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- An introduction to BASIC Guide: human biomonitoring and surveillance of chemical exposure in occupational settingsPublication . Zare Jeddi, Maryam; Jones, Kate; Leese, Elizabeth; Fustinoni, Silvia; Galea, Karen S.; Santonen, Tiina; Porras, Simo P.; Hopf, Nancy B.; Göen, Thomas; Bader, Michael; Tranfo, Giovanna; Tristram, Adrian; Iavicoli, Ivo; Leso, Veruscka; Koch, Holger M.; Pasanen-Kase, Robert; Boogaard, Peter J.; Persoons, Renaud; Esteban-López, Marta; Verpaele, Steven; Kasiotis, Konstantinos M.; Machera, Kyriaki; Carrieri, Mariella; Palmen, Nicole; Duca, Radu-Corneliu; van Nieuwenhuyse, An; Gonzales, Melissa; Haynes, Erin N.; Viegas, Susana; Bessems, Jos; Makris, Konstantinos C.; Connolly, Alison; Teixeira, João Paulo; Chung, Ming Kei; Parsons, Patrick J.; Kumar, Eva; Lin, Elizabeth Ziying; Kil, Jihyon; Kwon, Jung-Hwan; Tavares, Ana Maria; Vekic, Ana Maria; Souza, Gustavo; Scheepers, Paul T. J.Human biomonitoring (HBM) complements air and surface measurements by integrating exposure from all routes and sources, strengthening occupational exposure assessment and control. In occupational settings, HBM can quantify exposure during routine work and nonroutine activities, evaluate controls, investigate incidents (potential overexposures), and support medical surveillance. To use HBM to its full potential, occupational health and safety professionals (OHPs) should adopt harmonized biomonitoring approaches reflecting best practice. This short communication presents the BASIC Guide series (Human Biomonitoring and Surveillance of Chemical Exposure in Occupational Settings), initiated by the International Society of Exposure Science Human Biomonitoring working group (ISES Europe HBM WG) as an integral part of the HBM Global Network. These chemical-specific practical documents operationalize the OECD (Organisation for Economic Co-operation and Development) occupational biomonitoring guidance, supporting the consistent implementation of exposure biomonitoring programs. Each BASIC Guide provides clear instructions on biomarker selection, sample handling, analytical methods, quality assurance, and result interpretation and communication. By translating international frameworks into actionable protocols, the BASIC Guides improve reproducibility and regulatory alignment in occupational HBM and enable more defensible exposure assessments worldwide.
- Atypical MEGDHEL Syndrome: A Milder Phenotype With Hepatic Presentation and Failure to Thrive Associated With a Homozygous Nonsense Variant of SERAC1Publication . Marchante Pita, Rita; Amaral, Raquel; Vilarinho, Laura; Diogo, Luísa; Gonçalves, Isabel; Nobre, SusanaMEGDHEL syndrome, caused by a gene defect, is clinically defined as the association of 3-MGA-uria (MEG), deafness (D), hepatopathy (H), encephalopathy (E), and Leigh-like features (L). Clinical presentation typically begins in the neonatal period, with neurological symptoms becoming more evident by 2 years of age. Severe liver involvement has also been reported. We report the case of a 3-year-old boy with increased transaminases and failure to thrive of unknown cause. He was born prematurely at 35 weeks and needed neonatal intensive care support for 24 h due to transient tachypnea. At 18 months, laboratory investigations for failure to thrive revealed elevated transaminases without cholestasis, which persisted on subsequent evaluations. Abdominal wall collateral veins were found during physical examination, and the liver ultrasound revealed steatosis, prompting the decision to proceed with a liver biopsy. Common causes of chronic liver disease were ruled out. Following liver biopsy, performed under general anesthesia, he had an episode of unexplained decompensation (metabolic acidosis, hyperlactatemia, and 3-methylglutaconic aciduria). The aciduria persisted upon subsequent evaluation. Liver histology showed macro/microvesicular steatosis (25%), portal tract inflammation, and mild fibrosis. Cardiac evaluation, along with brain magnetic resonance imaging and spectroscopy, was normal. Further investigations revealed decreased hepatic activity of respiratory mitochondrial chain complexes and marginal mtDNA depletion (28.1%). Analysis of the gene showed homozygosity for p.Y259* (c.777T>G, exon 9). This case report raises awareness for an atypical presentation of MEGDHEL syndrome associated with a homozygous nonsense variant of SERAC1 clinically characterized by mild hypertransaminasemia, failure to thrive, no neurological involvement, and starting in early childhood rather than infancy.
