Human stem cells for cardiac disease modeling and preclinical and clinical applications—are we on the road to success?

Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.B.M.S. was awarded with a Ph.D. fellowship (reference: 2022.13253.BDANA) by Fundação para a Ciência e Tecnologia (FCT). S.M.C is supported by a Stimulus of Scientific Employment, Individual Support (2020.01532.CEECIND) by FCT. J.B. is grateful to the FCT and the Comissão de Coordenação e Desenvolvimento Regional do Algarve (CCDR Algarve) for the project ALG-45-2020-41 and to Algarve Biomedical Center (ABC) for the award “Bolsa de Investigação Translacional—José Mariano Gago by ABC, 2022”. M.T.F. thanks the FCT for funding the project with the reference 2022.09209.PTDC.info:eu-repo/semantics/publishedVersio

Efeito de um programa de tiro com zarabatana na função respiratória de adultos com Dificuldades Intelectuais e Desenvolvimentais

Introdução e Objetivos: A principal causa de morte e de internamento em pessoas com Dificuldades Intelectuais e Desenvolvimentais (DID) é a patologia respiratória. O treino de tiro com zarabatana tem o potencial de melhorar a função respiratória de populações com/sem patologia através de uma atividade lúdica com significado, que envolve todo o ciclo respiratório. No entanto, o seu impacto na população com DID não é claro. Este estudo explorou os efeitos de um programa de tiro com zarabatana na função respiratória de adultos com DID. Material e Métodos: Foram recrutados 16 adultos com DID na Organização de Apoio e Solidariedade para a Integração Social (OASIS) e distribuídos, de acordo com a disponibilidade para participar nas sessões, em 2 grupos: intervenção (tiro com zarabatana, GI, n=8) e controlo (usual care, GC, n=8). O programa de tiro com zarabatana foi realizado na OASIS 1 vez/semana durante 3 meses (início: 30-40 tiros a 4m do alvo; progressão: aumento da distância/n.º tiros). Foram avaliadas: 1) a função pulmonar, através do Volume Expiratório Forçado no 1º segundo (FEV1%previsto), Capacidade Vital Forçada (FVC%previsto) e Pico de Fluxo Expiratório (PEF); 2) a força dos músculos respiratórios através das Pressões Inspiratória (PIM) e Expiratória (PEM) Máximas. Foram analisadas as diferenças: 1) entre GI e GC na baseline (M0) e aos 3 meses (M1) (teste t-student ou teste Mann-Whitney; α=0,05) e 2) entre os momentos de avaliação (M0-M1) em cada grupo (teste Wilcoxon; α=0,05). Resultados: 12 participantes concluíram o estudo, 7 no GI (33,0±14,4 anos; 5 mulheres) e 5 no GC (51,8±9,3 anos; 3 mulheres). Os grupos apresentaram uma diferença estatisticamente significativa em relação à idade (t-student, p=0.029), mas não em relação ao sexo. Os grupos não apresentaram diferenças significativas em M0 (p>0.05). Não foram observadas diferenças significativas na função pulmonar e na força dos músculos respiratórios (p>0,05) em M1 entre o GI e o GC (FEV1-GI=62,3±14,6%previsto FEV1-GC=79,0±17,7%previsto; FVCGI=64,1±17,2%previsto FVCGC=70,8±19,4%previsto; PEFGI=146,3±36,0L/min PEFGC= 279,0±166,9L/min; PIMGI=28,0±22,3cmH2O PIMGC=33,6±13,1cmH2O; PEMGI= 38,4±25,9cmH2O PEMGC= 40,4±16,6cmH2O). Nenhum dos grupos apresentou diferenças entre M0 e M1 (p<0,05). Conclusões: O treino de tiro com zarabatana não parece produzir efeitos significativos na função respiratória em adultos com DID a curto prazo. No entanto, são necessários mais estudos com desenhos robustos para confirmar os resultados.N/

Beyond new neurons in the adult hippocampus: imipramine acts as a pro-astrogliogenic factor and rescues cognitive impairments induced by stress exposure

