National Institute of Health Dr. Ricardo Jorge
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Estudo mecanístico e aplicado da tradução não canónica de isoformas de p53 durante estresse e carcinogénese
No full textTumor suppressor p53 is mutated in half of all human cancers and for that reason it became one of the most studied genes in the history of medical research. Its functions as a transcription factor and its posttranslational regulation were subjects of intense studies for decades. But it was not until more recently that the importance of its translational regulation became clear.
p53 is involved in many cellular processes, stress response pathways, tumor suppressing signals, developmental checkpoints and even aging. In order to diversify and differentiate its action, p53 mRNA is translated into several different isoforms that harbor different functions and act independently or together as heterotetramers.
The possibility of expressing each isoform one by one through different regulatory structures in its DNA and mRNA gives p53 the ability to be activated in many different ways leading to specific and adequate cellular outcomes. p53 mRNAs can be translated into four different isoforms, each with its respective splice variations, from four diferente translation initiation codons present in codons 1, 40, 133 and 160, and named full length (FL) p53, delta40p53 (deltaNp53 or p53/47), delta133p53 and delta160p53, respectively. The shorter delta133p53 and delta160p53 isoforms are the products of an alternative transcript (delta133p53 mRNA) originating from an internal promoter in intron four of the p53 gene. Most of the p53 functions and regulatory mechanisms described so far are related to FLp53, because for many years, this was the only
known p53 isoform. In this study, we want to investigate the translational regulation of other p53 isoforms and its impact on the p53 pathway, stress response and carcinogenesis.FCTN/
Tratamento de doenças lisossomais de sobrecarga: relatório 2021
No full textRelatório anual sobre o Tratamento de doenças lisossomais de sobrecarga, referente às atividades desenvolvidas pela respetiva Comissão Coordenadora em 2021. As Doenças Lisossomais de Sobrecarga (DLS) constituem um grupo de patologias raras, progressivas, com elevada morbilidade, que engloba, atualmente, mais de 60 patologias, cuja apresentação clínica é extremamente variável, podendo ir desde doença neurológica grave até a casos menos graves.
Em Portugal, a prevalência deste tipo de patologias em recém-nascidos é de 25 por cada 100.000 nados-vivos. Nos últimos anos, várias terapêuticas de substituição enzimática e de redução do substrato e também um chaperone farmacológico têm sido desenvolvidas possibilitando o tratamento dos doentes com algumas destas patologias, nomeadamente, a Doença de Gaucher, a Doença de Fabry, a Doença de Pompe, as Mucopolissacaridoses tipo I, II, IVA, VI e VII, a Deficiência de lipase ácida lisossomal, a Alfa-manosidosee a Doença de Niemann-Pick tipo C.
Pelo Despacho n.º 2545/2013, foi criada a Comissão Coordenadora do Tratamento das Doenças Lisossomais de Sobrecarga (CCTDLS), que funciona junto do INSA, sendo atualmente constituída por profissionais designados pelo INSA, pelos Centros de Referência nesta área, pela Administração Central do Sistema de Saúde, pela Direção-Geral da Saúde e pela Autoridade Nacional do Medicamento e Produtos de Saúde (Infarmed).
