Repositório RCAAP

Introduction: Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP. Areas covered: A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders. Expert opinion: Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP. The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.

With the coronavirus disease of 2019 (COVID-19) becoming a full-blown outbreak in Africa, coupled with many other challenges faced on the African continent, it is apparent that Africa continues to need diagnostics to enable case identification and recovery to this and future challenges. With the slow vaccination rates across the continent, reliable diagnostic tests will be in demand, likely for years to come. Thus, access to reliable diagnostic tools to detect the severe acute respiratory syndrome of the coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, remain a critical pillar to monitor and contain new waves of COVID-19. Increasing the local capacity to manufacture and roll-out vaccines and decentralized COVID-19 testing are paramount for fighting the pandemic in Africa.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are safe procedures that may present sub-optimal results in superobesity (SO). A meta-analysis was performed aiming to summarize the available evidence on weight loss (primary outcome) and comorbidities resolution of LRYGB and LSG in patients with SO (BMI ≥ 50 kg/m2). From the 16 included studies, 7 integrated the meta-analysis. LRYGB showed a significantly higher weight loss at 6 to 12-months, but not after 24 months and a higher dyslipidemia resolution at 12 months. When compared with LSG, LRYGB achieved better weight loss after 6 and 12 months and higher dyslipidemia resolution after 1 year. There were no significant differences for resolution of the other co-morbidities studied.

The data presented here capture the structure of kitchen lay- outs belonging to consumers vulnerable to foodborne dis- eases and food risk-takers. Data were collected in the frame of the SafeConsume project by multidisciplinary research teams that visited consumers during preparing a meal and had the possibility to examine their cooking routines. Dis- tances between sink and stove, sink and refrigerator, stove and refrigerator, sink and working place (countertop or ta- ble), stove and working place were analyzed to correlate food safety practices applied during cooking with kitchen arrange- ments. The results arising from analyzing the ergonomics of kitchens versus potential cross-contamination events are presented in Mihalache et al., [1]. These data contribute to a better understanding of real kitchen layouts and can be used as a starting point for future research regarding food safety-oriented arrangements instead of ergonomics-focused designs, for food safety risk assessments, as study cases for explaining specific measures that can be established to im- prove food handling and hygiene practices in homes and for sociological research pointing consumers’ behavior during cooking.

Estudos anteriores demonstraram que os complexos organometálicos de molibdénio (II) possuem boas actividades anti-tumorais. Assim, sintetizaram-se novos complexos, de forma a expandir a gama de compostos com estas características, e realizar experiências mais esclarecedoras. A maioria dos complexos estudados apresentou actividades anti-tumorais interessantes. Foram feitos testes de inibição de crescimento para 8 compostos (A, B, C, D, E, F, G e H) em três linhas celulares: HeLa (linha celular derivada do cancro cervical humano), MCF-7 (linha celular derivada do cancro mamário humano) e N1E-115 (neuroblastoma derivado de rato, células não diferenciadas e diferenciadas). As células foram incubadas com os compostos numa gama de concentrações (1 a 1000 μM) durante 48 horas. O efeito antiproliferativo foi medido pelo ensaio do MTT. Os valores de IC50 obtidos para os diferentes compostos, variaram entre 2,1 e 458,6 μM, apresentando diferenças entre as linhas celulares. Estudou-se igualmente a estabilidade dos compostos durante o tempo de incubação, e concluiu-se que os compostos B e E mantêm a sua estrutura. Para avaliar a possibilidade de intercalação dos compostos com a molécula de DNA, efectuaram-se estudos espectrofotométricos e determinou-se a viscosidade de soluções de DNA com diferentes concentrações de compostos. Os resultados obtidos parecem indicar que os compostos B, G e H são intercaladores. Finalmente, os estudos biológicos, mostraram que existe degradação do DNA das células incubadas com os compostos. Embora a análise morfológica e a citometria de fluxo permitissem identificar células em apoptose, esta não foi detectada por electroforese. Por citometria de fluxo foi também possível detectar o aumento de espécies reactivas de oxigénio nas células incubadas com os compostos em estudo. Os mecanismos de acção dos compostos parecem assim envolver a indução de apoptose e a produção de espécies reactivas de oxigénio, contudo os estudos realizados não permitiram esclarecer a relevância de cada um destes processos.