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants—fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.ARMS: ELC, NDA, PP, AMP, JSC, MM, AJR, JFO, and L.P. received fellowships from the Portuguese Foundation for Science and Technology (FCT) (IF/00328/2015 to J.F.O.; 2020.02855.CEECIND to LP). This work was funded by FCT (IF/01079/2014, PTDC/MED-NEU/31417/2017 Grant to JFO), BIAL Foundation Grants (037/18 to J.F.O. and 427/14 to L.P.), “la Caixa” Foundation Health Research Grant (LCF/PR/HR21/52410024) and Nature Research Award for Driving Global Impact—2019 Brain Sciences (to L.P.). This was also co-funded by the Life and Health Sciences Research Institute (ICVS), and by FEDER, through the Competitiveness Internationalization Operational Program (POCI), and by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020. Moreover, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; “la Caixa” Foundation (ID 100010434 to A.J.R.), under the agreement LCF/PR/HR20/52400020; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 101003187 to A.J.R.)

Estratégia Nacional para a Medicina Genómica - PT_MedGen: desafios e prioridades

Documento preparado pela Comissão nomeada pelo Despacho n.º 5135/2021, de 20 de maio do SEAS (Diário da República n.º 98/2021, Série II de 2021-05-20, pp 107-108): Fernando de Almeida, Instituto Nacional de Saúde Doutor Ricardo Jorge I.P. – Presidente da Comissão; Astrid Moura Vicente, Instituto Nacional de Saúde Doutor Ricardo Jorge I.P. – Coordenadora da Comissão e responsável pelo GT Doenças Complexas; Patrícia Calado, Agência de Investigação Clínica e Inovação Biomédica – Cocoordenadora da Comissão e responsável pelo GT Comunicação; Manuel Santos, Universidade de Aveiro, GenomePT – Responsável pelo GT Boas práticas de Sequenciação; Ana Sofia Carvalho, ICBAS - Instituto de ciências Biomédicas Abel Salazar, Universidade do Porto - Responsável pelo GT Questões Éticas, Legais e Sociais; Cíntia Águas, Membro do GT Questões Éticas, Legais e Sociais; Cátia Sousa Pinto, Serviços Partilhados do Ministério da Saúde E.P.E. – Responsável pelo GT Dados de Saúde; Mário Jorge Gaspar da Silva, Instituto Superior Técnico, Universidade de Lisboa; BioData.pt – Responsável pelo GT Interoperabilidade de Partilha de Dados; Ana Portugal Melo, BioData.pt - Membro do GT Interoperabilidade de Partilha de Dados; Mónica Duarte Correia de Oliveira, Instituto Superior Técnico, Universidade de Lisboa – Responsável pelo GT Economia da Saúde; Joana Feijó, Health Cluster Portugal – Responsável pelo GT Indústria e Setor Privado; Laura Vilarinho, Instituto Nacional de Saúde Doutor Ricardo Jorge I.P. – Responsável pelo GT Doenças Raras; Carla Oliveira, I3S - Instituto de Investigação e Inovação, Universidade do Porto – Responsável pelo GT Cancro.Com os contributos adicionais de: Ana Berta Sousa, Centro Hospitalar Universitário de Lisboa Norte; Ana Fortuna, Centro Hospitalar Universitário do Porto; Gabriela Sousa, Instituto Português de Oncologia de Coimbra; Guiomar Oliveira, Centro Hospitalar Universitário de Coimbra; João Paulo Oliveira, Centro Hospitalar Universitário de São João; Jorge Pinto Basto, Colégio da Especialidade de Genética Médica da Ordem dos Médicos; Jorge Saraiva, Centro Hospitalar Universitário de Coimbra; Margarida Venâncio, Centro Hospitalar Universitário de Coimbra; Patrícia Dias, Centro Hospitalar Universitário de Lisboa Norte; Sérgio Sousa, Centro Hospitalar Universitário de Coimbra.À Comissão compete a definição de roadmap para o planeamento e implementação da Estratégia Nacional para a Medicina Genómica, que apoiará a contribuição de Portugal na iniciativa 1+MG.O presente documento visa propor o conceito e as linhas de ação prioritárias da Estratégia Nacional para a Medicina Genómica (PT_MedGen). O documento baseia-se na auscultação de alguns dos principais stakeholders nacionais, representados na Comissão nomeada pelo Despacho n.o 5135/2021 coordenada pelo INSA, e ainda na consulta de outras entidades e peritos de relevância. A estratégia PT_MedGen tem a meta global de criar infraestruturas e processos que permitam a adoção de abordagens de medicina personalizada na prática clínica, a par com a contribuição para a iniciativa 1+MG. Esta estratégia promoverá ainda a investigação, a inovação, a competitividade e a internacionalização, permitindo a criação de conhecimento e valor significativos na área da saúde.info:eu-repo/semantics/publishedVersio

