Publications by authors named "Filipa Ribeiro"

45 Publications

Are Video Games Effective to Promote Cognition and Everyday Functional Capacity in Mild Cognitive Impairment/Dementia Patients? A Meta-Analysis of Randomized Controlled Trials.

J Alzheimers Dis 2021 Sep 16. Epub 2021 Sep 16.

LASIGE, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.

Background: Mild cognitive impairment (MCI) and dementia are associated with increased age. MCI is a clinical entity described as a transitional state between normal cognition and dementia. Video games (VGs) can potentially promote cognition and functional capacity since multiple cognitive domains are recruited during gameplay. However, there is still a lack of consensus regarding the efficacy of VGs as therapeutic tools, particularly in neurodegenerative diseases.

Objective: We aimed to analyze the impact of VGs on cognition and functional capacity outcomes in MCI/dementia patients.

Methods: We conducted a systematic review and meta-analysis study (PROSPERO [CRD42021229445]). PubMed, Web of Science, Epistemonikos, CENTRAL, and EBSCO electronic databases were searched for RCT (2000-2021) that analyzed the impact of VGs on cognitive and functional capacity outcomes in MCI/dementia patients.

Results: Nine studies were included (n = 409 participants), and Risk of Bias (RoB2) and quality of evidence (GRADE) were assessed. Data regarding attention, memory/learning, visual working memory, executive functions, general cognition, functional capacity, quality of life were identified, and pooled analyses were conducted. An effect favoring VGs interventions was observed on Mini-Mental State Examination (MMSE) score (MD = 1.64, 95%CI 0.60 to 2.69).

Conclusion: Although promising, the effects observed should be interpreted with caution since serious methodological shortcomings were identified in the studies included. Nonetheless, the effect observed is higher than the minimum clinically important difference (1.4 points) established to MMSE. Future studies on the current topic urge. Recommendations for the design and conduction of cognitive RCT studies are presented.
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http://dx.doi.org/10.3233/JAD-210545DOI Listing
September 2021

Intervention of Brain-Derived Neurotrophic Factor and Other Neurotrophins in Adult Neurogenesis.

Adv Exp Med Biol 2021 ;1331:95-115

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Cell survival during adult neurogenesis and the modulation of each step, namely, proliferation, lineage differentiation, migration, maturation, and functional integration of the newborn cells into the existing circuitry, is regulated by intrinsic and extrinsic factors. Transduction of extracellular niche signals triggers the activation of intracellular mechanisms that regulate adult neurogenesis by affecting gene expression. While the intrinsic factors include transcription factors and epigenetic regulators, the extrinsic factors are molecular signals that are present in the neurogenic niche microenvironment. These include morphogens, growth factors, neurotransmitters, and signaling molecules secreted as soluble factors or associated to the extracellular matrix. Among these molecular mechanisms are neurotrophins and neurotrophin receptors which have been implicated in the regulation of adult neurogenesis at different levels, with brain-derived neurotrophic factor (BDNF) being the most studied neurotrophin. In this chapter, we review the current knowledge about the role of neurotrophins in the regulation of adult neurogenesis in both the subventricular zone (SVZ) and the hippocampal subgranular zone (SGZ).
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http://dx.doi.org/10.1007/978-3-030-74046-7_8DOI Listing
August 2021

An Overview of Adult Neurogenesis.

Adv Exp Med Biol 2021 ;1331:77-94

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Neurogenesis is maintained in the mammalian brain throughout adulthood in two main regions: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Adult neurogenesis is a process composed of multiple steps by which neurons are generated from dividing adult neural stem cells and migrate to be integrated into existing neuronal circuits. Alterations in any of these steps impair neurogenesis and may compromise brain function, leading to cognitive impairment and neurodegenerative diseases. Therefore, understanding the cellular and molecular mechanisms that modulate adult neurogenesis is the centre of attention of regenerative research. In this chapter, we review the main properties of the adult neurogenic niches.
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http://dx.doi.org/10.1007/978-3-030-74046-7_7DOI Listing
August 2021

Blending Wastes of Marble Powder and Dolomite Sorbents for Calcium-Looping CO Capture under Realistic Industrial Calcination Conditions.

