Repositório RCAAP

Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.

Contemporary sculpture, as a form of public art, has been a protagonist in urban regeneration and requalification projects, playing an active role in the experience provided by cities to their inhabitants, since the latter half of the 20th century. The new relationship established between sculpture and urban space, together with the recognition of its particularities as important aspects that contaminate and inform artistic production, has been gradually shaping a new cultural and aesthetic context within which we fit sculpture parks. In this dissertation, we intend not only to frame the emergence of the first sculpture parks located in public space, but also to reflect on the main characteristics of these exhibitional structures and the challenges they pose for both programmers and curators, during the process of planning, implementation and maintenance; and for artists, throughout the sculpture design process. Along with a reflection on the key concepts that structure the investigation, we developed a critical analysis of three portuguese sculpture parks - the International Museum of Contemporary Sculpture of Santo Tirso, the International Sculpture Park of Carrazeda de Ansiães and the Contemporary Sculpture Park from Vila Nova da Barquinha –, revisiting the history of their creation and ruminating on the impact they have on the urban centers in which they are located. Consequently, six sculptures that are integrated within these parks were selected to be objects of a deeper analysis in order to clarify the way in which these works are born and projected within the places they are inserted - unraveling the dialogue established between them, on a physical and symbolic level - and determining to what extent they exist as participating entities in their daily life, promoting the construction of new narratives and interpretations about the city space.

Introduction: About one-third of patients with epilepsy have a refractory form which is associated with important economic and psychosocial burden. Most of these patients also suffer from comorbidities. One of the most frequent is cognitive impairment. Resective surgery or neuromodulation techniques may improve seizure control. Several factors have been proposed as potential predictors of the success of surgery regarding seizure frequency. We aimed to study preoperative cognitive performance as a predictor of the epilepsy surgery outcome. Methods: In this ambispective study we studied total intelligence quotients (IQ) measured before surgery with the Wechsler Adult Intelligence Scale (WAIS) as a potential predictor of Engel Class at 1 year after surgery. Then we included IQ in a multivariate model and tested its performance. Results: Preoperative IQ was a significant and independent predictor of the Engel Class at 1 year after surgery (OR 0.94; CI 0.90-0.98; p = 0.007). The multivariate model including the age at epilepsy onset, education level, sex, and the type of surgery (resective versus palliative surgery) showed an area under the ROC curve of 0.85. Conclusions: A low intelligence level may constitute a marker of worse prognosis after epilepsy surgery. However, other predictors should also be considered when evaluating surgical candidates.

The congeneric freshwater fish Squalius carolitertii and S. torgalensis inhabit different Iberian regions with distinct climates; Atlantic in the North and Mediterranean in the South, respectively. While northern regions present mild temperatures, fish in southern regions often experience harsh temperatures and droughts. Previous work with two hsp70 genes suggested that S. torgalensis is better adapted to harsher thermal conditions than S. carolitertii as a result of the different environmental conditions. We present a transcriptomic characterisation of these species' thermal stress responses. Through differential gene expression analysis of the recently available transcriptomes of these two endemic fish species, comprising 12 RNA-seq libraries from three tissues (skeletal muscle, liver and fins) of fish exposed to control (18 °C) and test (30 °C) conditions, we intend to lay the foundations for further studies on the effects of temperature given predicted climate changes. Results showed that S. carolitertii had more upregulated genes, many of which are involved in transcription regulation, whereas S. torgalensis had more downregulated genes, particularly those responsible for cell division and growth. However, both species displayed increased gene expression of many hsps genes, suggesting that they are able to deal with protein damage caused by heat, though with a greater response in S. torgalensis. Together, our results suggest that S. torgalensis may have an energy saving strategy during short periods of high temperatures, re-allocating resources from growth to stress response mechanisms. In contrast, S. carolitertii regulates its metabolism by increasing the expression of genes involved in transcription and promoting the stress response, probably to maintain homoeostasis. Additionally, we indicate a set of potential target genes for further studies that may be particularly suited to monitoring the responses of Cyprinidae to changing temperatures, particularly for species living in similar conditions in the Mediterranean Peninsulas.

Despite great efforts to enhance European epidemiological surveillance on carbapenemase-producing Enterobacteriaceae (CPE), information from several countries remains scarce. To address CPE epidemiology in Portugal, we have undertaken a retrospective cohort study of adults with CPE cultures identified in the microbiology laboratory of a tertiary hospital, in 2012. Sixty patients from 25 wards or intensive care units were identified. This is, to the best of our knowledge, the first report of clinical data on CPE in Portugal. It shows a hospital-wide CPE dissemination and alerts us to an evolving epidemiological situation not previously described.