In recent decades, knowledge regarding stroke pathophysiology has greatly increased. Information regarding mechanism and pathogenesis of brain ischemia derived from basic, translational, and clinical studies has allowed the design of randomized clinical trials (RCTs) that by using advanced brain imaging methods evaluated the role of individual patterns of penumbra and perfusion in the extension of therapeutic windows for reperfusion treatments. The results of these RCTs successfully allowed the number of patients who receive acute stroke treatment to be increased.

The SARS-CoV-2 pandemic is a global public health crisis, with significant morbidity, mortality and socio-economical impacts. Vaccines were developed and granted emergency approvals by most drug agencies to tackle this crisis, but the safety profile of these vaccines is not fully clarified. We present a series of four cases of varicella zoster virus (VZV) reactivation after vaccination against SARS-CoV-2, who presented at the Dermatology Department, Centro Hospitalar Universitário Lisboa Norte, Lisbon (Portugal), from 30 January 2021 to 30 April 2021.

We describe maleic-acid derivatives as robust cysteine-selective reagents for protein labelling with comparable kinetics and superior stability relative to maleimides. Diamide and amido-ester derivatives proved to be efficient protein-labelling species with a common mechanism in which a spontaneous cyclization occurs upon addition to cysteine. Introduction of chlorine atoms in their structures triggers ring hydrolysis or further conjugation with adjacent residues, which results in conjugates that are completely resistant to retro-Michael reactions in the presence of biological thiols and human plasma. By controlling the microenvironment of the reactive site, we can control selectivity towards the hydrolytic pathway, forming homogeneous conjugates. The method is applicable to several scaffolds and enables conjugation of different payloads. The synthetic accessibility of these reagents and the mild conditions required for fast and complete conjugation together with the superior stability of the conjugates make this strategy an important alternative to maleimides in bioconjugation.

Dry microwave imaging (MWI) systems are more practical, hygienic, and fast to operate since they do not require immersion liquid. However, the dielectric contrast between air and the part of the body under examination is larger, causing larger refraction effects. Including refraction in the image reconstruction algorithm significantly increases the computational effort, especially when imaging nonuniform shapes. Hence, our systematic study aims to evaluate the impact of neglecting refraction effects on MWI by using quantitative metrics and define objective guidelines that are lacking in the literature. We perform comparative studies with a spherical numerical phantom (which is typically used to represent simplified breast or head phantoms) by varying the phantom relative permittivity values between 4 and 40, metallic targets diameter between 5 and 15 mm, and the number of probing antennas. Additionally, the refraction effects are evaluated with anthropomorphic body phantoms representing a breast and the axillary region. We numerically and experimentally show that refraction tends to have a greater impact on imaging results when phantom relative permittivity values exceed 8, while it has a minor effect in the remaining tested cases. This favors potential fast real-time image reconstruction. This letter provides useful criteria to decide whether refraction should be considered or not for imaging reconstruction when developing new dry medical MWI setups.

Although Higher Education Institutions (HEIs) develop and announce actions related to sustainable development (SD), these actions and the results achieved are often not perceived by their stakeholders. This article aims to analyse how the SD of HEIs can contribute to better development and regional transformation, through the promotion of sustainable practices with effects on the regional environment. To do so, an exploratory quantitative analysis, with a sample of 1325 stakeholders collected from seven Portuguese public HEIs, using a multinomial logistic regression, was carried out. The results indicate that HEIs’ stakeholders pay attention to sustainability practices, and that regional development and the sustainability of the region of influence can emerge positively from the links found between these two variables and the dimensions of SD in the HEIs studied. The contributions and implications of these results can be seen from the perspective of HEIs, because it shows that both students and lecturers/researchers are aware of and value this type of practice by the institution, and HEIs must create strategies integrating stakeholders more actively in sustainable practices through the development of sustainable skills and competences, and from the regional policy perspective, given the potential and importance of HEIs as integrated actors within their region of influence.