Materials (Basel) 2021 Aug 5;14(16). Epub 2021 Aug 5.

CQE-Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.

The use of wastes of marble powder (WMP) and dolomite as sorbents for CO capture is extremely promising to make the Ca-looping (CaL) process a more sustainable and eco-friendly technology. For the downstream utilization of CO, it is more realistic to produce a concentrated CO stream in the calcination step of the CaL process, so more severe conditions are required in the calciner, such as an atmosphere with high concentration of CO (>70%), which implies higher calcination temperatures (>900 °C). In this work, experimental CaL tests were carried out in a fixed bed reactor using natural CaO-based sorbent precursors, such as WMP, dolomite and their blend, under mild (800 °C, N) and realistic (930 °C, 80% CO) calcination conditions, and the sorbents CO carrying capacity along the cycles was compared. A blend of WMP with dolomite was tested as an approach to improve the CO carrying capacity of WMP. As regards the realistic calcination under high CO concentration at high temperature, there is a strong synergetic effect of inert MgO grains of calcined dolomite in the blended WMP + dolomite sorbent that leads to an improved stability along the cycles when compared with WMP used separately. Hence, it is a promising approach to tailor cheap waste-based blended sorbents with improved carrying capacity and stability along the cycles under realistic calcination conditions.
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http://dx.doi.org/10.3390/ma14164379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398223PMC
August 2021

Executive functioning in children with self-limited epilepsy with centrotemporal spikes: a systematic review and meta-analysis.

Child Neuropsychol 2021 Jul 12:1-31. Epub 2021 Jul 12.

Centro de Desenvolvimento da Criança Torrado da Silva do Hospital Garcia de Orta, Almada, Portugal.

Self-limited epilepsy with centrotemporal spikes (ECTS) is one of the most frequent focal epilepsies amongst children. Because remission usually occurs before 16 years old and patients present infrequent clinical manifestation, ECTS was considered benign for a long time. Despite the reports on cognitive deficits associated with ECTS in the last years, knowledge about the condition's specific executive function domains (inhibitory control, working memory, cognitive flexibility, verbal fluency, and higher-order executive functions) is still lacking. The following systematic review was conducted according to PRISMA guidelines. The and databases and gray literature were searched according to the following eligibility criteria: (1) original articles published in peer-review journals; (2) studies that present assessment of children with ECTS; and (3) studies with an available assessment of the executive function of the participants. A total of 43 studies (1179 patients and 1086 healthy controls) met the inclusion criteria. Data from 19 studies were extracted, and meta-analysis methods were used to compare results in the three main executive function domains and verbal fluency. The study quality was measured through the Newcastle-Ottawa Scale (NOS) and the evidence quality with the GRADEpro tool. Results and conclusions: The present systematic review is the first to gather information about executive functioning in children with ECTS. According to the meta-analyses, children with ECTS show weaker performances when compared with a control group in inhibitory control, cognitive flexibility, and verbal fluency. However, because the quality of evidence was classified as very low, caution is needed when interpreting the strength of the results.
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http://dx.doi.org/10.1080/09297049.2021.1945019DOI Listing
July 2021

Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer's Disease Model.

J Alzheimers Dis 2021 ;82(3):1183-1202

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Background: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges.

Objective: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42).

Methods: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration.

Results: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points.

Conclusion: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.
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http://dx.doi.org/10.3233/JAD-201567DOI Listing
September 2021

Breast cancer screening adherence rates and barriers of implementation in ethnic, cultural and religious minorities: A systematic review.

Mol Clin Oncol 2021 Jul 19;15(1):139. Epub 2021 May 19.

School of Medicine, University of Minho, Braga, Minho 4710-057, Portugal.