There are multiple stages in the life cycle of Plasmodium that invade host cells. Molecular machinery involved is such host-pathogen interactions constitute excellent drug targets and/or vaccine candidates. A screen using a phage display library has previously demonstrated presence of enolase on the surface of the Plasmodium ookinete. Phage-displayed peptides that bound to the ookinete contained a conserved motif (PWWP) in their sequence. Here, direct binding of these peptides with recombinant Plasmodium falciparum enolase (rPfeno) was investigated. These peptides showed specific binding to rPfeno, but failed to bind to other enolases. Plasmodium spp enolases are distinct in having an insert of five amino acids ((104)EWGWS(108)) that is not found in host enolases. The possibility of this insert being the recognition motif for the PWWP containing peptides was examined, (i) by comparing the binding of the peptides with rPfeno and a deletion variant Δ-rPfeno lacking (104)EWGWS(108), (ii) by measuring the changes in proton chemical shifts of PWWP peptides on binding to different enolases and (iii) by inter-molecular docking experiment to locate the peptide binding site. Results from these studies showed that the pentapeptide insert of Pfeno indeed constitutes the binding site for the PWWP domain containing peptide ligands. Search for sequences homologous to phage displayed peptides among peritrophic matrix proteins resulted in identification of perlecan, laminin, peritrophin and spacran. The possibility of these PWWP domain-containing proteins in the peritrophic matrix of insect gut to interact with ookinete cell surface enolase and facilitate the invasion of mosquito midgut epithelium is discussed.

Global greenhouse gas (GHG) emissions have continued to grow persistently since 1750. The United Nations Framework Convention on Climate Change (UNFCCC) entered into force in 1994 to stabilize GHG emissions. Since then, the increasingly harmful impacts of global climate change and repeated scientific warnings about future risks have not been enough to change the emissions trend and enforce policy actions. This paper synthesizes the climate change challenges and the insofar insufficient mitigation responses via an integrated literature review. The fossil industry, mainstream economic thinking, national rather than international interests, and political strive for short-term interests present key barriers to climate mitigation. A continuation of such trends is reflected in the Dice model, leading to a 3.5 °C temperature increase by 2100. Despite receiving the Nobel Prize for integrating climate change into long-run macroeconomic analysis via the Dice model, increases in global mean temperatures overshooting the 1.5 °C to 2 °C Paris targets imply an intensified disruption in the human–climate system. Past and present policy delays and climate disruption pave the way for solar radiation management (SRM) geoengineering solutions with largely unknown and potentially dangerous side effects. This paper argues against SRM geoengineering and evaluates critical mitigation solutions leading to a decrease in global temperatures without overshooting the Paris targets. The essential drivers and barriers are discussed through a unified approach to tipping points in the human–climate system. The scientific literature presents many economically and technologically viable solutions and the policy and measures required to implement them. The present paper identifies the main barriers to integrating them in a globally cooperative way, presenting an efficient, long-term, and ethical policy approach to climate change.

Long-term global emission scenarios enable the analysis of future climate change, impacts, and response strategies by providing insight into possible future developments and linking these different climate research elements. Such scenarios play a crucial role in the climate change literature informing the Intergovernmental Panel on Climate Change’s (IPCC) Assessment Reports (ARs) and support policymakers. This article reviews the evolution of emission scenarios, since 1990, by focusing on scenario critiques and responses as published in the literature. We focus on the issues raised in the critiques and the possible impact on scenario development. The critique (280) focuses on four areas: 1) key scenario assumptions (40%), 2) the emissions range covered by the scenarios and missing scenarios (25%), 3) methodological issues (24%), and 4) the policy relevance and handling of uncertainty (11%). Scenario critiques have become increasingly influential since 2000. Some areas of critique have decreased or become less prominent (probability, development process, convergence assumptions, and economic metrics). Other areas have become more dominant over time (e.g., policy relevance & implications of scenarios, transparency, Negative Emissions Technologies (NETs) assumptions, missing scenarios). Several changes have been made in developing scenarios and their content that respond to the critique.

