Biomarcadores no defeito cognitivo ligeiro e na doença de Alzheimer

Mestrado em Métodos Biomoleculares AvançadosA doença de Alzheimer é a forma de demência mais comum no idoso, afectando cerca de 10% dos indivíduos com 65 anos. Considera-se que tenha uma origem multifactorial, sendo vários os factores que contribuem para a formação das placas senis, bem como das tranças neurofibrilares, características desta patologia. O diagnóstico baseia-se no exame clínico, testes neuropsicológicos e técnicas de imagiologia cerebral, sendo feito por exclusão de outras formas de demência de causa conhecida. O defeito cognitivo ligeiro (DCL) caracteriza-se pela ocorrência de défices cognitivos subtis mantendo-se, de uma forma geral, intactas a cognição e a realização de actividades da vida quotidiana. A identificação de um biomarcador seria útil não só para o diagnóstico destas patologias, mas também para o início e monitorização de uma terapêutica neuroprotectora, para o acompanhamento da progressão da doença e para a avaliação da população em risco para a doença. Assim, pretendeu-se com este trabalho identificar parâmetros inflamatórios, de stresse oxidativo e níveis de expressão de proteínas envolvidas na morte celular, a nível do sangue periférico, que permitissem diferenciar indivíduos cognitivamente saudáveis de indivíduos com doença de Alzheimer ligeira e DCL. Analisaram-se também polimorfismos genéticos na tentativa de identificar, não só marcadores entre grupos, como indicadores de susceptibilidade para a doença. Pretendeu-se também encontrar preditores de prognóstico da conversão do estadio de DCL para doença de Alzheimer, tendo para isso sido realizado um estudo longitudinal. Os resultados obtidos sugerem que na doença de Alzheimer existe um aumento da percentagem de monócitos a produzir citocinas pró-inflamatórias, o que poderá traduzir um estado inflamatório persistente nesta patologia. Neste contexto, os monócitos, mas não os linfócitos, poderão ser considerados bons alvos de estudo para o controlo da evolução de DCL para doença de Alzheimer. Os parâmetros de stresse oxidativo estudados revelaram um decréscimo das defesas antioxidantes nos grupos de doentes com uma activação evidente do ciclo do glutatião nestas doenças e um aumento significativo nos níveis de metabolitos do monóxido de azoto. Os polimorfismos genéticos estudados não revelaram diferenças significativas entre grupos, à excepção do genótipo da apolipoproteína E. Relativamente à totalidade dos parâmetros avaliados, o grupo DCL apresentou valores intermédios entre o grupo controlo e o grupo de doentes de Alzheimer, o que confirma que esta fase se situa entre o envelhecimento normal e a demência. A confirmação destes resultados, englobando um maior número de indivíduos e o seu acompanhamento ao longo do tempo por um período previsível de cinco anos, abrem novas perspectivas na identificação de biomarcadores da doença, que poderão ser úteis no diagnóstico e prevenção da demência de Alzheimer.Alzheimer’s Disease (AD) is the most common form of dementia in the elderly, afecting about 10% of individuals with 65 years of age, and doubling it’s incidence for every 5 years. AD is thought to be a multifactorial disease, with several factors contributing to the formation of senil plaques and neurofibrilary tangles, pathological hallmarks of the disease. Diagnose is performed by clinical examination, neuropsychological tests and brain imaging, ultimately diagnose is made by exclusion of other known forms of dementia. Mild Cognitive Impairment (MCI) is characterized by the ocorrence of subtle cognitive impairments, generaly keeping intact cognition and ordinary daily activities. Identification of a biomarker would be useful in order to allow the beginning of neuroprotective therapy as early as possible, to monitor this treatment, to relate to the progression of the disease and to identify individuals who are at risk to develop the disease. The aim of this work was to identify peripheral markers of inflammation, oxidative stress and expression levels of cell death related proteins, in order to distinguish between AD, MCI and healthy individuals. Furthermore, genetic polimorphisms were also analysed in the atempt not only to identify genetic differences between these groups, but also to identify markers of susceptibility to the disease. In addition, we also intended to find markers of conversion from an MCI condition to AD, and in order to achieve this goal, we performed a logitudinal study. Our results suggest that in AD there’s an increase in the percentage of monocytes producing pro-inflammatory cytokines, what is in accordance with a persistent inflammatory state in this pathology. Being so, monocytes, but not lymphocytes, may be considered as good biological targets in the control of the evolution from MCI to AD. Oxidative stress results showed a decrease of antioxidant defenses in our patients groups, with a clear activation of the glutathione cycle, additionaly we also found a significant increase in the levels of nitric oxide metabolites in these groups. Genetic polymorphisms screened showed no differences between groups, with the exception of ApoE genotype, as previously described. When analysing all the results from this work, it is clear that MCI’s are in between the ones from AD and the ones from healthy controls, clearly showing that this condition is probably a transition phase between healthy aging and dementia. Confirmation of these results, using a larger sample series and with a duration of approximately 5 years, will probably allow the identification of suitable biomarkers, that may be of extreme importance in diagnose and prevention of AD