Breast cancer is the most common cancer affecting women worldwide. Adherence to breast cancer screening guidelines is frequently lower in racial, ethnic and cultural minority populations and is affected by potential inequities or barriers to screening that these minorities face. Therefore, the aim of the present study was to collect information from different minority groups worldwide, assess adherence to breast cancer screening and evaluate barriers or limitations causing non-adherence, which should facilitate the development of effective interventions. A search was conducted through PubMed and Web of Science. Studies were considered as eligible if they met the following criteria: i) Female patients; ii) breast cancer screening program implemented in the country; iii) minority groups; iv) asymptomatic; v) report written in Portuguese or English; vi) study published from 2015 onwards. The Critical Appraisal Skills Programme checklist was used for qualitative studies and the Strengthening The Reporting of Observational Studies in Epidemiology checklist for cross-sectional studies. From the 348 initial articles, 86 were removed due to duplication and 19 were selected, analyzed and summarized, accordingly. Of the 19 studies included, 5.3% were classified as high quality, 52.6% as moderate to high and 42.1% as moderate. A total of 15 studies were cross-sectional and 4 were qualitative, collectively including 250,733 women. The rate of adherence to mammogram in different minorities was evaluated, obtaining a mean value of 49.7% in the last 2 years, and statistically significant barriers were selected and divided into sociodemographic; personal; ethnic, cultural and religious; and external factors. The characteristics of each population play a major role in the population's breast health practices. If the population, adherence rates, barriers and inequities are carefully studied, screening models may be customized and participation to breast cancer screening can be optimized, thereby reducing the high breast cancer-associated mortality.
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http://dx.doi.org/10.3892/mco.2021.2301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145341PMC
July 2021

Developmental bifurcation of human T follicular regulatory cells.

Sci Immunol 2021 May;6(59)

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Germinal centers (GCs) are anatomic structures where B cells undergo affinity maturation, leading to production of high-affinity antibodies. The balance between T follicular helper (T) and regulatory (T) cells is critical for adequate control of GC responses. The study of human T and T cell development has been hampered because of the lack of in vitro assays reproducing in vivo biology, along with difficult access to healthy human lymphoid tissues. We used a single-cell transcriptomics approach to study the maturation of T and T cells isolated from human blood, iliac lymph nodes (LNs), and tonsils. As independent tissues have distinct proportions of follicular T cells in different maturation states, we leveraged the heterogeneity to reconstruct the maturation trajectory for human T and T cells. We found that the dominant maturation of T cells follows a bifurcated trajectory from precursor T cells, with one arm of the bifurcation leading to blood T cells and the other leading to the most mature GC T cells. Overall, our data provide a comprehensive resource for the transcriptomics of different follicular T cell populations and their dynamic relationship across different tissues.
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http://dx.doi.org/10.1126/sciimmunol.abd8411DOI Listing
May 2021

Regulation of hippocampal postnatal and adult neurogenesis by adenosine A receptor: Interaction with brain-derived neurotrophic factor.

Stem Cells 2021 May 27. Epub 2021 May 27.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Adenosine A receptor (A R) activation modulates several brain processes, ranging from neuronal maturation to synaptic plasticity. Most of these actions occur through the modulation of the actions of the neurotrophin brain-derived neurotrophic factor (BDNF). In this work we studied the role of A Rs in regulating postnatal and adult neurogenesis in the rat hippocampal dentate gyrus (DG). Here we show that A R activation with CGS 21680 promoted neural stem cell self-renewal, protected committed neuronal cells from cell death and contributed to a higher density of immature and mature neuronal cells, particularly glutamatergic neurons. Moreover, A R endogenous activation was found to be essential for BDNF-mediated increase in cell proliferation and neuronal differentiation. Our findings contribute to further understand the role of adenosinergic signaling in the brain and may have an impact in the development of strategies for brain repair under pathological conditions.
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http://dx.doi.org/10.1002/stem.3421DOI Listing
May 2021

The neurosphere assay: an effective technique to study neural stem cells.