Replicative stress (RS) is a cell-intrinsic phenomenon enhanced by oncogenic transformation. Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. Taking this knowledge into account, one would predict CHK1 behaves strictly as a tumor suppressor. However, the reality seems far more complex. CHEK1 loss-of-function mutations have not been found in human tumors, and transgenic expression of Chek1 in mice promotes oncogene-induced transformation through RS inhibition. Moreover, CHK1 is overexpressed in various human cancers and CHK1 inhibitors have been developed as sensitizers to enhance the cytotoxicity of DNA damage-inducing chemotherapies. Here, we summarize the literature on the involvement of CHK1 in cancer progression, including our recent observation that CHK1 sustains T-cell acute lymphoblastic leukemia (T-ALL) cell viability. We also debate the importance of identifying patients that could benefit the most from treatment with CHK1 inhibitors, taking T-ALL as a model, and propose possible markers of therapeutic response.

Objective: Assistive devices based on keyboard access support communication and control tools for patients with Amyotrophic Lateral Sclerosis (ALS). The aim of this work was to explore movement activity in the use of keyboards and identify markers for upper limb (UL) dysfunction. Methods: We present a longitudinal study including 19 ALS patients, followed for 2-20 months. Typing activity was recorded with an accelerometer placed on the posterior part of patients' index finger. Participants performed the same 10-word typing task (2-6 assessments). Time and acceleration during keystroke were the main outcomes of this study. Patients were compared with 20 healthy subjects and 6 patients with other neuromuscular disorders. Results: During disease progression, mean time in holding down a key increased and was longer than in control subjects. Acceleration at key press and key release decreased with progression of UL dysfunction. Delay between tapping and pressing down each key increased with UL dysfunction. Conclusions: Delay in pressing and releasing keys are markers of UL dysfunction in ALS. The decrease in the acceleration of movements related to keystroke can contribute to monitor disease progression. Significance: Typing activity can be explored to access remotely and continuously to ALS progression by patients who use assistive communication devices.

A emigração macaense, entre as décadas de 1840 e 1950, elegeu dois territórios para destino de todos os que decidiram deixar Macau, principalmente a partir de 1842: Hong Kong e Xangai. O desfecho da I Guerra do Ópio (1839-1842) conduziu a profundas mudanças políticas, económicas e sociais em toda a Ásia Oriental e, em particular na China imperial. Em Macau, a saída das principais casas de comércio teve um forte impacte social, atingindo ainda uma maior dimensão se considerarmos que a emigração foi a resposta encontrada pela comunidade macaense às transformações económicas e sociais que ocorreram na cidade. A abertura ao comércio internacional catapultou Xangai para a liderança das cidades chinesas e atraiu ao seu porto, todos os anos, milhares de migrantes das mais variadas origens nacionais e culturais, entre os quais se encontravam os macaenses. Entre Macau e Xangai iniciou-se um importante fluxo migratório que deu origem à comunidade dos “portugueses de Xangai”. Herdeiros do passado migratório que esteve na origem da comunidade macaense ao longo de muitas décadas, os “portugueses de Xangai” acompanharam, dia a dia, o processo de formação, desenvolvimento e extinção das concessões estrangeiras, revelando estratégias que favoreceram a sua integração na sociedade que os acolheu sem, todavia, perderem os seus laços com Macau, o seu território de origem.

Objective: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation. Methods: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility. Results: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure. Conclusion: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice.

Objective: To evaluate the correlation between diaphragm thickness assessed by ultrasound (US) with respiratory function tests and the diaphragm motor responses, in patients with amyotrophic lateral sclerosis (ALS). Methods: 42 consecutive ALS patients were studied (11 with bulbar-onset), excluding patients with marked orofacial paresis. Investigation included: revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), maximal voluntary ventilation (MVV), maximal inspiratory (MIP) and expiratory (MEP) pressures, nasal inspiratory pressure during sniff (SNIP); peak-to-peak amplitude of the diaphragmatic motor response to phrenic nerve stimulation (Diaphragm-CMAP), diaphragmatic thickness measured by ultrasound during maximal inspiration and during maximal expiration. Patients were analysed in bulbar or spinal subgroups. Correlations and multiple linear regression models were studied. Results: The mean age at disease onset was 58.4 ± 11.1 years and with a mean disease duration of 17.8 ± 13.6 months. Ultrasound studies of diaphragm thickness in full inspiration correlated with diaphragm CMAP in the whole population and in spinal-onset patients; and were similar in the two groups. Multiple linear modelling showed that FVC, SNIP and MVV were dependent on the change of thickness (p=0.001, 0.001 and 0.020, respectively) and that MIP and MEP were related to diaphragm CMAP p=0.003 and p=0.025, respectively). Conclusion: Diaphragm thickness correlates with Diaphragm-CMAP, except in bulbar-onset patients. Respiratory tests are dependent on both diaphragm thickness and Diaphragm-CMAP. Significance: US thickness of the diaphragm correlates with the number of functional motor units as assessed by the phrenic nerve motor amplitude.