O Capital, corresponde a projeto de investigação iniciado em 2016 sob a designação de Dinheiro, com uma primeira exposição no ISEG, Instituto Superior de Economia e Gestão, na qual participaram dez artistas. Posteriormente foi para Múrcia, Espanha, onde se realizaram cinco exposições com a participação de mais vinte artistas, tendo sido apresentada em diversos espaços expositivos: Universidad Popular de Mazarrón, Museo de Archena, Museo Universidad de Murcia, Universidad Politecnica de Cartagena. Agora, em 2021, na Biblioteca da NOVA School of Science and Technology, em Almada, reúnem-se obras de vinte e cinco artistas numa exposição sucessivamente adiada desde fevereiro de 2020 pelos motivos universalmente conhecidos (SARS-CoV-2) com um título que apela a uma conclusão, o Capital.

We compared the performance of 31 non-demented Parkinson's disease (PD) patients to 61 healthy controls in an action verbal fluency task. Semantic and phonemic fluencies, cognitive impairment and behavioural dysfunction were also assessed. The mean disease duration of PD was 9.8 years (standard deviation (SD) = 6.13). There were no age (U = 899.5, p = 0.616), gender(chi-square = 0.00, p = 1.00) or literacy (U = 956, p = 0.96) differences between the two groups. A significant difference was observed between the two groups in the action verbal fluency task (U = 406.5, p < 0.01) that was not found in the other fluency tasks. The education level was the only biographical variable that influenced the action (verb) fluency outcomes, irrespective of disease duration. Our findings suggest a correlation between the disease mechanisms in PD and a specific verb deficit, support the validity of the action (verb) fluency as an executive function measure and suggest that this task provides unique information not captured with traditional executive function tasks.

We present a 48 year-old female patient with a previous history of Tetralogy of Fallot submitted to surgical repair at 18 years old. Recent echocardiograms were remarkable for the absence of residual interventricular communication, a good left ventricular systolic function without regional wall motion abnormalities, and a moderate pulmonary regurgitation.

Alguns estudos demonstram que mesmo não conhecendo nada relativo às Nanotencologias, as pessoas conseguem fazer inferências e julgamentos que são consistentes entre várias pessoas (Palma-Oliveira, Gaspar-Carvalho, Luis & Vieira, 2009). Existem várias explicações propostas para essas evidências, como é o caso da Abordagem Cognitivo-Ecológica, na qual a nova informação é julgada conforme o contexto que lhe está associado em memória (Gaspar, Carvalho, Soeiro, & Palma-Oliveira, under review) e a constação de que o afecto, enquanto tipo de avaliação, é um preditor universal nestes contextos desconhecidos (Gaspar et al., under review). É objectivo da presente investigação, continuar nesta linha de estudo, tentando detalhar quais os mecanismos de percepção de risco das tencologias, mais concretamente da Nanotencologia. Para isso, vão ser apronfundados e testados os mecanismos psicossociais mais básicos, como o é exemplo o afecto e qual o seu papel na Percepção de Risco, partindo para isso através do estudo de Gaspar e colaboradores (under review). Na experiência realizada neste estudo espera-se que o afecto seja componente mais automática e acessível do que a componente descritiva do mesmo objecto de atitude, e isto significa que as respostas às perguntas com esta conotação têm uma latência menor, como não são interferidas por uma tarefa de sobrecarga cognitiva, bem como se espera que o afecto tenha alguma função de monitorização no julgamento descritivo, tornando-o mais rápido. Para o efeito foi utilizado o questionário “Nanotecnologia e Sociedade” (Gaspar et al., under review) uma tarefa de sobrecarga cognitva que constava em gravações com descrições de países e a medida dependente era a rapidez de resposta. Os resultados demonstram que, ao contrário do previsto, a componente descritiva é sempre mais acessível que a componente afectiva, mas que, de acordo com as hipóteses, torna mais acessível a componente descritiva, enquanto o contrário não se verifica. O afecto tem se demonstrado como preditor fundamental do risco e permite explicar evidências que antes eram atribuidas a outras heurísticas (Slovic, Finucane, Peters, & MacGregor, 2004), bem como permite evidenciar o papel do medo e da preocupação na Percepção de Risco (e.g., Breackwell, 2007).