Neural Regen Res 2021 Nov;16(11):2229-2231

Instituto de Medicina Molecular João Lobo Antunes; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

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http://dx.doi.org/10.4103/1673-5374.310678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354118PMC
November 2021

Isolation and Expansion of Neurospheres from Postnatal (P1-3) Mouse Neurogenic Niches.

J Vis Exp 2020 05 23(159). Epub 2020 May 23.

Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa;

The neurosphere assay is an extremely useful in vitro technique for studying the inherent properties of neural stem/progenitor cells (NSPCs) including proliferation, self-renewal and multipotency. In the postnatal and adult brain, NSPCs are mainly present in two neurogenic niches: the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus (DG). The isolation of the neurogenic niches from postnatal brain allows obtaining a higher amount of NSPCs in culture with a consequent advantage of higher yields. The close contact between cells within each neurosphere creates a microenvironment that may resemble neurogenic niches. Here, we describe, in detail, how to generate SVZ- and DG-derived neurosphere cultures from 1-3-day-old (P1-3) mice, as well as passaging, for neurosphere expansion. This is an advantageous approach since the neurosphere assay allows a fast generation of NSPC clones (6-12 days) and contributes to a significant reduction in the number of animal usage. By plating neurospheres in differentiative conditions, we can obtain a pseudomonolayer of cells composed of NSPCs and differentiated cells of different neural lineages (neurons, astrocytes and oligodendrocytes) allowing the study of the actions of intrinsic or extrinsic factors on NSPC proliferation, differentiation, cell survival and neuritogenesis.
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http://dx.doi.org/10.3791/60822DOI Listing
May 2020

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases.

Front Cell Neurosci 2020 24;14:90. Epub 2020 Apr 24.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.

Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.
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http://dx.doi.org/10.3389/fncel.2020.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194075PMC
April 2020

IMRT national audit in Portugal.

Phys Med 2019 Sep 23;65:128-136. Epub 2019 Aug 23.

Dosimetry and Medical Radiation Physics Section, International Atomic Energy Agency, Vienna, Austria.

Purpose: The IAEA newly developed "end-to-end" audit methodology for on-site verification of IMRT dose delivery has been carried out in Portugal in 2018. The main goal was to evaluate the physical aspects of the head and neck (H&N) cancer IMRT treatments. This paper presents the national results.

Methods: All institutions performing IMRT treatments in Portugal, 20 out of 24, have voluntarily participated in this audit. Following the adopted methodology, a Shoulder, Head and Neck End-to-End phantom (SHANE) - that mimics an H&N region, underwent all steps of an IMRT treatment, according to the local practices. The measurements using an ionization chamber placed inside the SHANE phantom at four reference locations (three in PTVs and one in the spinal cord) and an EBT3 film positioned in a coronal plane were compared with calculated doses. FilmQA Pro software was used for film analysis.

Results: For ionization chamber measurements, the percent difference was within the specified tolerances of ±5% for PTVs and ±7% for the spinal cord in all participating institutions. Considering film analysis, gamma passing rates were on average 96.9%±2.9% for a criterion of 3%/3 mm, 20% threshold, all above the acceptance limit of 90%.

Conclusions: The national results of the H&N IMRT audit showed a compliance between the planned and the delivered doses within the specified tolerances, confirming no major reasons for concern. At the same time the audit identified factors that contributed to increased uncertainties in the IMRT dose delivery in some institutions resulting in recommendations for quality improvement.
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http://dx.doi.org/10.1016/j.ejmp.2019.08.013DOI Listing
September 2019

Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology.

Molecules 2019 Apr 5;24(7). Epub 2019 Apr 5.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, 1649-028 Lisboa, Portugal.

With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.
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http://dx.doi.org/10.3390/molecules24071350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480122PMC
April 2019

[Clinical Validation of The Portuguese Version of the Children's Sleep Habits Questionnaire (CSHQ-PT) in Children with Sleep Disorder and ADHD].

