Systematic comparison of the molecular mechanisms underlying the spreading of pathology in different neurodegenerative diseases

Misfolding and accumulation of disease-related proteins are common hallmarks among several neurodegenerative diseases. This phenomenon causes the progressive loss of cognitive and motor functions correlated with specific cell loss in the brain. Despite the different clinical manifestations, these disorders share common features and molecular mechanisms, such as aggregation and accumulation of disease-related proteins in specific regions of the brain. These include alpha-synuclein aggregates in Parkinson’s disease and other synucleinopathies, inclusions of hyperphosphorylated microtubule-binding Tau in tauopathies, and extended polyglutamine protein aggregates (huntingtin) in Huntington’s disease. The association between the progression of clinical symptoms and the topographical distribution of pathology in neurodegenerative diseases has led to the hypothesis that specific pathological disease-related proteins can be transferred intercellularly in a prion-like manner. This hypothesis was created after the observation Lewy body pathology, a characteristic hallmark in synucleinopathies, within fetal dopaminergic neurons grafts in Parkinson’s disease patients. Later, injection of Tau aggregates into animal models was shown to induce pathology. More recently, similar mechanisms were proposed to occur in monogenic forms of neurodegenerative diseases after the observation of mutant huntingtin aggregates within fetal striatal allografts in the brain of Huntington’s disease patients. Furthermore, the presence of co-pathology in the brain of patients with distinct neurodegenerative diseases has implied that several proteins may overlap to contribute to the neuropathophysiology and can share common molecular mechanisms in neurodegeneration. Several mechanisms have been suggested to contribute to the spreading of alpha-synuclein, Tau and huntingtin pathology. These include diffusion through the plasma membrane, release via extracellular vesicles (as ectosomes and exosomes), misfolded-associated protein secretion pathway, membrane carriers, membrane pores, tunnelling nanotubes, endocytosis, and receptor-mediated endocytosis. To date, it is unclear if alpha-synuclein, Tau and huntingtin release to the extracellular milieu occurs through similar cellular mechanisms and their effect in receptor cells. Also, the role of protein secretion and their involvement in neuronal dysfunction and disease progression remains elusive. Further elucidation of these questions will permit a better understanding of protein propagation on disease pathogenesis in neurodegenerative diseases. In recent years, extracellular vesicles have emerged as central mediators in intercellular communication under physiological and pathological conditions. Their heterogeneity and presence in several human biofluids have led to extensive research regarding their content and functional properties as relevant biomarkers in neurodegenerative diseases. In particular, ectosomes and exosomes are considered important carriers of misfolded proteins between cells in disease. These can be internalized in diverse cell types, although their effect in neuronal activity is unclear. Discernment between ectosomes and exosomes has been difficult due to the moderate differences in their physical properties and absence of reliable markers. While exosomes have been extensively studied in the field, the role of ectosomes in the pathogenesis of neurodegenerative diseases has not been explored. Additional studies focusing in the role of ectosomes and other types of extracellular vesicles in neurodegenerative diseases will open new avenues to uncover potential disease biomarkers and therapeutic targets. In our first study, we developed a detailed differential ultracentrifugation protocol to efficiently purify ectosomes and exosomes, and provided a proteomic and functional characterization of these vesicles subtypes. Comprehensive proteomic analysis revealed specific protein composition and pathways enrichment for ectosomes and exosomes. Interestingly, ectosomes isolated from human cerebrospinal fluid and from cell media displayed enrichment in annexin-A2, suggesting this protein as an important marker for ectosomes characterization. Furthermore, treatment of neuronal cortical cultures with ectosomes and exosomes resulted in their internalization at similar ratios. Using multi-electrode array technology, we further demonstrated that extracellular vesicles internalization affects differently the spontaneous activity of neuronal cells. In our second study, we demonstrated that common cellular mechanisms are used for the transfer of alpha-synuclein, Tau and huntingtin exon-1 fragments between cells. Interestingly, we observed that these proteins are handled in different ways depending on the receptor cells. Our results reveal the release of the different disease-related proteins to the cell media at different levels in a free form and in extracellular vesicles. Overall, alpha-synuclein, Tau and normal huntingtin exon-1 were found in higher levels in the cell media in contrast to mutant huntingtin exon-1. We further observed discernible alterations in the spontaneous firing activity in primary cortical neurons after treatment with the different recombinant proteins, suggesting that the effects of alpha-synuclein, Tau and huntingtin in the extracellular space and on neuronal activity are dependent of the protein properties and not only correlated with their secretion levels. Interestingly, alpha-synuclein, Tau and huntingtin exon-1 were present in higher levels in ectosomes than in exosomes. We revealed that these vesicles could be internalized in microglial and astrocytic cells, and resulted in the production of pro-inflammatory cytokines and autophagy activation. Neuronal cells also internalized ectosomes and exosomes enriched with alpha-synuclein, Tau or huntingtin, and exhibited irregularity in the cell bursting properties that overall was correlated with the vesicles subtype. Overall, our work indicates that extracellular vesicles cargoes likely reflect core pathophysiological intracellular processes in their origin cells. A clear understanding of the specific functional properties of different vesicles subtypes might represent a step forward in the search of novel biomarkers. Furthermore, our results propose that common cellular mechanisms are used for the transfer of alpha-synuclein, Tau and huntingtin between cells. These similarities could suggest common therapeutic targets for neurodegenerative diseases, and the need to target several cellular mechanisms to halt the detrimental effects of protein transmission and pathology progression.2021-10-2

