Browsing by Author "Oliveira, S."
Now showing 1 - 6 of 6
Results Per Page
Sort Options
- Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivoPublication . Costa, M.; Cruz, E.; Oliveira, S.; Benes, Vl.; Ivacevic, T.; Silva, M.; Vieira, I.; Dias, F.; Fonseca, S.; Gonçalves, M.; Lima, M.; Leitão, C.; Muckenthaler, M.; Pinto, J.; Porto, G.Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.
- MODELO DE ACTUAÇÃO NA ABORDAGEM AO DOENTE SUBMETIDO A TRANSPLANTE DE ÓRGÃO HEPÁTICOPublication . Silva, E.; Silva, I.; Silva, R.; Oliveira, S.
- Multicentric Genome-Wide Association Study for Primary Spontaneous PneumothoraxPublication . Sousa, I.; Abrantes, P.; Francisco, V.; Teixeira, G.; Monteiro, M.; Neves, J.; Norte, A.; Robalo-Cordeiro, C.; Moura-Sá, J.; Reis, E.; Santos, P.; Oliveira, M.; Sousa, S.; Fradinho, M.; Malheiro, F.; Negrão, L.; Feijó, S.; Oliveira, S.Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.
- Physiological implications of NTBI uptake by T lymphocytesPublication . Pinto, J.; Arezes, J.; Dias, V.; Oliveira, S.; Vieira, I.; Costa, M.; Vos, M.; Carlsson, A.; Rikers, Y.; Rangel, M.; Porto, G.In iron overload disorders a significant fraction of the total iron circulates in the plasma as low molecular weight complexes not bound to transferrin, known as non-transferrin-bound iron (NTBI). By catalyzing the formation of free radicals, NTBI accumulation results in oxidative stress and cellular damage, being a major cause of organ toxicity. NTBI is rapidly and preferentially cleared from circulation by the liver and the myocardium, the main disease targets in iron overload conditions. We have recently demonstrated that human peripheral blood T lymphocytes take up NTBI in vitro, with a pattern that resembles that of hepatocytes. Since T lymphocytes constitute a numerically important component of the circulating cell pool, these findings support a putative role for this cell type in the systemic protection against iron toxicity. Here we tested the hypothesis that the circulating peripheral blood T lymphocyte pool constitutes an important storage compartment for NTBI and is thus a modifier of NTBI deposition in target organs. First we show that NTBI uptake by human T lymphocytes increases the expression of the iron-storage protein ferritin and of the iron exporter ferroportin via an IRE-dependent mechanism. NTBI retention by T lymphocytes is shown to be critically controlled by the hepcidin-mediated modulation of ferroportin both in vitro and in vivo. Finally, the protective effect of T lymphocytes was tested by analyzing the patterns of iron accumulation in the T lymphocyte-deficient mouse model Foxn1(nu) before and after reconstitution with T lymphocytes by adoptive transfer. The results confirmed a significant increase of liver and pancreas iron accumulation in T lymphocyte-deficient mice. NTBI accumulation in the liver and spleen was prevented by reconstitution with syngeneic T lymphocytes. Altogether, our results demonstrate that T lymphocytes are important components of a circulating "NTBI storage compartment" and show its physiological relevance as a modifier of tissue iron overload.
- Tuberculose miliar no século XXI – a propósito de um caso clínicoPublication . Pinho, L.; Oliveira, S.; Serino, J.; Febra, T.; Ramos, S.; Silva, C.; Dinis, M.Introdução: Atualmente, a tuberculose ainda representa um sério problema de saúde pública. A idade precoce e a infeção VIH constituem importantes fatores de risco para doença grave ou disseminada. Caso clínico: Apresentamos o caso de uma menina de três anos de idade observada por febre prolongada sem foco infecioso evidente ao exame físico. O estudo analítico inicial foi sugestivo de infeção urinária, pelo que iniciou antibioticoterapia empírica. A urocultura confirmou esse diagnóstico, mas a febre persistiu. Na investigação complementar, a radiografia torácica revelou um infiltrado pulmonar com padrão miliar. O Mycobacterium tuberculosis foi isolado no aspirado gástrico, líquor e urina. Iniciou tratamento com antituberculosos e corticóide, com melhoria clínica significativa. Conclusões: Nesta era de tecnologia médica avançada, a tuberculose ainda é um desafio diagnóstico, especialmente quando a apresentação clínica é atípica e extrapulmonar. Um elevado índice de suspeição clínica é fundamental, pois a instituição precoce do tratamento é decisiva para o prognóstico.
- Tumor carcinóide brônquico: uma imagem que persiste…?Publication . Pinho, L.; Oliveira, S.; Cardoso, J.; Santos, L.; Franco, C.; Coelho, E.RESUMO Introdução: O tumor carcinóide brônquico é raro, mas constitui a neoplasia maligna pulmonar primária mais frequente na idade pediátrica. Tem como principal forma de apresentação clínica a pneumonia recorrente na mesma localização, sendo diagnosticado mais frequentemente na adolescência tardia. O único tratamento potencialmente curativo é cirúrgico e o prognóstico é muito variável. Caso clínico: Os autores apresentam o caso clínico de um adolescente de 16 anos com história de dois episódios de pneumonia na mesma localização em menos de um ano cuja investigação revelou um tumor carcinóide brônquico. Foi submetido a excisão cirúrgica, com evolução favorável. Conclusão: Na abordagem da pneumonia recorrente na mesma localização os tumores endobrônquicos nomeadamente os carcinóides devem ser equacionados, sendo importante um elevado índice de suspeição para o diagnóstico atempado. ABSTRACT Introduction: Although rare, bronchial carcinoid tumor is the most common malignant pulmonary neoplasm in pediatric patients. Recurrent pneumonia in the same pulmonary segment or lobe is the main form of clinical presentation, typically in late adolescence. Surgery is the mainstay of treatment and prognosis is highly variable. Case report: The authors report the case of a sixteen year old boy with a history of two episodes of pneumonia in the same location within less than one year whose investigation revealed a bronchial carcinoid tumor. He underwent surgical excision, with favorable outcome. Conclusion: Endobronchial tumors including carcinoids should be addressed in the approach of recurrent pneumonia in the same location. A high index of suspicion is important for timely diagnosis.