective loss of thalamic-cortical fibers. Cortical thickness quantification failed to reveal hemispheric asymmetries. Impact on EEG rhythms was mild, with a volume-loss-related decrease in alpha power and preservation of sleep spindles. The sleep continuous spiking was lateralized to the hemisphere with the lesion. Visual cortex stimulation in five patients with posterior cortex spiking revealed an abnormal frequency-dependent excitability at 10-20Hz on the side of the lesion. SIGNIFICANCE: Unilateral selective thalamic-cortical disconnection is a common feature in our patients and is associated with both a focal pattern of CSWS and a pathological type of frequency-dependent excitability (peak: 10-20Hz). We propose that this excitability represents an abnormal synaptic plasticity previously described as the augmenting response. This synaptic plasticity has been described as absent in the corticocortical interactions in healthy experimental animals, emerging after ablation of the thalamus and producing a frequency-dependent potentiation with a peak at 10-20Hz. Because this response is potentiated by sleep states of reduced brainstem activation and by appropriate stimulating rhythms, such as sleep spindles, the simultaneous occurrence of these two factors in nonrapid-eye-movement sleep is proposed as an explanation for CSWS in our patients.
- Asthma App Use and Interest Among Patients With Asthma: A Multicenter StudyPublication . Jácome, C; Almeida, R; Pereira, AM; Araújo, L; Correia, MA; Pereira, M; Couto, M; Lopes, C; Chaves Loureiro, C; Catarata, MJ; Santos, LM; Ramos, B; Mendes, A; Pedro, E; Cidrais Rodrigues, JC; Oliveira, G; Aguiar, AP; Arrobas, AM; Costa, J; Dias, J; Todo Bom, A; Azevedo, J; Ribeiro, C; Alves, M; Pinto, PL; Neuparth, N; Palhinha, A; Marques, JG; Martins, P; Trincão, D; Neves, A; Todo Bom, F; Santos, M A; Branco, J; Loyoza, C; Costa, A; Silva Neto, A; Silva, D; Vasconcelos, MJ; Teixeira, MF; Ferreira-Magalhães, M; Taborda Barata, L; Carvalhal, C; Santos, N; Sofia Pinto, C; Rodrigues Alves, R; Moreira, AS; Morais Silva, P; Fernandes, R; Ferreira, R; Alves, C; Câmara, R; Ferraz de Oliveira, J; Bordalo, D; Calix, MJ; Marques, A; Nunes, C; Menezes, F; Gomes, R; Almeida Fonseca, J
- Doenças Neuromusculares na Idade Pediátrica em Portugal - Estudo PreliminarPublication . Santos, MA; Fineza, I; Moreno, T; Cabral, P; Ferreira, JC; Lopes Silva, R; Vieira, JP; Moreira, A; Dias, AI; Calado, E; Monteiro, JP; Fonseca, MJ; Moço, C; Furtado, F; Campos, MM; Gonçallves, O; Gomes, R; Barbosa, C; Figueiroa, S; Temudo, T; Fagundes, F
- Feasibility and Acceptability of an Asthma App to Monitor Medication Adherence: Mixed Methods StudyPublication . Jácome, C; Almeida, R; Pereira, AM; Amaral, R; Mendes, S; Alves-Correia, M; Vidal, C; López Freire, S; Méndez Brea, P; Araújo, L; Couto, M; Antolín-Amérigo, D; de la Hoz Caballer, B; Barra Castro, A; Gonzalez-De-Olano, D; Todo Bom, A; Azevedo, J; Leiria Pinto, P; Pinto, N; Castro Neves, A; Palhinha, Ana; Todo Bom, F; Costa, A; Chaves Loureiro, C; Maia Santos, L; Arrobas, A; Valério, M; Cardoso, J; Emiliano, M; Gerardo, R; Cidrais Rodrigues, JC; Oliveira, G; Carvalho, J; Mendes, A; Lozoya, C; Santos, N; Menezes, F; Gomes, R; Câmara, R; Rodrigues