Do relatório da CCTDLS relativo ao ano 2021, destaca-se a realização das seguintes atividades:
- Casos clínicos − Discussão e avaliação de 97 casos clínicos, resultando na emissão de 62 pareceres positivos para pedidos de início de tratamento (33), ajuste de dose (19) ou mudança de fármaco (10). Foram emitidos pareceres para Doença de Gaucher, Doença de Fabry, Mucopolissacaridoses tipos I, II e VI, Doença de Pompe e Doença de Niemann-Pick tipo C;
- Monitorização − Análise de 21 processos de monitorização da evolução clínica dos doentes com terapias em curso;
- Total de doentes − Atualização dos dados referentes ao número total de doentes com DLS em tratamento no território continental, detalhado por centro hospitalar, patologia e terapêutica. No final de 2021, 331 doentes estavam em tratamento, sendo 154 com Doença de Fabry, 95 com Doença de Gaucher, 31 com Doença de Pompe, 14 com Doença de Niemann-Pick tipo C, 9 com Mucopolissacaridose tipo I, 9 com Mucopolissacaridose tipo II, 3 com Mucopolissacaridose tipo IVA, 11 com Mucopolissacaridose tipo VI, 3 com Mucopolissacaridose tipo VII e 2 com Deficiência de lipase ácida lisossomal;
- Terapêutica domiciliária − Elaboração de um documento base para a criação de uma Norma no âmbito do Departamento da Qualidade da DGS, estabelecendo um modelo de Terapêutica Domiciliária a ser aplicado de forma equitativa a todos os doentes com DLS tratados em território nacional. Este documento foi enviado ao diretor do Departamento da Qualidade da DGS e ao Presidente do Conselho Diretivo do INSA, que posteriormente o encaminhou ao Gabinete do Secretário de Estado Adjunto da Saúde;
- Documentos técnicos − Disponibilização de dois novos documentos de referência técnica na página da CCTDLS no website do INSA: um com os critérios de início da terapêutica com sebelipase alfa nos doentes com Deficiência de lipase ácida lisossomal (LAL) e outro com os critérios de início da terapêutica com alglucosidase alfa nos doentes com Doença de Pompe.info:eu-repo/semantics/publishedVersio
Genomic characterization of Salmonella Newport: identification of genetic clusters, January 1991-May 2024
Get PDFSalmonella enterica subsp. enterica serovar Newport (S. Newport) é um serotipo
pouco frequente na União Europeia. No entanto, devido à sua associação
com alguns surtos de origem alimentar, a sua importância não deve
ser negligenciada. Em Portugal, os dados sobre a infeção por S. Newport
são escassos.
Este estudo teve como principais objetivos caracterizar fenotípica e genotipicamente
isolados clínicos de S. Newport entre 1991 e maio de 2024, e identificar
possíveis clusters genéticos.
Após serotipagem, 98 isolados foram submetidos a testes de suscetibilidade
aos antibióticos e sequenciação total do genoma.
Apesar da maioria dos isolados estudados (96,9%) terem sido suscetíveis
aos antibióticos testados, em 2024 foi identificado um isolado multirresistente,
que, entre outros, continha o gene blaDHA-1. A análise core genome
multilocus sequence typing (Enterobase cgMLST V2 + HierCC V1), considerando
um threshold de cinco diferenças alélicas, permitiu identificar oito
clusters distintos, dois dos quais de maiores dimensões: o Cluster 1, com
32 isolados de 2019, e o Cluster 2, com quatro isolados de 2022 e 18 de
2023.
Embora S. Newport seja um serotipo pouco frequente em Portugal e não
apresentar, na maioria dos casos, resistências aos antibióticos, é essencial
manter uma vigilância laboratorial contínua, que permita de forma atempada
implementar medidas de prevenção e controlo eficazes.Salmonella enterica subsp. enterica serovar Newport (S. Newport) is a
relatively uncommon serotype within the European Union. Nevertheless,
due to the relevance of some related outbreaks, its significance should not
be underestimated. In Portugal, data on S. Newport infection is scarce.
The objectives of this study were to characterise clinical isolates of S.
Newpor t received between Januar y 1991 and May 2024, and to identif y
potential genetic clusters.
Following serotyping, 98 isolates were subjected to antibiotic susceptibility
testing and whole genome sequencing.
Most of the isolates (96.9%) were susceptible to the tested antibiotics.
However, a multidrug-resistant isolate was identified in 2024, which
contained the blaDHA-1 gene, among others. The core genome multilocus
sequence typing analysis (Enterobase cgMLST V2 + HierCC V1), with a
threshold of five allelic dif ferences, enabled the identification of eight
clusters, two of them considered as major clusters: Cluster 1, comprising 32 isolates from 2019, and Cluster 2 including four isolates from 2022
and 18 from 2023.