Local versus foreigners´emotion-motivational responses towards traditional and non-traditional food

Rita, P., Arriaga, P., Guerreiro, J., & Moura, A. (2022). Local versus foreigners´emotion-motivational responses towards traditional and non-traditional food. Spanish Journal of Marketing - ESIC. https://doi.org/10.1108/SJME-11-2021-0213----- Paulo Rita (P.R.) and Patrícia Arriaga (P.A.) were supported by national funds through the Fundação para a Ciência e a Tecnologia; P.R. through Centro de Investigação em Gestão de Informação (MagIC/NOVA IMS) (UIDB/04152/2020); and P.A. through Centro de Investigação e Intervenção Social (Cis-Iscte) (UID/PSI/03125/2020).Purpose: The purpose of this paper was to study responses to traditional food of a country, focusing on emotion-motivational responses by locals and foreigners. Design/methodology/approach Through an experimental design study, Portuguese and Foreign participants were exposed to both traditional and nontraditional food pictures of a country and asked to evaluate their emotional and motivational responses while physiological responses of electrodermal activity were being continuously recorded. Predisposition factors of body dissatisfaction, food neophobia and food involvement were also evaluated given their potential role in predicting the responses to the visualization of the food pictures. Findings: This study found that local traditional food received a higher positive evaluation than nontraditional food with locals evaluating it even higher than foreigners. Higher feelings of arousal and desire as well as willingness to try in response to traditional food were also found as well as higher feelings of pleasure by locals. However, interestingly, and contrary to expectations derived from previous literature, emotion-motivational responses were not significantly different between locals and foreigners. Originality/value: To the best of the authors’ knowledge, this research addressed an identified research gap in the literature, being the first one evaluating the autonomic responses of consumers to traditional food by exploring how local and foreign consumers respond to traditional food versus nontraditional food using psychophysiological measures of emotion.publishersversionepub_ahead_of_prin

Cost-effectiveness of cladribine tablets versus fingolimod in patients with highly active relapsing multiple sclerosis in Portugal

© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. www.tandfonline.com/ijmeAims: To assess the cost-utility of cladribine tablets versus fingolimod in patients with highly active relapsing-remitting multiple sclerosis (RRMS) in Portugal. Methods: A 1-year cycle cohort-based Markov state transition model was developed to simulate disease progression, measured by Kurtzke Expanded Disability Status Scale (EDSS), relapses, and conversion to secondary-progressive MS (SPMS). Patients were assumed to remain on treatment until progression to EDSS level 7, conversion to SPMS, or complete loss of efficacy due to waning effect. Natural history was based on British Columbia Multiple Sclerosis registry, London Ontario database, UK MS Trust, and cladribine tablets clinical trial (CLARITY). Portuguese all-cause mortality was adjusted for the MS associated increased mortality. Clinical inputs for active treatments (disability progression and relapse rate) were estimated on a network meta-analysis. Utility weights were derived from UK-MS Survey and published literature. Resource consumption by EDSS and due to relapses was based on published literature, National DRG microdata and expert opinion. Unit costs were obtained from official sources. The analysis was conducted from payers’ perspective, time horizon of 50 years and discount rate of 5%, for both costs and benefits. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses. Results: Compared to fingolimod, cladribine tablets were associated with a delay in progression, resulting in a gain of 0.85 quality adjusted life years (QALYs) and a cost decrease of 25,935 e. Probabilistic sensitivity analysis resulted in a mean ICER of 31,781 e per QALY and was dominant in 98.7% of the simulations. Cladribine tablets were dominant across the scenario analyses tested. Conclusions: Treatment of highly active RRMS with cladribine tablets was less costly and more effective than treatment with fingolimod. Hence, it is a dominant strategy in the Portuguese setting. No conclusions can be drawn from the present study regarding other treatment options, in particular natalizumab and alemtuzumab.The study was funded by Merck S.A. Funding was independent of the study outcome. The sponsor did not participate in the design, analysis or interpretation of the data. The drafting and final version of the paper is the solely responsibility of the authors.info:eu-repo/semantics/publishedVersio

insights from an echo and cardiovascular magnetic resonance study of patients referred for surgical aortic valve replacement