Alves, R; Moreira, AS; Bordalo, D; Alves, C; Ferreira, JA; Lopes, C; Silva, D; Vasconcelos, MJ; Teixeira, MF; Ferreira-Magalhães, M; Taborda-Barata, L; Cálix, MJ; Alves, A; Almeida Fonseca, JBackground: Poor medication adherence is a major challenge in asthma, and objective assessment of inhaler adherence is needed. The InspirerMundi app aims to monitor adherence while providing a positive experience through gamification and social support. Objective: This study aimed to evaluate the feasibility and acceptability of the InspirerMundi app to monitor medication adherence in adolescents and adults with persistent asthma (treated with daily inhaled medication). Methods: A 1-month mixed method multicenter observational study was conducted in 26 secondary care centers from Portugal and Spain. During an initial face-to-face visit, physicians reported patients' asthma therapeutic plan in a structured questionnaire. During the visits, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients registered the intake (inhaler, blister, or other drug formulation) by using the image-based medication detection tool. At 1 month, patients were interviewed by phone, and app satisfaction was assessed on a 1 (low) to 5 (high) scale. Patients were also asked to point out the most and least preferred app features and make suggestions for future app improvements. Results: A total of 107 patients (median 27 [P25-P75 14-40] years) were invited, 92.5% (99/107) installed the app, and 73.8% (79/107) completed the 1-month interview. Patients interacted with the app a median of 9 (P25-P75 1-24) days. At least one medication was registered in the app by 78% (77/99) of patients. A total of 53% (52/99) of participants registered all prescribed inhalers, and 34% (34/99) registered the complete asthma therapeutic plan. Median medication adherence was 75% (P25-P75 25%-90%) for inhalers and 82% (P25-P75 50%-94%) for other drug formulations. Patients were globally satisfied with the app, with 75% (59/79) scoring ≥4,; adherence monitoring, symptom monitoring, and gamification features being the most highly scored components; and the medication detection tool among the lowest scored. A total of 53% (42/79) of the patients stated that the app had motivated them to improve adherence to inhaled medication and 77% (61/79) would recommend the app to other patients. Patient feedback was reflected in 4 major themes: medication-related features (67/79, 85%), gamification and social network (33/79, 42%), symptom monitoring and physician communication (21/79, 27%), and other aspects (16/79, 20%). Conclusions: The InspirerMundi app was feasible and acceptable to monitor medication adherence in patients with asthma. Based on patient feedback and to increase the registering of medications, the therapeutic plan registration and medication detection tool were redesigned. Our results highlight the importance of patient participation to produce a patient-centered and engaging mHealth asthma app.
- Impairment of Adenosinergic System in Rett syndrome: Novel Therapeutic Target to Boost BDNF SignallingPublication . Miranda-Lourenço, C; Duarte, ST; Palminha, C; Gaspar, C; Rodrigues, TM; Magalhães-Cardoso, T; Rei, N; Colino-Oliveira, M; Gomes, R; Ferreira, S; Rosa, J; Xapelli, S; Armstrong, J; García-Cazorla, A; Correia-de-Sá, P; Sebastião, AM; Diógenes, MJRett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.