Acta Med Port 2019 Mar 29;32(3):195-201. Epub 2019 Mar 29.

Unidade de Neurodesenvolvimento. Centro da Criança e do Adolescente. CUF Descobertas Hospital. Lisboa. Portugal.

Introduction: The Portuguese version of the Children's Sleep Habits Questionnaire showed adequate psychometric properties in a community sample but the American cut-off seemed inadequate. This study aimed to validate this questionnaire in clinical populations of children with sleep disorders and with attention deficit/ hyperactivity disorder.

Material And Methods: The study sample included 148 Portuguese children aged 2 to 10 years old that where divided in 3 groups: 1. Clinical group with sleep disorders (behavioral insomnias, parasomnias or sleep-related breathing disorders); 2. Clinical group with attention deficit/ hyperactivity disorder; 3.

Control Group: The sleep habits and sleep problems were evaluated using the Children's Sleep Habits Questionnaire. Sleep-related disorders were confirmed by polysomnography.

Results: The questionnaire's internal consistency (Cronbach α) in the clinical sample (sleep disorders and attention deficit/ hyperactivity disorder) was 0.75 and ranged from 0.55 to 0.85 for the subscales. Children with sleep disorders and attention deficit/ hyperactivity disorder had a higher sleep disturbance index (full scale score) compared to the control group. The subscales presented significant differences between the subgroups with different sleep disorders showing discriminative validity. The receiver operating characteristic analysis of the sleep disturbance index comparing the sleep disorder and control sample determined a cut-off of 48 (sensibility 0.83; specificity 0.69).

Discussion: Children with sleep disorders and attention deficit/ hyperactivity disorder evidenced higher Sleep Disturbance Index (full scale score) comparing to the control group. The subscales presented significative differences between the subgroups with different sleep disorders showing discriminative validity Conclusion: The Portuguese version of the Children's Sleep Habits Questionnaire showed adequate psychometric properties for children with sleep disorders and/or attention deficit/ hyperactivity disorder. The cut-off value 48 is better adjusted for the Portuguese population.
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http://dx.doi.org/10.20344/amp.10906DOI Listing
March 2019

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr-cell compartments.

Immunol Rev 2019 03;288(1):112-127

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody-mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3 regulatory T cells with unique access to the B-cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody-mediated diseases, and to the identification of novel therapeutic targets.
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http://dx.doi.org/10.1111/imr.12739DOI Listing
March 2019

Brain-Derived Neurotrophic Factor (BDNF) Role in Cannabinoid-Mediated Neurogenesis.

Front Cell Neurosci 2018 28;12:441. Epub 2018 Nov 28.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

The adult mammalian brain can produce new neurons in a process called adult neurogenesis, which occurs mainly in the subventricular zone (SVZ) and in the hippocampal dentate gyrus (DG). Brain-derived neurotrophic factor (BDNF) signaling and cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to independently modulate neurogenesis, but how they may interact is unknown. We now used SVZ and DG neurosphere cultures from early (P1-3) postnatal rats to study the CB1R and CB2R crosstalk with BDNF in modulating neurogenesis. BDNF promoted an increase in SVZ and DG stemness and cell proliferation, an effect blocked by a CB2R selective antagonist. CB2R selective activation promoted an increase in DG multipotency, which was inhibited by the presence of a BDNF scavenger. CB1R activation induced an increase in SVZ and DG cell proliferation, being both effects dependent on BDNF. Furthermore, SVZ and DG neuronal differentiation was facilitated by CB1R and/or CB2R activation and this effect was blocked by sequestering endogenous BDNF. Conversely, BDNF promoted neuronal differentiation, an effect abrogated in SVZ cells by CB1R or CB2R blockade while in DG cells was inhibited by CB2R blockade. We conclude that endogenous BDNF is crucial for the cannabinoid-mediated effects on SVZ and DG neurogenesis. On the other hand, cannabinoid receptor signaling is also determinant for BDNF actions upon neurogenesis. These findings provide support for an interaction between BDNF and endocannabinoid signaling to control neurogenesis at distinct levels, further contributing to highlight novel mechanisms in the emerging field of brain repair.
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http://dx.doi.org/10.3389/fncel.2018.00441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279918PMC
November 2018

Erythropoietin Induces Homeostatic Plasticity at Hippocampal Synapses.