Otimização de amortecedor rotativo para tampos de sanitas e acompanhamento de respetiva linha de montagem

O presente trabalho consistiu no desenvolvimento de um amortecedor rotativo que permita efetuar queda amortecida dos tampos de sanita. Foi essencial fazer uma pesquisa bibliográfica sobre os amortecedores, as suas aplicações e o seu modo de funcionamento. Foi também bastante importante detetar os pontos fracos dos amortecedores importados, para que durante o desenvolvimento do amortecedor JBMC esses erros fossem evitados. Os vários componentes constituintes do amortecedor rotativo sofreram alterações com o objetivo de melhorar e otimizar o seu funcionamento. Assim, os moldes foram atualizados e a injeção de peças ficou planeada. Infelizmente, não foi possível retirar os componentes atualizados injetados antes do fim do estágio curricular. Outro ponto que ficou por realizar foi a escolha do fluído para o mecanismo devido a problemas com comunicação com os fornecedores e atrasos no prazo de entrega dos produtos. Apesar de alguns objetivos não terem sido integralmente concluídos, o desenvolvimento do amortecedor rotativo sofreu alterações importantes para um bom funcionamento no futuro. Para além disso, o método de selagem e a montagem automatizada do mecanismo já ficou delineada com os fornecedores e os respetivos equipamentos encomendados. Assim que esses equipamentos fossem entregues, seriam iniciados todos os ensaios de montagem, selagem e funcionamento.The present work consisted in the development of a rotary damper applied to toilet seats, allowing a damped fall. It was essential to do a thorough bibliographic research about rotary dampers, their applications, and their mode of operation. Also important was to detect the weaknesses in the rotary dampers available on market, in order to avoid the mistakes that cause them, in the developing of the JBMC damper. With the commitment of improve and optimize rotary damper functioning, changes were made in the various components of the set. Existing molds were updated, and a small production was scheduled. Unfortunately, that was not possible within the time this curricular internship occurs. Another point also not concluded was the choice of mechanism internal fluid due to supplier issues, mainly communication and delivery deadlines. Despite some goals were not fully achieved, rotary damper development took major steps towards a future good functioning result. Besides, sealing method and assemble automatization of the mechanism were already planned with suppliers, and the equipment has been ordered. As soon as this equipment was delivered, would be initiated to do all the necessary assemble, sealing and function tests.Mestrado em Engenharia Mecânic