The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. We report a 71-year-old man who developed hemorrhagic bullae at sites distant from subcutaneous enoxaparin injections. It is important that clinicians be aware of the different adverse reactions of these widely used drugs.

Objective: Fasciculations are occasionally observed in root lesions, but their site of origin is uncertain. Methods: We studied the origin of fasciculations (FPs) in consecutive patients with mild chronic L5 root lesions, excluding peripheral nerve lesion. We used a novel technique of double-EMG needle recording, in which each needle was placed in the territory of separate motor units. With this technique the observation of synchronous FPs implies an origin proximal to distal axonal branching. Results: FPs were found in 13% of 84 consecutive patients with mild chronic L5 root lesions. In 25% they were synchronous in different motor units. Conclusions: We suggest that in mild L5 root lesions most FPs have an origin at distal branches but some FPs originate proximally (25%), possibly at the site of nerve compression. Significance: The proximal site of compression and more distal sites may both initiate fasciculation potentials in proximal root lesions.

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.

Introduction: Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods: 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results: RANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion: In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.

Objective: To postulate a new possible cause of a unilaterally reduced arm swing in addition to the known medical conditions such as shoulder pathology, Erb's palsy, stroke, and Parkinson's disease. Methods: Analysis of YouTube videos depicting the gait of highly ranked Russian officials. Results: We found a similar walking pattern in President Vladimir Putin, Prime Minister Dmitry Medvedev and three other highly ranked Russian officials, all presenting with a consistently reduced right arm swing in the absence of other overt neurological abnormalities. Conclusions: We propose that this new gait pattern, which we term "gunslinger's gait," may result from a behavioural adaptation, possibly triggered by KGB or other forms of weapons training where trainees are taught to keep their right hand close to the chest while walking, allowing them to quickly draw a gun when faced with a foe. This should be included in the differential diagnosis of a unilaterally reduced arm swing.

Background: Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need. We have shown, in vitro, that celastrol inhibits both IL-1β and TNF, which play an important role in RA, and, in vivo, that celastrol has significant anti-inflammatory properties. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA). Methods: Celastrol was administered to AIA rats both in the early (4 days after disease induction) and late (11 days after disease induction) phases of arthritis development. The inflammatory score, ankle perimeter and body weight were evaluated during treatment period. Rats were sacrificed after 22 days of disease progression and blood, internal organs and paw samples were collected for toxicological blood parameters and serum proinflammatory cytokine quantification, as well as histopathological and immunohistochemical evaluation, respectively. Results: Here we report that celastrol significantly decreases the number of sublining CD68 macrophages and the overall synovial inflammatory cellularity, and halted joint destruction without side effects. Conclusions: Our results validate celastrol as a promising compound for the treatment of arthritis.

Amyotrophic lateral sclerosis (ALS) is a dreadful degenerative disorder, characterized by rapidly progressing weakness causing respiratory impairment and death, in spite of moderate benefits from non-invasive ventilation, gastrostomy, riluzole treatment and multidisciplinary care (Andersen et al., 2012). Over the years a large of number of drugs have been tested to deal with this disorder, but all trials have been negative except for riluzole. We can observe that different strategies have been explored in the past, from immunosuppression to neuroprotection, from nerve growth factors to antiglutamatergic compounds (de Carvalho et al., 2005). Threshold tracking has been used to investigate axonal excitability in peripheral nerve motor axons in ALS (Vucic and Kiernan, 2006). Increased persistent Na+ conductance and reduced K+ conductance have been described (Vucic and Kiernan, 2006), which tend to become more marked with disease duration and may be a predictor of survival (Cheah et al., 2012). More recently, it has been suggested that motor neurons have an abnormal function of the membrane ion channels, in ALS (Devlin et al., 2015). These observations have opened a new window of opportunity in clinical trials for ALS, for testing drugs that modulate ion channels in order to stabilize membranes.