- Monitoring Adherence to Asthma Inhalers Using the InspirerMundi App: Analysis of Real-World, Medium-Term Feasibility StudiesPublication . Jácome, C; Almeida, R; Pereira, AM; Amaral, R; Vieira-Marques, P; Mendes, S; Alves-Correia, M; Ferreira, JA; Lopes, I; Gomes, J; Araújo, L; Couto, M; Chaves Loureiro, C; Maia Santos, L; Arrobas, A; Valério, M; Todo Bom, A; Azevedo, J; Teixeira, MF; Ferreira-Magalhães, M; Leiria Pinto, P; Pinto, N; Castro Neves, A; Morête, A; Todo Bom, F; Costa, A; Silva, D; Vasconcelos, MJ; Falcão, H; Marques, ML; Mendes, A; Cardoso, J; Cidrais Rodrigues, JC; Oliveira, G; Carvalho, J; Lozoya, C; Santos, N; Menezes, F; Gomes, R; Câmara, R; Rodrigues Alves, R; Moreira, AS; Abreu, C; Silva, R; Bordalo, D; Alves, C; Lopes, C; Taborda-Barata, L; Fernandes, RM; Ferreira, R; Chaves-Loureiro, C; Cálix, MJ; Alves, A; Almeida Fonseca, JBackground: Poor medication adherence is a major challenge in asthma and objective assessment of inhaler adherence is needed. InspirerMundi app aims to monitor inhaler adherence while turning it into a positive experience through gamification and social support. Objective: We assessed the medium-term feasibility of the InspirerMundi app to monitor inhaler adherence in real-world patients with persistent asthma (treated with daily inhaled medication). In addition, we attempted to identify the characteristics of the patients related to higher app use. Methods: Two real-world multicenter observational studies, with one initial face-to-face visit and a 4-month telephone interview, were conducted in 29 secondary care centers from Portugal. During an initial face-to-face visit, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients took a photo of the medication (inhaler, blister, or others) using the image-based medication detection tool. Medication adherence was calculated as the number of doses taken as a percentage of the number scheduled. Interacting with the app ≥30 days was used as the cut-off for higher app use. Results: A total of 114 patients {median 20 [percentile 25 to percentile 75 (P25-P75) 16-36] years, 62% adults} were invited, 107 (94%) installed the app and 83 (73%) completed the 4-month interview. Patients interacted with the app for a median of 18 [3-45] days, translated on a median use rate of 15 [3-38]%. Median inhaler adherence assessed through the app was 34 [4-73]% when considering all scheduled inhalations for the study period. Inhaler adherence assessed was not significantly correlated with self-reported estimates. Median adherence for oral and other medication was 41 [6-83]% and 43 [3-73]%, respectively. Patients with higher app use were slightly older (p = 0.012), more frequently taking medication for other health conditions (p = 0.040), and more frequently prescribed long-acting muscarinic antagonists (LAMA, p = 0.024). After 4 months, Control of Allergic Rhinitis and Asthma Test (CARAT) scores improved (p < 0.001), but no differences between patients interacting with the app for 30 days or less were seen. Conclusions: The InspirerMundi app was feasible to monitor inhaler adherence in patients with persistent asthma. The persistent use of this mHealth technology varies widely. A better understanding of characteristics related to higher app use is still needed before effectiveness studies are undertaken.
- Mutations in the MECP2 Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male PatientsPublication . Santos, M; Temudo, T; Kay, T; Carrilho, I; Medeira, A; Cabral, H; Gomes, R; Lourenço, T; Venâncio, M; Calado, E; Moreira, A; Oliveira, G; Maciel, PRett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.