Cereb Cortex 2018 08;28(8):2795-2809

Institute of Pharmacology and Neurosciences, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, Portugal.

The cytokine erythropoietin (EPO) is the master regulator of erythropoiesis. Intriguingly, many studies have shown that the cognitive performance of patients receiving EPO for its hematopoietic effects is enhanced, which prompted the growing interest in the use of EPO-based strategies to treat neuropsychiatric disorders. EPO plays key roles in brain development and maturation, but also modulates synaptic transmission. However, the mechanisms underlying the latter have remained elusive. Here, we show that acute (40-60 min) exposure to EPO presynaptically downregulates spontaneous and afferent-evoked excitatory transmission, without affecting basal firing of action potentials. Conversely, prolonged (3 h) exposure to EPO, if followed by a recovery period (1 h), is able to elicit a homeostatic increase in excitatory spontaneous, but not in evoked, synaptic transmission. These data lend support to the emerging view that segregated pathways underlie spontaneous and evoked neurotransmitter release. Furthermore, we show that prolonged exposure to EPO facilitates a form of hippocampal long-term potentiation that requires noncanonical recruitment of calcium-permeable AMPA receptors for its maintenance. These findings provide important new insight into the mechanisms by which EPO enhances neuronal function, learning, and memory.
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http://dx.doi.org/10.1093/cercor/bhx159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117472PMC
August 2018

Neurogenesis in a rat model of sporadic Alzheimer's disease: .

Porto Biomed J 2017 Sep-Oct;2(5):205. Epub 2017 Sep 1.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

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http://dx.doi.org/10.1016/j.pbj.2017.07.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806778PMC
September 2017

Interaction between Cannabinoid Type 1 and Type 2 Receptors in the Modulation of Subventricular Zone and Dentate Gyrus Neurogenesis.

Front Pharmacol 2017 10;8:516. Epub 2017 Aug 10.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de LisboaLisboa, Portugal.

Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CBR and CBR) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CBR and CBR in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CBR and CBR to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CBR or CBR selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CBR and CBR. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CBR selective activation. However, either CBR or CBR selective antagonists abolished the effect of the CBR agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CBR or CBR selective agonists and blocked by either CBR or CBR selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CBR and CBR to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.
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http://dx.doi.org/10.3389/fphar.2017.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554396PMC
August 2017

Human blood T cells are indicators of ongoing humoral activity not fully licensed with suppressive function.

Sci Immunol 2017 Aug;2(14)

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Germinal center (GC) responses are controlled by T follicular helper (T) and T follicular regulatory (T) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue T cells has been established, the relationship between blood and tissue T cells defined as CXCR5Foxp3 T cells remains elusive. We found that blood T cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood T cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood T cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5Foxp3 T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating T cells.
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http://dx.doi.org/10.1126/sciimmunol.aan1487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116402PMC
August 2017

Executive functioning of Portuguese preschoolers in the Shape School test: A cross cultural study.

Appl Neuropsychol Child 2018 Jul-Sep;7(3):200-207. Epub 2017 Feb 22.

a Center for Interdisciplinary Research in Health (CIIS) , Institute of Health Sciences, Universidade Católica Portuguesa , Lisbon , Portugal.