Although S. Newpor t is an uncommon serotype in Por tugal and most of
the isolates do not exhibit antibiotic resistance, it is essential to maintain
a continuous laborator y surveillance programme in order to implement
ef fective prevention and control measures.info:eu-repo/semantics/publishedVersio
Health beliefs and attitudes toward Influenza and COVID-19 vaccination in Portugal: a study using a mixed-method approach
Get PDFSec. Infectious Diseases: Epidemiology and PreventionIntroduction: Vaccination is one of the most effective population strategies to prevent infectious diseases and mitigate pandemics, and it is important to understand vaccine uptake determinants since vaccine hesitancy has been increasing for the past few decades. The Health Belief Model (HBM) has been widely used for understanding vaccination behavior. The current study aimed to assess influenza vaccine (IV) non-uptake and attitudes toward COVID-19 vaccination, two important respiratory diseases with similar symptoms, and routes of transmission in the Portuguese population.
Methods: We conducted a cross-sectional study using a panel sample of randomly chosen Portuguese households. A total of 1,050 individuals aged 18 years and over responded to a telephone or online questionnaire. Through a mixed-method approach, we employed thematic content analysis to describe reasons for not taking the IV, considering the HBM dimensions, and quantitative statistical analysis to estimate IV and COVID-19 vaccine coverage.
Results: The IV uptake for the overall population was 30.7% (CI 95%: 26.5, 35.2). Susceptibility was found to be a main factor for IV non-uptake, followed by barriers, such as stock availability and fear of adverse effects. The uptake of the COVID-19 vaccine was very high in the study population (83.1%, CI 95%: 13.6%−20.9%). There was a high perception of COVID-19-associated severity and fear of the consequences. Individuals who reported IV uptake seemed to perceive a higher severity of COVID-19 and a higher benefit of taking the COVID-19 vaccine for severe complications.
Discussion: Thus, the population does not seem to consider influenza to be a health risk, as opposed to COVID-19, which is considered to be a possibly severe disease. The association between IV uptake and COVID-19 perceptions highlights that an overall attitude toward vaccination in general may be an important individual determinant.info:eu-repo/semantics/publishedVersio
Evolução da infeção pelo vírus da Hepatite C em dadores de sangue e população geral em Portugal entre 2015 e 2022
Get PDFIntrodução
A elevada taxa de progressão para a cronicidade e o potencial evolutivo para cirrose e carcinoma hepatocelular, fazem da infeção pelo vírus da Hepatite C (VHC) um grave problema de saúde pública. O risco de transmissão do VHC por transfusão sanguínea tem sido minimizado pelo desenvolvimento de testes cada vez mais sensíveis na deteção dos anticorpos anti-VHC, bem como da implementação da detecção do RNA-VHC através de Testes de Amplificação de Ácidos Nucleicos.
Objetivo
Caracterizar a evolução da infeçáo por VHC em dadores de sangue e população geral em Portugal (2015-2022).
Material e métodos
Estudo retrospetivo com dados obtidos do Instituto Português do Sangue e da Transplantação (IPST), DGS e INE. Foi calculada a proporção anual de dadores VHC positivos por 100 000 dadores e a proporção de VHC positivos por 100 000 habitantes (população geral). A tendência da variação percentual média anual (AAPC) foi estimada através do software Joinpoint®.
Resultados
Entre 2015 e 2022, foram identificadas 135 dadores com VHC, correspondendo a uma média de 17 casos/ano (min-max: 9-22). Na população geral, foram notificados no mesmo período 1721 casos, correspondendo a uma média de 215 casos/ano. Em termos de tendência, a proporção de dádivas VHC positivas ter vindo a diminuir mas esta tendência decrescente não foi estatisticamente significativa (AAPC=-2.9, p=0.45). Na população geral, a tendência de casos notificados de VHC tem vindo a diminuir de forma estatisticamente significativa (AAPC=-7.4, p=0.02). Globalmente, a maioria dos casos são do sexo masculino em ambas as populações. Anualmente, na população em geral o número de homens é sempre cerca 3x superior ao das mulheres (2.5-3.6), mas nos dadores os valores são mais próximos ou chegando mesmo a inverter (mulheres>homens).