- Patient-Physician Discordance in Assessment of Adherence to Inhaled Controller Medication: a Cross-Sectional Analysis of Two CohortsPublication . Jácome, C; Pereira, AM; Almeida, R; Ferreira-Magalhaes, M; Couto, M; Araujo, L; Pereira, M; Alves Correia, M; Chaves Loureiro, C; Catarata, MJ; Maia Santos, L; Pereira, J; Ramos, B; Lopes, C; Mendes, A; Cidrais Rodrigues, JC; Oliveira, G; Aguiar, AP; Afonso, I; Carvalho, J; Arrobas, A; Coutinho Costa, J; Dias, J; Todo Bom, A; Azevedo, J; Ribeiro, C; Alves, M; Leiria Pinto, P; Neuparth, N; Palhinha, A; Gaspar Marques, J; Pinto, N; Martins, P; Todo Bom, F; Alvarenga Santos, M; Gomes Costa, A; Silva Neto, A; Santalha, M; Lozoya, C; Santos, N; Silva, D; Vasconcelos, MJ; Taborda-Barata, L; Carvalhal, C; Teixeira, MF; Rodrigues Alves, R; Moreira, AS; Sofia Pinto, C; Morais Silva, P; Alves, C; Câmara, R; Coelho, D; Bordalo, D; Fernandes, R; Ferreira, R; Menezes, F; Gomes, R; Calix, MJ; Marques, A; Cardoso, J; Emiliano, M; Gerardo, R; Nunes, C; Câmara, R; Ferreira, JA; Carvalho, A; Freitas, P; Correia, R; Fonseca, JOBJECTIVE: We aimed to compare patient's and physician's ratings of inhaled medication adherence and to identify predictors of patient-physician discordance. DESIGN: Baseline data from two prospective multicentre observational studies. SETTING: 29 allergy, pulmonology and paediatric secondary care outpatient clinics in Portugal. PARTICIPANTS: 395 patients (≥13 years old) with persistent asthma. MEASURES: Data on demographics, patient-physician relationship, upper airway control, asthma control, asthma treatment, forced expiratory volume in one second (FEV1) and healthcare use were collected. Patients and physicians independently assessed adherence to inhaled controller medication during the previous week using a 100 mm Visual Analogue Scale (VAS). Discordance was defined as classification in distinct VAS categories (low 0-50; medium 51-80; high 81-100) or as an absolute difference in VAS scores ≥10 mm. Correlation between patients' and physicians' VAS scores/categories was explored. A multinomial logistic regression identified the predictors of physician overestimation and underestimation. RESULTS: High inhaler adherence was reported both by patients (median (percentile 25 to percentile 75) 85 (65-95) mm; 53% VAS>80) and by physicians (84 (68-95) mm; 53% VAS>80). Correlation between patient and physician VAS scores was moderate (rs=0.580; p<0.001). Discordance occurred in 56% of cases: in 28% physicians overestimated adherence and in 27% underestimated. Low adherence as assessed by the physician (OR=27.35 (9.85 to 75.95)), FEV1 ≥80% (OR=2.59 (1.08 to 6.20)) and a first appointment (OR=5.63 (1.24 to 25.56)) were predictors of underestimation. An uncontrolled asthma (OR=2.33 (1.25 to 4.34)), uncontrolled upper airway disease (OR=2.86 (1.35 to 6.04)) and prescription of short-acting beta-agonists alone (OR=3.05 (1.15 to 8.08)) were associated with overestimation. Medium adherence as assessed by the physician was significantly associated with higher risk of discordance, both for overestimation and underestimation of adherence (OR=14.50 (6.04 to 34.81); OR=2.21 (1.07 to 4.58)), while having a written action plan decreased the likelihood of discordance (OR=0.25 (0.12 to 0.52); OR=0.41 (0.22 to 0.78)) (R2=44%). CONCLUSION: Although both patients and physicians report high inhaler adherence, discordance occurred in half of cases. Implementation of objective adherence measures and effective communication are needed to improve patient-physician agreement.
- Pyruvate Dehydrogenase Complex Deficiency: Updating the Clinical, Metabolic and Mutational Landscapes in a Cohort of Portuguese PatientsPublication . Pavlu-Pereira, H; Silva, MJ; Florindo, C; Sequeira, S; Ferreira, AC; Duarte, S; Rodrigues, AL; Janeiro, P; Oliveira, A; Gomes, D; Bandeira, A; Martins, E; Gomes, R; Soares, S; Tavares de Almeida, I; Vicente, JB; Rivera, IBackground: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.
- Rett Syndrome With and Without Detected MECP2 Mutations: an Attempt to Redefine PhenotypesPublication . Temudo, T; Santos, M; Ramos, E; Dias, K; Vieira, JP; Moreira, A; Calado, E; Carrilho, I; Oliveira, G; Levy, A; Barbot, C; Fonseca, M; Cabral, A; Cabral, P; Monteiro, J; Borges, L; Gomes, R; Mira, G; Pereira, SA; Santos, M; Fernandes, A; Epplen, JT; Sequeiros, J; Maciel, PBackground: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. Patients and Methods: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. Results: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. Conclusion: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.