The Shape School is a neuropsychological test of executive functions (EF) for preschool-aged children. The purposes of this study were: (a) to adapt the use of the Shape School for European Portuguese preschool children and (b) to examine the cultural sensitivity of this test comparing the performance of Portuguese sample and U.S. normative sample. The executive functioning of 233 typically developing children aged 3 to 5 years old (M = 57.52; SD = 10.25; in months) was analyzed and according to our results, the adapted version was appropriate to obtain the discrimination among age-groups. Portuguese and American preschoolers show similar EF profiles. It was possible, in both samples, to note the sensitivity of the measurement to age-related differences, with the older age groups outperforming the younger. Therefore, the Portuguese version of the Shape School was considered suitable for research and clinical purposes.
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http://dx.doi.org/10.1080/21622965.2017.1287569DOI Listing
November 2018

Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats.

Mol Neurobiol 2018 May 22;55(5):3725-3738. Epub 2017 May 22.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.

Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.
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http://dx.doi.org/10.1007/s12035-017-0592-5DOI Listing
May 2018

Cost-efficient method for unsymmetrical meso-aryl porphyrins and iron oxide-porphyrin hybrids prepared thereof.

Dalton Trans 2016 Oct;45(41):16211-16220

CQC, Departamento de Química, Faculdade de Ciências e Tecnologia da Universidade de Coimbra, Rua Larga, 3004-535 Coimbra, Portugal.

Herein, the synthesis and characterisation of magnetic iron oxide-porphyrin hybrids, constituted of iron-oxide magnetic nanoparticles covalently linked to an unsymmetrically substituted meso-aryl porphyrin, are described. The methodology features for the preparation of the key unsymmetrically substituted meso-aryl porphyrin synthons are discussed, with emphasis on sustainability and in economical terms. The "NaY method" herein reported allows large scale and economical preparation, which are demonstrated by its reusability and at least two-fold yields, when compared with classical porphyrin synthetic methods and also presents a much better cost-efficiency rationale and lower environmental impact. Upon covalent linking to iron-oxide magnetic nanoparticles, the new hybrids are fully characterised by thermogravimetry/differential scanning calorimetry, transmission electron microscopy and infrared spectroscopy and their photophysical properties were measured, which demonstrate that the presence of the magnetic nanoparticle counterparts does not affect these properties, thus allowing the materials to keep the photophysical features imparted by their porphyrin counterparts.
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http://dx.doi.org/10.1039/c6dt02428aDOI Listing
October 2016

Adenosine A2A receptors in neuronal outgrowth: a target for nerve regeneration?

Neural Regen Res 2016 May;11(5):706-8

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

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http://dx.doi.org/10.4103/1673-5374.182683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904447PMC
May 2016

Comparing the performance of the EQ-5D-3L and the EQ-5D-5L in young Portuguese adults.

Health Qual Life Outcomes 2016 Jun 8;14:89. Epub 2016 Jun 8.

School of Management, Hospitality and Tourism, University of the Algarve, Campus da Penha, Faro, 8005-139 Faro, Portugal.

Background: Some studies have reported a ceiling effect in EQ-5D-3L, especially in healthy and/or young individuals. Recently, two further levels have been included in its measurement model (EQ-5D-5L). The purposes of this study were (1) to assess the properties of the EQ-5D-5L in comparison with the standard EQ-5D-3L in a sample of young adults, (2) to foreground the importance of collecting qualitative data to confirm, validate or refine the EQ-5D questionnaire items and (3) to raise questions pertaining to the wording in these questionnaire items.

Methods: The data used came from a sample of respondents aged 30 or under (n = 624). They completed both versions of the EQ-5D, which were compared in terms of feasibility, level of inconsistency and ceiling effect. Agreement between the instruments was assessed using correlation coefficients and Bland-Altman plots. Known-groups validity of the EQ-5D-5L was also assessed using non-parametric tests. The discriminative properties were compared using receiver operating characteristic curves. Finally, four interviews were conducted for retrospective reports to elicit respondents' understanding and perceptions of the format, instructions, items, and responses.

Results: Quantitative results show a ceiling effect reduction of 25.3 % and a high level agreement between both indices. Known-groups validity was confirmed for the EQ-5D-5L. Explorative interviews indicated ambiguity and low degree of certainty in regards to conceptualizing differences between levels moderate-slight across three dimensions.