Discussão e Conclusão
Os resultados obtidos permitem constatar que a infecção pelo VHC permance um problema de saúde pública em Portugal, continuando a existir indivíduos que desconhecem que se encontram infetados. A não deteção destes casos assintomáticos representa um problema não só em termos de transmissão do agente na comunidade, mas também como potencial risco de transmissão através da dádiva de sangue. Os dados da hemovigilância em Portugal demonstram um esforço continuado na melhoria da deteção destes casos, especialmente através do avanço tecnológico das técnicas de rastreio, o que tem permitido manter o risco residual infecioso em valores perto de zero (0.0-0.06/100 000 dádivas).info:eu-repo/semantics/publishedVersio
Insights into macrolide resistance in Arcobacter butzleri: potential resistance mechanisms and impact on bacterial fitness and virulence
No full textBackground: Macrolides are recommended for treating the emerging enteropathogen Arcobacter butzleri; nonetheless, this bacterium often exhibits highly variable resistance rates, and the mechanisms behind this resistance phenotype remain largely unexplored.
Objectives: To understand the phenotypic and genotypic consequences associated with the acquisition of erythromycin resistance in A. butzleri, as well as the effects on the fitness of this species.
Methods: Resistant strains resulting from spontaneous mutations and adaptive laboratory evolution under increasing erythromycin concentrations were examined regarding their cross-resistance and collateral susceptibility profiles. Genetic causes of phenotypic antibiotic resistance were analysed by sequencing and bioinformatics, with functional correlation through ethidium bromide accumulation assays. Growth profiles in the presence and absence of erythromycin, motility and biofilm formation abilities were assessed to detect potential changes in fitness and virulence.
Results: Clones from spontaneous mutation rate evolution demonstrated decreased susceptibility to erythromycin and other classes of antibiotics, associated with mutations in the transcriptional repressor areR, causing overexpression of the AreABC efflux pump. In turn, WGS analysis of the evolved strain showed additional mutations in the ribosomal proteins L4 and L22 and in the areR gene. Furthermore, the acquisition of macrolide resistance altered A. butzleri virulence and entailed a high biological cost.
Conclusions: The findings of this study have proved that efflux activity contributes synergistically with mutations in the ribosomal proteins L4 and L22 to A. butzleri's high-level macrolide resistance. The results further suggest an impact on the bacterial physiology and virulence, with the increased fitness cost justifying the low worldwide prevalence of high-level resistant circulating strains.This work was supported by funds from the CICS-UBI base funding (https://doi.org/10.54499/UIDB/00709/2020) and programme funding (https://doi.org/10.54499/UIDP/00709/2020) with national funds registered in the budget of the Foundation for Science and Technology
Firefighters’ Occupational Exposure in Preparation for Wildfire Season: Addressing Biological Impact
No full text(This article belongs to the Special Issue Firefighters’ Occupational Exposures and Health Risks)The characterization of wildland firefighters’ occupational exposure must consider different exposures, including those at the fire station. The present study aimed to characterize the occupational exposure of 172 Northern Portuguese wildland firefighters in fire stations during the pre-wildfire season of 2021. The biological impact of estimated inhaled doses of PM10 and PM2.5 (indoor/outdoor) was accessed through a buccal micronucleus cytome (BMCyt) assay in exfoliated buccal cells of a subgroup of 80 firefighters. No significant association was found between estimated inhaled doses