- A 30-year experience in neuro-Behçet diseasePublication . Silva, Lénia; Silva, Isabel Fonseca; Fonseca, Tomás; Pinto, Luísa Serpa; Leal, Bárbara; Pinho e Costa, Paulo; Igreja, Liliana; Moreira, Bruno; Santos, Ernestina; Vasconcelos, Carlos; Marinho, António; Correia, João AraújoBackground: Behçet disease (BD) is a systemic vasculitis affecting multiple organs with a wide range of severity. Neuro-Behçet (NBD) is a severe form, characterized by high morbidity, disability, and mortality rates. Methods: Retrospective analysis (1993-2023) of neurological involvement in BD patients at a tertiary center. Results: Of 296 BD patients, 93(31.4 %) underwent neurological evaluation. Definite NBD was identified in 30(10.1 %), probable NBD in 2(0.5 %) and "other neurological symptoms in BD" in 26(8.6 %) patients. The definite NBD group (median age: 36 years, 50 % female) had 44 neurological attacks: 24(55 %) parenchymatous and 20(45 %) non-parenchymatous. The most common syndromes were brainstem (27.3 %) and multifocal (25.6 %), with ataxia being the most frequent sign (40.9 %). One-third had a relapsing course. NBD onset concurred with BD diagnosis in 50 % of cases, followed in 30 %, and preceded in 20 %. Brain MRI revealed predominant involvement of the brainstem and diencephalic regions. The HLA-B*51 allele was more prevalent in definite NBD versus BD patients (53.8 % vs 31.2 %, p = 0.036). Treatments included corticosteroids (70.5 %), cyclophosphamide (15.9 %), infliximab (9.1 %), and conventional synthetic disease-modifying antirheumatic drugs (13.6 %). Better outcomes were achieved with cyclophosphamide and infliximab. The probable NBD and "other neurological symptoms in BD" groups (median age: 37 years) were mostly female (92.9 %). Headache (85 %) and cognitive complaints (23 %) were common symptoms.
- The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditionsPublication . Martins-Ferreira, Ricardo; Calafell-Segura, Josep; Leal, Bárbara; Rodríguez-Ubreva, Javier; Martínez-Saez, Elena; Mereu, Elisabetta; Pinho e Costa, Paulo; Laguna, Ariadna; Ballestar, EstebanDysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer's disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies.
- Distinct exercise modalities on GUT microbiome in sarcopenic older adults: study protocol of a pilot randomized controlled trialPublication . Merelim, Ana Sofia; Zacca, Rodrigo; Moreira-Gonçalves, Daniel; Costa, Paulo P.; C. Baptista, LilianaBackground: Sarcopenia is a progressive and age-related skeletal muscle disease related to adverse health outcomes and to an increased economic burden. Recent evidence pinpoints the human gut microbiota (GM) as a contributing factor in the development of sarcopenia via the gut-muscle axis. To date, no study specifically analyzed the optimal type of exercise modality in older adults with sarcopenia considering the impact of GM composition in skeletal muscle mass and function. Therefore, the DEMGUTS study intents to explore the impact of three different exercise regimens on GM composition and gut-derived metabolites in older adults with sarcopenia. Methods:: This pilot single center three-arm parallel open-label randomized control trial (RCT) will randomly assign eligible participants to: (i) moderate aerobic exercise (AER); (ii) resistance exercise (RES); or (iii) concurrent exercise training (RES + AER). Participants will engage in a supervised center-based exercise intervention (12-weeks, 3 d/week, 60 min/d), and will be assessed at (i) baseline, (ii) end of intervention (14 weeks), and (iii) at close-out (26-weeks). The primary outcome will be the change in the relative abundance of Faecalibacterium prausnitzi and other short-chain fatty acid producing bacteria after the intervention (14-weeks). A set of complementary outcomes will also be assessed to broadly characterize the impact of each exercise intervention on body composition, skeletal muscle function, functional performance and general GM composition. Conclusion: Unraveling the impact of these exercise regimens on GM is crucial to help clarify the optimal exercise modality to manage sarcopenia disease, contributing to clinical guidance and enhancing exercise prescription in older adults with sarcopenia. Clinical trial registration identifier NCT06545123
- Do (xeno)estrogens pose a risk to earthworms? Soy isoflavones and estradiol impact gonad structure and induce oxidative stress in Eisenia fetidaPublication . Azevedo, Tiago; Silva-Reis, Rita; Medeiros-Fonseca, Beatriz; Gonçalves, Mariana; Mendes, Gabriel; Roboredo, Marta; Rocha, Maria J.; Peixoto, Francisco; Pinto, Maria de Lurdes; Matos, Manuela; Sousa, João R.; Oliveira, Paula A.; Coimbra, Ana M.Understanding the impact of endocrine disruptor compounds (EDCs) across a wide range of species is crucial, given their ubiquitous presence. Although invertebrate species lack sex steroid hormone pathways, they exhibit sensitivity to EDCs, which could affect population dynamics. This study assessed reproductive endpoints and oxidative stress parameters in Eisenia fetida following exposure to estradiol and soy isoflavones, resembling the concentrations found in livestock manure. The experiment used artificial soil, as recommended by OECD guidelines (7:2:1 sand, kaolin and peat). Adult specimens were randomly divided into seven groups (n = 11/replicate): one control, three estradiol (156.1, 283.4 and 633.8 μg/kg of dry soil) and three soy isoflavones (113.0, 215.3 and 405.0 mg/kg of dry soil) concentrations. After eight weeks, samples were collected for cytological, histological and biochemical analysis. Offspring development was assessed after 12 additional weeks. Higher estradiol and isoflavone concentrations led to lower germ cell number and increased abnormalities, especially in the seminal vesicles and ovaries. Catalase and peroxidase activities were significantly increased in all treated groups. The exposure did not significantly affect the number of E. fetida offspring. These findings highlight E. fetida’s sensitivity to EDCs at a biochemical and tissue level, suggesting its use as a bioindicator for assessing EDC contamination in soils.
- Lipidome plasticity in medium- and long-chain fatty acid oxidation disorders: Insights from dried blood spot lipidomicsPublication . Guerra, Inês; Rocha, Hugo; Moreira, Sónia; Gaspar, Ana; Ferreira, Ana C.; Santos, Helena; Rodrigues, Esmeralda; Castro-Chaves, Paulo; Melo, Tânia; Goracci, Laura; Domingues, Pedro; Moreira, Ana S.P.; Domingues, M. RosárioFatty acid (FA) oxidation disorders (FAOD) are characterized by accumulation of specific acylcarnitines (CAR)and FA and can lead to potentially severe complications. In this study, dried blood spots (DBS) combined with LC-MS lipidomics analysis were used to assess lipidome plasticity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), compared to control (CT) individuals, for screening potential prognostic biomarkers. Statistically significant variations were found in CAR, biomarkers for FAOD diagnosis, but other lipid species showed variations depending on the FAOD. Common changes in all FAOD included a few phosphatidylcholine (PC) lipid species, notably an up-regulation of LPC 16:1, possibly associated with a higher risk of cardiovascular disease (CVD). In LCHADD and VLCADD, an up-regulation of odd-chain PC (PC 33:0, PC 35:4 and PC 37:4) was observed. VLCADD exhibited higher levels of odd-chain TG, while LCHADD showed an up-regulation of ceramide (Cer 41:2;O2). The increase in the Cer class has been found to be associated with neurodegeneration and may contribute to the risk of developing this condition in LCHADD. An upregulation of ether-linked PC lipid species, including plasmenyl (known as endogenous antioxidants), was observed in MCADD, possibly as a response to increased oxidative stress reported in this disorder. Overall, DBS combined with lipidomics effectively pinpoints the lipid plasticity in FAOD, highlighting potential specific biomarkers for disease prognosis that warrant further validation for their association with the development of FAOD comorbidities.
- Unraveling the genome-wide repertoire of the novel chromosomally encoded mcr-8.6 gene variant in Klebsiella michiganensis isolated from manurePublication . Rivière, Rani; Teixeira, Pedro; Silva, Catarina; Ramos, Miguel; Dias, Elsa; Manageiro, Vera; Caniça, ManuelaThe increasing rates of colistin resistance worldwide poses a significant threat to public health. While the most commonly described variant is , other variants such as have been detected, typically associated with . However, little is known about the prevalence of in other bacterial species and environmental reservoirs. This study aimed to characterize a novel subvariant identified in a strain isolated from manure in Portugal, collected during an annual longitudinal survey at an Open Air laboratory, as well as to depict its genomic context and potential mobility mechanisms. The strain was subjected to phenotypic susceptibility testing, whole-genome sequencing and hybrid genome assembly. analysis included identification of resistance genes and mobile genetic element. The new gene variant and its genetic environment were characterized. The F731 strain presented susceptibility to colistin with a MIC = 0.25 mg/L, despite carrying a novel subvariant, , which was located within a 61.6 kb chromosomal genomic island. This variant presented 23-24 amino acid substitutions compared to previous characterized MCR-8 proteins. The genomic island also harbored multiple insertion sequences (IS, IS, IS), virulence factors, and metabolic and regulatory proteins, among others. Synteny analysis revealed high sequence identity between this genomic island and both chromosomal and plasmid regions from other bacterial strains isolated from different reservoirs worldwide, indicating prior mobility. Furthermore, other antimicrobial resistance genes were detected [e.g., ', ], but no plasmid replicons were identified. This is the first report of a gene in a , as well as the first occurrence in Portugal. Although F731 remains colistin-susceptible, the presence of a novel chromosomally encoded but located in a mobile genomic island underscores the risk of future horizontal gene transfer. These findings highlight the importance of further monitoring and continued surveillance in environmental and animal compartments in order to track the dissemination of antimicrobial resistance.
- BlaGES-6 producing Pseudomonas aeruginosa ST235 is involved in resistance to different β-lactamsPublication . de Sousa, Telma; Machado, Sandro; Carvalho, Márcia; Caniça, Manuela; Ramos, Miguel J.N.; Santos, Daniela; Beyrouthy, Racha; Bonnet, Richard; Hébraud, Michel; Gomes, João Paulo; Igrejas, Gilberto; Poeta, PatríciaMultidrug resistance in Pseudomonas aeruginosa, particularly resistance to carbapenem, represents a major challenge for public health. This study investigated resistance mechanisms in three P. aeruginosa isolates: HU63 (blaGES-6 carbapenemase-positive), HU141 (carbapenem-resistant without carbapenemase), and PAO1 (control). Genomic analysis revealed distinct sequence types (ST235 for HU63, ST253 for HU141) and chromosomal integration of resistance genes. HU63 harbored diverse resistance mechanisms, including β-lactamases (bla, bla, bla) and efflux pumps. Minimum inhibitory concentration assays demonstrated HU63's resistance to all β-lactams tested (meropenem, imipenem-cilastatin, ceftazidime, piperacillin-tazobactam), while HU141 remained susceptible except to cefoxitin and cloxacillin. Time-kill assays revealed tolerance phenotypes, with HU63 showing regrowth after 8-24 h despite initial reductions in bacterial density. Gene expression varied significantlydepending on the antibiotic and the isolate. The HU63 isolate (GES-6 positive) stands out for its marked induction of bla in all the antibiotics tested, contributing to its resistance to carbapenems and broad-spectrum cephalosporins. These expression profiles corroborate the classic molecular mechanisms of resistance: regulation of entry pores (oprD), activation of efflux pumps (mexA) and production of β-lactamases (bla, ampC) adapted to each situation. These findings underscore the multifactorial nature of resistance in Carbapenem-resistant Pseudomonas aeruginosa (CRPA), combining enzymatic inactivation, efflux, and genetic adaptability. The study emphasizes the urgent need for genomic surveillance to track high-risk clones and develop therapies targeting tolerance mechanisms alongside traditional resistance.
- LIMP-2 deficiency-associated glycolipid abnormalities in micePublication . da Silva Gaspar, Paulo Jorge Miranda; Marques, André R.A.; Ferraz, Maria J.; Damme, Markus; Krame, Gertjan; Mirzaian, Mina; Gijbels, Marion; Ottenhoff, Roelef; van Roomen, Cindy; Overkleeft, Herman S.; Schwake, Michael; Heybrock, Saskia; Macário, Maria Carmo; Saftig, Paul; Aerts, Johannes M.Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 − /− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 − /− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 − /− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.