AIMS: This study aims to assess the prevalence of relative apical sparing pattern (RASP) in patients with severe symptomatic aortic stenosis (AS), referred for surgical aortic valve replacement (AVR), to evaluate its significance, possible relation to amyloid deposition, and persistence after surgery. METHODS AND RESULTS: Prospective study of 150 consecutive patients [age 73 (interquartile range: 68-77), 51% women], with severe symptomatic AS referred to surgical AVR. All patients underwent cardiac magnetic resonance (CMR) before surgery. RASP was defined by [average apical longitudinal strain (LS)/(average basal LS + average mid LS)] > 1 by echocardiography. AVR was performed in 119 (79.3%) patients. Both Congo red and sodium sulphate-Alcian blue (SAB) stain were used to exclude amyloid on septal myocardial biopsy. LV remodelling and tissue characterization parameters were compared in patients with and without RASP. Deformation pattern was re-assessed at 3-6 months after AVR.RASP was present in 23 patients (15.3%). There was no suspicion of amyloid at pre-operative CMR [native T1 value 1053 ms (1025-1076 ms); extracellular volume (ECV) 28% (25-30%)]. None of the patients had amyloid deposition at histopathology. Patients with RASP had significantly higher pre-operative LV mass and increased septal wall thickness. They also had higher N-terminal pro b-type natriuretic peptide (NT-proBNP) levels [1564 (766-3318) vs. 548 (221-1440) pg/mL, P = 0.010], lower LV ejection fraction (53.7 ± 10.5 vs. 60.5 ± 10.2%, P = 0.005), and higher absolute late gadolinium enhancement (LGE) mass [9.7 (5.4-14.1) vs. 4.8 (1.9-8.6) g, P = 0.016] at CMR. Follow-up evaluation after AVR revealed RASP disappearance in all except two of the patients. CONCLUSION: RASP is not specific of cardiac amyloidosis. It may also be found in severe symptomatic AS without amyloidosis, reflecting advanced LV disease, being mostly reversible after surgery.publishersversionepub_ahead_of_prin

MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile

Funding: SJ was funded by Fundação Calouste Gulbenkian. TO was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2067/1- 390729940). AR and TC-O were funded by Fundação para a Ciência e a Tecnologia and European Regional Development Fund (CENTRO-01-0145-FEDER000012- HealthyAging2020), (POCI-010145-FEDER-007440), and (POCI-01-145-FEDER-29297). MS and MG were funded by UID/NEU/04539/2019 (Strategic Plan CNC.IBILI).Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.publishersversionpublishe

Molecular characterization of Portuguese patients with hereditary cerebellar ataxia

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.This work was funded by National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020. It was also supported in part by the FCT grant FCT-ANR/BEX-GMG/0008/2013; the Porto Neurosciences and Neurologic Disease Research Initiative at the i3S (Norte-01-0145-FEDER-000008), supported by Norte Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement, also through FEDER; and by GenomePT (POCI-01-0145-FEDER-022184). M.S. was the recipient of a fellowship (SFRH/BPD/116046/2016) and acknowledges funding from FCT through program DL 57/2016—Norma Transitória.info:eu-repo/semantics/publishedVersio

A Multiple-UAV Software Architecture for Autonomous Media Production

The use of UAVs in media production has taken off during the past few years, with increasingly more functions becoming automated. However, current solutions leave a lot to be desired with regard to autonomy and drone fleet support. This paper presents a novel, complete software architecture suited to an intelligent, multiple-UAV platform for media production/cinematography applications, covering outdoor events (e.g., sports) typically distributed over large expanses. Increased multiple drone decisional autonomy, so as to minimize production crew load, and improved multiple drone robustness/safety mechanisms (e.g., regarding communications, flight regulation compliance, crowd avoidance and emergency landing mechanisms) are supported.publishersversionpublishe

Origin of the hemoglobin S gene in a northern Brazilian population: the combined effects of slave trade and internal migrations

ABSTRACT We analyzed DNA polymorphisms in the -globin gene cluster of 30 sickle cell anemia patients from Belém, the capital city of the State of Pará, in order to investigate the origin of the S mutation. Sixty-seven percent of the S chromosomes were Bantu type, 30% were Benin type, and 3% were Senegal type. The origin of the S mutation in this population, estimated on the basis of bS-linked haplotypes, contradicts the historical records of direct slave trade from Africa to the northern region of Brazil. Historical records indicate a lower percentage of people from Benin. These discrepancies are probably due to domestic slave trade and later internal migrations, mainly from northeastern to northern regions. Haplotype distribution in Belém did not differ significantly from that observed in other Brazilian regions, although historical records indicate that most slaves from Atlantic West Africa, where the Senegal haplotype is prevalent, were destined for the northern region, whereas the northeast (Bahia, Pernambuco and Maranhão) was heavily supplied with slaves from Central West Africa, where the Benin haplotype predominates

Violência doméstica em tempos de pandemia COVID-19 em Portugal

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Mineral Interaction in Biofortified Tomatoes (Lycopersicum esculentum L.) with Magnesium

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