of PM10 and PM2.5 (mean 1.73 ± 0.43 µg kg−1 and 0.53 ± 0.21 µg kg−1, respectively) and biological endpoints. However, increased frequencies of cell death parameters were found among subjects of the Permanent Intervention Teams (full-time firefighters). The intake of nutritional supplements was associated with a significant decrease in micronucleus frequencies (i.e., DNA damage or chromosome breakage). In addition, our findings showed a significantly increased frequency of cell death endpoints (i.e., nuclear fragmentation) with coffee consumption, while daily consumption of vegetables significantly decreased it (i.e., nuclear shrinkage). Our results provide data on the occupational exposure of wildland firefighters while working in fire stations during the pre-wildfire season, providing the essential baseline for further studies throughout the wildfire season.This work received financial support from the project PCIF/SSO/0017/2018 (http://doi.org/10.54499/PCIF/SSO/0017/2018) by the Fundação para a Ciência e a Tecnologia (FCT), Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through national funds. Filipa Esteves, the PhD grant UI/BD/150783/2020 recipient, is supported by FCT and the European Social Fund (ESF). This work is financed by national funds through the FCT within the scope of projects UIDB/04750/2020 (http://doi.org/10.54499/UIDB/04750/2020) and LA/P/0064/2020 (http://doi.org/10.54499/LA/P/0064/2020), LA/P/0045/2020 (http://doi.org/10.54499/LA/P/0045/2020), UIDP/00511/2020 (http://doi.org/10.54499/UIDP/00511/2020) and UIDB/00511/2020 (http://doi.org/10.54499/UIDB/00511/2020), LA/P/0008/2020 (http://doi.org/10.54499/LA/P/0008/2020), UIDP50006/2020 (http://doi.org/10.54499/UIDP/50006/2020) and UIDB/50006/2020 (http://doi.org/10.54499/UIDB/50006/2020)
Circulating miR-134 in mesial temporal lobe epilepsy: implications in hippocampal sclerosis development and drug resistance
No full text(The RNA World: Non-Coding RNAs and Innovative Therapies in Neurological Disorders - Volume II)Aim: miR-134 has been widely reported as upregulated in experimental and human studies of Mesial Temporal Lobe Epilepsy the most common drug-resistant epilepsy (DRE). Studies have shown that the use of antagomirs, anti-miR-134, may be a promising therapeutic approach to these epilepsies. However, data on miR-134 in other epileptic syndromes is scarce. In this study, we aimed to quantify serum levels of miR-134 in a cohort of patients with Mesial Temporal Lobe Epilepsy-Hippocampal Sclerosis (MTLE-HS) and with Genetic Generalized Epilepsies (GGE). Additionally, we explored the correlation between miR-134 serum levels and clinical parameters, such as age at onset or febrile seizures antecedents, to evaluate its potential as a biomarker and therapeutic target in epilepsy.
Methods: miR-134 levels were evaluated in cell-free serum of 131 patients with epilepsy (75 women, 56 men; age 41.10 ± 13.12 years; 72 with DRE) and 42 healthy individuals (25 women, 17 men; age 42.40 ± 9.80 years). The epilepsy cohort included 77 MTLE-HS patients and 54 GGE patients.
Results: Patients with elevated miR-134 circulating levels were at higher risk of drug-resistant epilepsy (OR [95% CI] = 2.246 [1.111–4.539], p = 0.021). Other risk factors included an older age (OR [95% CI] = 1.032 [1.004–1.061], p = 0.025), history of febrile seizures (OR [95% CI] = 2.994 [1.385–6.471], p = 0.005) and higher disease duration (OR [95% CI] = 1.038 [1.011–1.066], p = 0.006). The strongest predictor of DRE was hippocampal sclerosis (OR [95% CI] = 10.338 [4.566–23.404], p < 0.001). Circulating miR-134 levels were significantly higher in MTLE-HS patients compared to controls (p < 0.05) and GGE patients (p < 0.05). However, the clinical utility of miR-134 in discriminating MTLE-HS patients from controls was only moderated (AUC = 0.651 ± 0.051 95% CI 0.551–0.751, p = 0.007).
Conclusion: We show that miR-134 circulating levels are associated with DRE, especially in MTLE-HS, a syndrome characterized by severe hippocampal damage, consistent with activity-regulated miR-134 expression. This overexpression likely contributes to disease progression and our results support the potential of targeting miR-134 as a novel therapeutic approach for refractory epilepsy.This study was partially funded by a BICE Tecnifar grant. Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by FCT Portugal (grant numbers UIDB/00215/2020, and UIDP/00215/2020), and the Laboratory for Integrative and Translational Research in Population Health (ITR) (LA/P/0064/2020)
Effectiveness of the autumn 2023 COVID-19 vaccine dose in hospital-based healthcare workers: results of the VEBIS healthcare worker vaccine effectiveness cohort study, seven European countries, season 2023/24
No full textCOVID-19 vaccination recommendations prioritise healthcare workers (HCWs), considering their exposure to severe acute respiratory coronavirus 2 (SARS-CoV-2) and their key role in the functioning of healthcare systems. In the European Union/European Economic Area (EU/EEA), HCWs were considered a priority for COVID-19 revaccination during the autumn 2023 campaign [1], and the World Health Organization (WHO) recommended revaccination of HCWs 12 months after their last dose [2]. Because the Omicron sub-lineage XBB.1.5 predominated in spring 2023, the COVID-19 vaccines were adapted to target this emerging strain, and the first XBB.1.5 vaccine was authorised for use in the EU/EEA in August 2023. Omicron BA.2.86/JN.1 emerged in the EU/EEA at the end of 2023, according to data available on the European Respiratory Virus Surveillance Summary (ERVISS) [3]. Evidence for COVID-19 vaccine recommendation in the HCW population remains scarce. Within the Vaccine Effectiveness, Burden and Impact (VEBIS) project, we aimed to measure the COVID-19 vaccine effectiveness (CVE) in HCWs, in the winter season 2023/24.This study was funded by European Centre for Disease Prevention and Control through “Vaccine Effectiveness, Burden and Impact Studies” (VEBIS) Lot 2 “Assessment of COVID-19 and influenza vaccine effectiveness among healthcare workers” framework contract ECDC/2021/017
Adapting to COVID-19: Insights from Portuguese residents' home-based life
No full textBackground: The COVID-19 pandemic led to widespread lockdowns and remote work and educational practices that have impacted the lives of many families.
Objective: We aimed to investigate how parents and caregivers altered their routines due to online schooling and teleworking, exploring their association with increased anxiety and depression symptoms.
Methods: We conducted an online cross-sectional study and collected data through snowball sampling. We asked questions about age, gender, dwelling area, educational level, and marital status, as well as an open-ended question about teleworking and homeschooling - "Did your routine change due to your children being forced to stay home and take online classes? If so, please explain how it has influenced your personal and professional life, both positively and negatively". Thematic analysis was used to analyse the responses.
Results: A total of 181 respondents, primarily women (72.4%), averaging 36.6 years old, holding bachelor's degrees (44.2%), were included. About 78.5% reported routine adjustments. Four salient themes emerged: 1) Perceived changes in professional and personal life, 2) Perceived changes in learning methods, 3) Mental health issues and 4) Perceived advantages of working from home with children at online school. Regarding mental health, 25.4% exhibited symptoms of anxiety, and 7.7% displayed depression symptoms, predominantly linked (80%) to the pandemic's impact.
Conclusion: Family routines were disrupted, causing stress. In future crises, policymakers, public health experts, and researchers must acknowledge these challenges to mitigate negative consequences. Simultaneously, they should focus on strategies that enhance the positive aspects of restrictive measures and related policies.This work received financial support from the Portuguese Funds through FCT – Foundation for Science and Technology, I.P., under the projects UIDB/04750/2020 and LA/P/0064/2020 and DOI identifiers https://doi.org/10.54499/UIDB/04750/2020 and https://doi.org/10.54499/LA/P/0064/2020. It was also partially supported by FCT (reference: CEECINST/00049/2021/CP2817/CT0001 and DOI: 10.54499/CEECINST/00049/2021/CP2817/CT0001). The corresponding author, Ana Aguiar, was supported by her PhD Grant (Reference: 2020.09390.BD; DOI: https://doi.org/10.54499/2020.09390.BD), co-funded by the Fundação para a Ciência e a Tecnologia (FCT) and the Fundo Social Europeu (FSE) Program