Perante a circunstância de uma sociedade que se vê incapacitada de cumprir as suas obrigações fiscais é usual seguir-se a cobrança coerciva das mesmas, em sede de processo executivo. Na instância executiva, várias são as vicissitudes que podem ocorrer, sendo uma delas a sociedade revelar inexistência ou insuficiência patrimonial para liquidar as dívidas a pagamento. É neste momento que poderá ser visado o administrador/gerente da sociedade, que responderá através do seu património pessoal, por ação do mecanismo de reversão fiscal, que tem como fundamento, por exemplo, o princípio da eficácia processual, mas também apresenta os seus traços menos favoráveis. Quem poderá ser o administrador/gerente é uma questão sobre a qual nos debruçaremos, devido às diferentes interpretações suscitadas pelo artigo 24.º, n. 1 da LGT, especialmente no que toca ao conceito de administrador de facto. Esta sua responsabilidade será efetivada, se for possível avaliar que por culpa do administrador/gerente o património da sociedade se tornou insuficiente para liquidação da dívida, nos termos do artigo 24.º, n.1 al. a) e b) da LGT. No caso de existir mais do que um administrador/gerente da mesma sociedade, a sua responsabilidade será solidária, nos termos da parte final do preceito referido. Neste âmbito, várias questões se podem colocar, uma vez que constitui um regime potencialmente gravoso para o único administrador/gerente demandado. Também merece, neste contexto, a referência à problematização do direito de regresso, que vemos ser uma questão controvertida devido ao facto de constituir um regime que se mostra passível de manter o administrador/gerente que liquidou a dívida numa situação de incerteza jurídica, que tem efeitos perniciosos diretos na sua situação patrimonial. A terminar o nosso trabalho tentaremos verificar se a solução jurídica para os problemas identificados é adequada e se poderemos sugerir uma outra, ainda que no plano de iure condendo.

Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disorder that mainly targets the joints. Several lines of evidence have pointed to B cell function as a critical factor in the development of RA. B cells play several roles in the pathogenesis of RA, such as autoantibody production, antigen presentation and T cell activation, cytokine release, and ectopic lymphoid organogenesis. The success of B cell depletion therapy in RA further supports the relevance of these cells in RA progression. In addition, recent studies have also highlighted the B cell role in the first weeks of RA onset. The present article is a review focused in the immunopathogenic B cell-dependent mechanisms associated with RA development and chronicity and the importance of the recent discoveries documented in untreated very early RA patients with less than 6 weeks of disease duration.