Modelos da provisão de entretenimento e a aprendizagem de línguas

Mestrado em Línguas e Relações EmpresariaisA presente dissertação propõe-se explorar a indústria do entretenimento, em particular televisivo e de cinema, e as recentes mudanças nos métodos de distribuição. Adicionalmente, procura explorar a utilização de conteúdos de entretenimento em Inglês como ferramentas de aprendizagem da língua. A dissertação tem o objetivo de compreender qual a expetativa dos jovens portugueses em relação a estas mudanças e qual a sua perceção do papel dos novos métodos de distribuição de conteúdo na aprendizagem do Inglês.This dissertation aims to explore the entertainment industry, in particular television and cinema, along with recent changes in their distribution methods. Additionally, it aims to explore the role of video content in English as a language learning tool. The main goal of this dissertation is to understand the expectations of Portuguese young people regarding these changes and their perception as to these new content distribution methods’ role in learning Englis

A informação contabilística nas PME portuguesas da indústria do calçado como ferramenta de gestão ou obrigatoriedade fiscal?

A informação contabilística proveniente dos sistemas contabilísticos, gerada por subsistemas de contabilidade financeira e de gestão, constitui um importante recurso que deve ser acessível e útil aos gestores das empresas. Relativamente à informação contabilística na vertente da contabilidade financeira, esta é elaborada por imposição legal nas empresas. Nas Pequenas e Médias Empresas, dada a usual carência de meios, aquele sistema de informação deve ser tido em conta como um recurso económico e imprescindível de acesso a informação que permita a criação de valor nos seus negócios. O presente estudo tem como objetivo analisar a perceção dos gestores das Pequenas e Médias Empresas do setor do calçado perante a utilização da informação contabilística. Para esta investigação foi redigido um questionário que foi partilhado por via eletrónica com os gestores ou pessoas ligadas à gestão das Pequenas e Médias Empresas membros da Associação Portuguesa dos Industriais de Calçado, Componentes, Artigos de Pele e seus Sucedâneos, sendo as respostas tratadas estatisticamente. Os resultados evidenciaram os principais utilizadores, são os gestores, a banca e o Estado. Os gestores reconhecem a utilização efetiva da informação financeira nas suas funções, recorrendo fundamentalmente ao balancete, balanço e demonstração dos resultados. Foram ainda identificadas caraterísticas da empresa, do gestor e do serviço de contabilidade que influenciam a utilização da informação contabilística, nomeadamente a dimensão da empresa, a idade do gestor, a experiência profissional, a valorização do contabilista, a qualidade percebida da informação, a acessibilidade à informação e a perceção da informação contabilística como obrigação legal ou algo mais.The accounting information comes from the accounting systems, which through the financial accounting and management subsystems, generates quality information which managers must have access to. Financial accounting information is drawn up by legal obligation in businesses. Therefore, in small and medium enterprises this information should be considered as an economic and indispensable option, in the face of resource shortages, to acquire data that enables companies to create value to the business. This study aims to analyze the perception of managers of small and medium footwear companies in the use of accounting information. Information was obtained for the realization of statistical inference through the answers to a questionnaire that was shared via e-mail with the managers of the small and medium companies associated with the Portuguese Association of Footwear Industrialists, Components, Leather Goods and their Substitutes. The results showed that the managers, the banking system and the Government are the main users. In this way they admit using the accounting information in management functions mainly from the balance sheet, balance and statement of results. Characteristics of the company, of the managers and of the accounting services that have an influence on the use of the accounting information have been identified. Namely the size of the company, manager's age, professional experience, accountant appreciation, quality of the information, access to information and the perception of accounting information as legal obligation

Putting Portuguese and European data into perspective

Publisher Copyright: © 2016 Sociedade Portuguesa de Cardiologia.Introduction and Objectives Acute heart failure (AHF) is a heterogeneous clinical syndrome requiring urgent therapy. The prognosis is poor after the index hospitalization, with a high risk for rehospitalization and early death. The costs of managing AHF are thus increasing rapidly. A literature review was performed to gather and compare data on prevalence and treatment and to identify gaps in AHF management, based on European and Portuguese studies. Methods A literature search from 1995 to 2014 was conducted in selected databases (BIOSIS Previews, EMBASE and Ovid MEDLINE). Results and Discussion Seven Portuguese and nine European studies were analyzed. The mean age of AHF patients was ≥65 years and 30-50% were women. Coronary artery disease (42.3% vs. 61.9%) and hypertension (53.3% vs. 76.7%) were identified as primary etiologies in Europe and in Portugal. Similar proportions of heart failure with preserved ejection fraction were found in the Portuguese (19.9-44.7%) and European (32.8-39.1%) studies. Overall, all-cause mortality rates were comparable (six months: 9.3-25.5% vs. 13.5-27.4%; one year: 15.9-31% vs. 17.4-46.5%), as was in-hospital mortality (5.5-14% vs. 3.8-12%) in Portuguese and European studies, respectively. Length of stay was comparable. The studies were performed in very different hospital settings and data on treatment were scarce. Conclusions Gaps were identified in treatment and clinical pathways of patients with AHF. Based on the results of this review, collection and investigation of data on the disease and treatment solutions, training in disease management, and improved organization of healthcare should be the subject of further investment.publishersversionpublishe

Maus tratos a idosos : uma análise da eficácia do presente regime

O propósito deste estudo foi analisar a actual tutela, a título de Direito Penal substantivo, das situações de maus tratos a idosos, detectar potenciais lacunas e apresentar algumas propostas legislativas e de integração. Após breve análise do envelhecimento populacional e medidas de apoio na União Europeia (UE), procurou-se perspetivar em Direito Comparado alguns países da UE face a terceiros, bem como a actual tutela em Portugal, salientando os artigos 152.º e 152.º-A do Código Penal, que revelam diferenças nas condutas previstas pelos dois artigos, sendo que o segundo tipifica mais condutas do que o primeiro, defendendo-se uma interpretação extensiva dos conceitos de maus tratos físicos e psíquicos no artigo 152º de forma a englobar estas condutas. Posteriormente pretendeu-se analisar a questão dos abusos financeiros, omissos nos artigos em questão, explicitando o conceito, sinais e condutas englobadas e a tutela que se encontra a título de Direito Civil e Direito Penal. Referem-se dados estatísticos que confirmam a incidência das práticas de abusos financeiros, identifica-se o bem jurídico em causa e conclui-se pela dignidade penal e carência de tutela. Por fim, referem-se alguns projetos de lei que procuraram englobar certas práticas de abusos patrimoniais no Código Penal, apresentando posteriormente uma proposta de uma ligeira alteração legislativa. Finalmente procedemos ao enquadramento dos maus tratos institucionais, responsabilidade da pessoa colectiva, e determinámos, pela via interpretativa, a não isenção da Santa Casa da Misericórdia e das Instituições Particulares de Solidariedade Social, bem como de outras entidades particulares. Defendemos um alargamento do leque de crimes abrangidos pelo artigo 11.º do Código Penal e analisámos a tutela contra-ordenacional relativamente aos maus tratos institucionais, de modo a determinar a solução a nível de concurso entre as previsões de Direito Penal e Contra-ordenacional. Por último, propusemos soluções para questões relacionadas com o enquadramento típico no Código Penal dos cuidadores domiciliares ou serviços de apoio ao domicílio e de acolhimento familiar, determinando por nossa parte a aplicação do artigo 152.º-A.The purpose of this study was to analyze the current Criminal Law protection of situations of elder abuse, detect potential loopholes, and to present solutions to close them. After a brief analysis of the trends in population aging and support measures in the European Union, we presented the current Criminal Law predictions in some EU countries and third countries, as well as in Portugal, particularly the articles 152.º and 152.º-A of the Portuguese Penal Code, which reveal differences in the conducts that are predicted by each of these articles, since this last article predicts more conducts than the first one, which, we defend, could be solved through an extensive interpretation of the concepts of physical and psychological abuse in the article 152.º in order to include such behaviors. Subsequently, we introduced the matter of financial abuse, omitted in the articles mentioned, explaining its concept, warning signs, and conducts included in its scope and the current protection offered by Civil and Criminal Law. We proceed to present statistics referring to the incidence of financial abuse practices, identify the legal good in question, and determine its criminal dignity and need for protection. Afterward, we studied some bills that sought to include certain practices of financial abuse in the Penal Code, concluding this chapter with our own proposal for a slight legislative change. Finally, we present the current legal framework for institutional elder abuse, the criminal responsibility of the legal person, and determined, by the way of interpretation, the non-exemption of the Santa Casa da Misericórdia and the Private Social Solidarity Institutions, as well as other private entities. We defended an extent of the range of crimes covered by the article 11.º of the Penal Code, and analyzed the administrative legal predictions regarding institutional mistreatment, in order to determine the solution when both this branch of law and Criminal law are applicable. Lastly, we suggested solutions to issues related to the framing in the Criminal Law predictions for abuse of cases of home care providers and services and host families, concluding by the application of the article 152.º-A

Apresentação Atípica de uma Doença Muito Rara

Creutzfeldt-Jakob disease typically presents as rapidly progressive dementia. We describe the case of a 59-year-old male patient presenting with sudden onset of central facial palsy and dysarthria, followed by myoclonus of his left upper and lower limbs. Initial brain magnetic resonance showed hyperintensity of the right caudate and putamen on diffusion-weighted imaging and T2 sequences. Cerebrospinal fluid analysis showed increased protein count. The workup to investigate autoimmune, infectious and paraneoplastic causes was negative. Symptoms progressively worsened, with left hemiplegia, dysphagia, urinary incontinence, and, later, akinetic mutism. The follow-up brain magnetic resonance scan revealed hyperintensity of bilateral basal ganglia as well as cerebral cortical abnormalities on diffusion-weighted imaging. Electroencephalography showed periodic activity and tau protein levels in the cerebrospinal fluid were elevated. Genetic analysis showed mutation c-598G > A. The patient died four months later. We report a case of familial Creutzfeldt-Jakob disease with atypical clinical and radiological features, namely neurological focal signs with sudden onset, absence of significant cognitive impairment and unilateral radiological findings. With disease progression, characteristic clinical and radiological features led to the diagnosis.publishersversionpublishe

Humanização dos cuidados de enfermagem a crianças até idade pré-escolar e família: scoping review

info:eu-repo/semantics/publishedVersio

estimativas para o século XXI em Portugal

Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.INTRODUCTION AND OBJECTIVE: Heart failure is a major public health problem that affects a large number of individuals and is associated with high mortality and morbidity. This study aims to estimate the probable scenario for HF prevalence and its consequences in the short-, medium- and long-term in Portugal. METHODS: This assessment is based on the EPICA (Epidemiology of Heart Failure and Learning) project, which was designed to estimate the prevalence of chronic heart failure in mainland Portugal in 1998. Estimates of heart failure prevalence were performed for individuals aged over 25 years, distributed by age group and gender, based on data from the 2011 Census by Statistics Portugal. RESULTS: The expected demographic changes, particularly the marked aging of the population, mean that a large number of Portuguese will likely be affected by this syndrome. Assuming that current clinical practices are maintained, the prevalence of heart failure in mainland Portugal will increase by 30% by 2035 and by 33% by 2060, compared to 2011, resulting in 479 921 and 494 191 affected individuals, respectively. CONCLUSIONS: In addition to the large number of heart failure patients expected, it is estimated that the hospitalizations and mortality associated with this syndrome will significantly increase its economic impact. Therefore, it is extremely important to raise awareness of this syndrome, as this will favor diagnosis and early referral of patients, facilitating better management of heart failure and helping to decrease the burden it imposes on Portugal.publishersversionpublishe