Identification and characterization of Candida spp. from denture stomatitis patients

info:eu-repo/semantics/publishedVersio

Cell cycle regulation of hippocampal progenitor cells in experimental models of depression and after treatment with fluoxetine

Changes in adult hippocampal cell proliferation and genesis have been largely implicated in depression and antidepressant action, though surprisingly, the underlying cell cycle mechanisms are largely undisclosed. Using both an in vivo unpredictable chronic mild stress (uCMS) rat model of depression and in vitro rat hippocampal-derived neurosphere culture approaches, we aimed to unravel the cell cycle mechanisms regulating hippocampal cell proliferation and genesis in depression and after antidepressant treatment. We show that the hippocampal dentate gyrus (hDG) of uCMS animals have less proliferating cells and a decreased proportion of cells in the G2/M phase, suggesting a G1 phase arrest; this is accompanied by decreased levels of cyclin D1, E, and A expression. Chronic fluoxetine treatment reversed the G1 phase arrest and promoted an up-regulation of cyclin E. In vitro, dexamethasone (DEX) decreased cell proliferation, whereas the administration of serotonin (5-HT) reversed it. DEX also induced a G1-phase arrest and decreased cyclin D1 and D2 expression levels while increasing p27. Additionally, 5-HT treatment could partly reverse the G1-phase arrest and restored cyclin D1 expression. We suggest that the anti-proliferative actions of chronic stress in the hDG result from a glucocorticoid-mediated G1-phase arrest in the progenitor cells that is partly mediated by decreased cyclin D1 expression which may be overcome by antidepressant treatment.This research was funded by FCT (grant number IF/01079/2014 and 2020.02855.CEECIND to LP) and the Nature Research Award for Driving Global Impact-2019 Brain Sciences (to LP); the Life and Health Sciences Research Institute (ICVS); FEDER, through the Competitiveness Internationalization Operational Program (POCI); National funds through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; the projects NORTE-01- 0145-FEDER-000013 and NORTE-01-0145-FEDER-000023.; the ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145- FEDER-022122); National funds through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020. Part of this work was also funded by “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400020; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 101003187)

Portuguese recommendations for the use of methotrexate in the treatment of rheumatoid arthritis

Objectives:To develop Portuguese evidence-based recommendations for the use of methotrexate (MTX) in daily clinical practice in rheumatic disorders. Methods:The Portuguese project was integrated in the multinational 3E Initiative (Evidence, Expertise, Exchange) 2007-2008 where a total of 751 rheumatologists from 17 countries have participated. Ten clinical questions concerning the use of MTX in rheumatic diseases were formulated and the Portuguese group added three more questions. A systematic literature search in Medline, Embase, Cochrane Library and 2005-2007 ACR/EULAR meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford Levels of Evidence. In Portugal, a national meeting was held in Obidos on February 15 th and 16 th, 2008, involving 50 rheumatologists who discussed and voted by Dephi method the recommendations. Finally, the agreement among the rheumatologists and the potential impact on their clinical practice was assessed. Results: Thirteen national key recommendations on the use of MTX were formulated: work-up before starting MTX, optimal dosage and route of administration, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy, management in the perioperative period, during infections, before/during pregnancy and after clinical remission, screening and treatment of tuberculosis and the role of MTX as a steroid-sparing agent in rheumatic diseases. Discussion: The Portuguese recommendations for the use of MTX in daily clinical practice were developed, which are evidence-based and supported by a panel of 50 rheumatologists, enhancing their validity and practical use. This project was integrated in a multinational initiative that led to the recent publication of ten multinational recommendations which differ from ours in some specific aspects.publishersversionpublishe

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved