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- Challenges of Congenital HHV6 Infection Diagnosis and Treatment: Two Case Reports and Literature ReviewPublication . Fernandes, Andreia; Pereira, Mafalda; Oliveira, Íris; Novo, Marta; Soares, Marta; Ramalho, Ana Raquel; Santos, Vera; Vinagre, Elsa; Lopo, Silvia; Gaspar, LuísaIntroduction: Congenital human herpesvirus 6 (HHV6) infection occurs in 1% of the general population and may result from the transmission of an inherited chromosomally integrated HHV6 (iciHHV6) or transplacental infection. It is mostly asymptomatic. Case reports: Case 1: a 29th-week-old female preterm newborn, admitted to the neonatal intensive care unit, became clinically unstable and irritable on the 20th day of hospitalization. Cranial ultrasound, revealed a significant posthemorrhagic tetraventricular dilation, with signs of ventriculitis. Investigations revealed HHV6 positivity on cerebrospinal fluid polymerase chain reaction multiplex panel testing and HHV6-DNA high viral loads in plasma samples. Case 2: a female late preterm newborn was admitted to the neonatal intensive care unit due to early-onset sepsis. Investigations revealed group B streptococcus positive blood cultures and cerebrospinal fluid HHV6 positivity on polymerase chain reaction multiplex panel testing, with negative bacterial culture. After 3 days of adequate antibiotic treatment, she maintained persistent moaning, which motivated a cranial ultrasound, revealing mild brain edema. Clinical improvement was observed only after beginning antiviral treatment in both newborns. Due to the persistency of high viral loads in both cases, despite antiviral treatment and clinical improvement, an iciHHV6 was suspected and posteriorly confirmed. Discussion/conclusion: Congenital iciHHV6 infection diagnosis is challenging because the presence of an iciHHV6 results in persistently high viral loads, even in the absence of active infection. Only a few diagnostic techniques can confirm active replication; unfortunately, these are not available in most countries. The decision to initiate antiviral treatment should be based on clinical judgment. Better ways for the diagnosis of active infection are needed.
- Pharmacogenomic Risk Profiling of Statin Response in Portuguese Familial Hypercholesterolemia and General Population CohortsPublication . Chora, Joana Rita; Grade, M. M.; Antunes, M.; Bourbon, M.Background/Aims: Genetic variants in pharmacogenes involved in statin transport, metabolism, and excretion can increase the risk of adverse effects, particularly statin-associated musculoskeletal symptoms (SAMS). Loss-of-function haplotypes in SLCO1B1 are reliably linked to elevated SAMS risk. Familial hypercholesterolemia (FH), a high cardiovascular disease risk condition, requires lifelong lipid-lowering therapy, often from a young age. However, studies of statin pharmacogenomics in FH patients remain scarce. The Portuguese population, shaped by millennia of admixture, displays a complex genetic background with potential implications for pharmacogenomic diversity. This study aimed to assess the prevalence of high-risk alleles in genes related to statin metabolism and transport, including variants relevant to therapeutic efficacy, in both the general Portuguese population and FH patients. Methods: We analysed 738 adults from the nationally representative e_Cor cohort and 489 clinical FH patients. Genotyping of 13 statin-related single-nucleotide variants (SNV) was conducted using both OpenArrayTM technology and NGS target sequencing. Statin-medicated individuals from both cohorts (N=903) were further analysed for pharmacogenomic risk. Results: Compared to public databases, the frequency of the APOE rs429358 risk allele was significantly lower in the general Portuguese cohort, but significantly higher in statin-medicated individuals and FH patients. Genotype distributions of SLCO1B1, ABCB1, HMGCR, and MTHFR SNVs differed significantly between medicated individuals from the general population and FH patients. Among all participants, 2% had SLCO1B1 poor-function and 22% decreased-function haplotypes; these frequencies were slightly higher in the medicated group (3% and 23%, respectively). Notably, 40% of poor-function and 32% of decreased-function carriers were prescribed a statin dose/type considered high-risk for SAMS. Differences between FH-positive and negative individuals were only observed for APOE rs429358. Conclusion: This study presents a comprehensive overview of statin-related pharmacogenetic variation in the Portuguese population and FH patients. The high prevalence of actionable variants underlines the importance of pharmacogenomic-informed prescribing in high-risk groups. Integrating genetic information into clinical decision-making can optimise statin therapy, mitigate adverse effects, and enhance the effectiveness of personalised lipid-lowering strategies in Portugal.
- Principais alterações da norma ISO 7218Publication . Caiado Rocha, CristinaNesta formação dirigida a toda a equipa do Laboratório de Microbiologia do Departamento de Alimentação e Nutrição do INSA Porto (DAN P), foram abordadas as principais alterações da nova Norma ISO 7218:2024 - Microbiology of the food chain General requirements and guidance for microbiological examinations” e o seu impacte no trabalho laboratorial realizado no Laboratório de Microbiologia do DAN P.
- Translational regulation of the human PERK by upstream open reading framesPublication . Silvestre, SamuelUpstream open reading frames (uORFs) are cis-acting elements located within the 5’ leader sequence (5’UTR) of transcripts, which can regulate protein synthesis, i.e. mRNA translation, of the correspondent main open reading frame (mORF). During endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins activates the ER-resident PKR-like ER kinase (PERK), which results in phosphorylation of eIF2α to inhibit global mRNA translation, while allowing the selective uORF-mediated translation of downstream effectors responsible for stress resolution or, ultimately, cell death. The dual role of PERK in regulating cell fate was implicated in human diseases, like diabetes, neurodegenerative disorders and cancer. Moreover, mutations in the EIF2AK3 gene (encoding PERK) were associated with the rare genetic disease, Wolcott-Rallison Syndrome (WRS). In this work, we aimed to study the translational regulatory role of 5 AUG- and 3 non-AUG-uORFs identified in the PERK 5’UTR and assess its biological relevance. Altogether, we highlight the importance of including 5’UTRs in the screening of disease-related mutations and the necessity of functional studies to assess their role in pathogenesis.