Conclusions: The EQ-5D-5L performed better than the EQ-5D-3L. However, the explorative interviews demonstrated several limitations in the EQ-5D questionnaire wording and high context-dependent answers point to lack of illnesses' experience amongst young adults.
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http://dx.doi.org/10.1186/s12955-016-0491-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897861PMC
June 2016

Metastatic Breast Cancer in Uterine Cervix: A Rare Presentation.

J Low Genit Tract Dis 2016 Jan;20(1):e1-3

Department of Gynecology and Obstetrics, Hospital de Cascais Dr. José de Almeida, Cascais, Portugal.

Uterine cervix involvement by a distant primary tumor is a rare event. We report the following 2 cases of breast tumor metastasis to the uterine cervix with different presentations: case 1 is an isolated cervix metastasis and case 2 is a disseminated metastatic disease with cervix involvement. In both, clinical examination raised the suspicion of cervical tumor, which was confirmed to be a metastatic adenocarcinoma.The poor outcome and lack of symptoms suggest that although its rareness, all patients with breast cancer should undergo a careful routine gynecologic examination.
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http://dx.doi.org/10.1097/LGT.0000000000000154DOI Listing
January 2016

Purine nucleosides in neuroregeneration and neuroprotection.

Neuropharmacology 2016 05 11;104:226-42. Epub 2015 Nov 11.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. Electronic address:

In the present review, we stress the importance of the purine nucleosides, adenosine and guanosine, in protecting the nervous system, both centrally and peripherally, via activation of their receptors and intracellular signalling mechanisms. A most novel part of the review focus on the mechanisms of neuronal regeneration that are targeted by nucleosides, including a recently identified action of adenosine on axonal growth and microtubule dynamics. Discussion on the role of the purine nucleosides transversally with the most established neurotrophic factors, e.g. brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), is also focused considering the intimate relationship between some adenosine receptors, as is the case of the A2A receptors, and receptors for neurotrophins. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
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http://dx.doi.org/10.1016/j.neuropharm.2015.11.006DOI Listing
May 2016

Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons.

Brain Struct Funct 2016 06 12;221(5):2777-99. Epub 2015 Jun 12.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.

Axon growth and dendrite development are key processes for the establishment of a functional neuronal network. Adenosine, which is released by neurons and glia, is a known modulator of synaptic transmission but its influence over neuronal growth has been much less investigated. We now explored the action of adenosine A2A receptors (A2AR) upon neurite outgrowth, discriminating actions over the axon or dendrites, and the mechanisms involved. Morphometric analysis of primary cultures of cortical neurons from E18 Sprague-Dawley rats demonstrated that an A2AR agonist, CGS 21680, enhances axonal elongation and dendritic branching, being the former prevented by inhibitors of phosphoinositide 3-kinase, mitogen-activated protein kinase and phospholipase C, but not of protein kinase A. By testing the influence of a scavenger of BDNF (brain-derived neurotrophic factor) over the action of the A2AR agonist and the action of a selective A2AR antagonist over the action of BDNF, we could conclude that while the action of A2ARs upon dendritic branching is dependent on the presence of endogenous BDNF, the influence of A2ARs upon axonal elongation is independent of endogenous BDNF. In consonance with the action over axonal elongation, A2AR activation promoted a decrease in microtubule stability and an increase in microtubule growth speed in axonal growth cones. In conclusion, we disclose a facilitatory action of A2ARs upon axonal elongation and microtubule dynamics, providing new insights for A2ARs regulation of neuronal differentiation and axonal regeneration.
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http://dx.doi.org/10.1007/s00429-015-1072-1DOI Listing
June 2016

Protein contact dermatitis caused by fishing bait in a patient with contact urticaria caused by shrimp.

Contact Dermatitis 2014 Aug;71(2):126-8

Dermatology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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http://dx.doi.org/10.1111/cod.12226DOI Listing
August 2014
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