O Direito Penal e o Direito Processual Penal são cada vez mais confrontados com os desafios que advêm de uma sociedade global. À estrutura hierarquizada e à opacidade do modus operandi que caracterizam as organizações criminosas soma-se a influência que é exercida e consolidada nos mais diversos domínios da sociedade. Por estas razões, o recurso a métodos ocultos de investigação criminal afigura-se como necessário, estando a sua utilização sujeita a apertadas exigências constitucionais invariavelmente reflectidas nos regimes legislativos que os consagram e que obrigam a uma harmonização constante entre a necessidade de administrar a justiça e as garantias de defesa dos arguidos. É neste contexto que se move o agente encoberto cuja consagração foi antecedida da utilização de agentes provocadores, nos dias de hoje reconduzidos a métodos proibidos. Uma vez estabelecida a provocação, distinguindo-a do ardil tolerável e próprio do método em causa, há que apurar as consequências jurídico-probatórias. Com efeito, as provas imediata e mediatamente obtidas estarão sujeitas a um regime próprio, com fundamento constitucional, que tem por efeito torná-las inutilizáveis, através de uma proibição de valoração. Esta proibição terá ainda efeito sobre as provas obtidas mediatamente. Este efeito, designado por efeito-à-distancia, é inabalável a qualquer uma das excepções e soluções compromissórias que têm sido reconhecidas e importadas para o ordenamento jurídico português. Resposta diferente é dada para as situações em que a prova mediata resulta de um acto de vontade esclarecido e livre do arguido ou da existência de um processo autónomo e efectivo.

Specific inhibition of signaling elements essential for the viability of B-cell chronic lymphocytic leukemia (CLL) cells offers great promise for the design of more efficient therapies. The protein serine/threonine kinase CK2 is frequently upregulated in cancer, and it is overexpressed and hyperactivated in primary CLL cells from untreated patients. We have shown that inhibition of CK2 induces apoptosis of CLL cells, whereas it does not significantly impact normal lymphocytes, demonstrating the selectivity of the CK2 inhibitors toward leukemia cells. Notably, although co-culture with OP9 stromal cells and BCR stimulation both promote leukemia cell survival in vitro, they do not prevent apoptosis of CLL cells treated with CK2 inhibitors. PI3K signaling pathway was previously shown to be essential for CLL cell viability, an observation we confirmed in all patient samples analyzed. Further, we observed that CK2 blockade decreases PTEN phosphorylation, leading to PTEN activation, and that apoptosis of CLL cells upon CK2 inhibition is mediated by PKC inactivation. This suggests that activation of PI3K/PKC signaling pathway is involved in the pro-survival effects of CK2 in CLL cells. Sensitivity to CK2 inhibition does not correlate with expression of ZAP-70 or CD38, or with IGVH mutation status. However, it positively correlates with the percentage of CLL cells in the peripheral blood, β2 microglobulin levels, and Binet clinical stage. CK2 appears to play an important role in the biology of CLL and constitutes a promising target for the development of leukemia-specific therapies.

Protein misfolding and aggregation are central events in many disorders including several neurodegenerative diseases. This suggests that alterations in normal protein homeostasis may contribute to pathogenesis, but the exact molecular mechanisms involved are still poorly understood. The budding yeast Saccharomyces cerevisiae is one of the model systems of choice for studies in molecular medicine. Modeling human neurodegenerative diseases in this simple organism has already shown the incredible power of yeast to unravel the complex mechanisms and pathways underlying these pathologies. Indeed, this work has led to the identification of several potential therapeutic targets and drugs for many diseases, including the neurodegenerative diseases. Several features associated with these diseases, such as formation of protein aggregates, cellular toxicity mediated by misfolded proteins, oxidative stress and hallmarks of apoptosis have been faithfully recapitulated in yeast, enabling researchers to take advantage of this powerful model to rapidly perform genetic and compound screens with the aim of identifying novel candidate therapeutic targets and drugs. Here we review the work undertaken to model human brain disorders in yeast, and how these models provide insight into novel therapeutic approaches for these diseases.

In the last decades there was a surge of research on serum haematological, biochemical and immunological biomarkers in stroke, which unfortunately has not yet translated into clinical practice. Serum biomarkers can theoretically be useful for the diagnosis, prognosis, and understanding of the pathophysiology and eventually for the selection of treatments in stroke care. Ideally a biomarker or a set of biomarkers can identify a stroke, in the prehospital setting, prior to neuroimaging, similarly to what is done for myocardial infarction. Several other molecules can be useful biomarkers of recanalization and reperfusion, of opening of collaterals, of the several steps of the ischemic cascade and of the early neuroinflammatory and neuroregenerative response. Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management.