Browsing by Author "Pinto, J."
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- Anomalias congénitas gastrintestinais e da parede abdominalPublication . Rocha, G.; Pinto, S.; Pinto, J.; Monteiro, J.; Guedes, M.RESUMO Introdução: as anomalias congénitas gastrintestinal e da parede abdominal anterior constituem um grupo frequente de patologias em cuidados intensivos, sendo responsáveis por elevadas morbilidade e mortalidade neonatais. Objectivos: caracterização e avaliação da importância destas anomalias numa unidade de cuidados intensivos neonatais. Material e métodos: estudo retrospectivo das referidas anomalias congénitas, diagnosticadas em 142 recém-nascidos admitidos na Unidade de Cuidados Intensivos do Serviço de Neonatologia do Hospital de São João, entre 1 de Janeiro de 1997 e 31 de Dezembro de 2001. Resultados: a amostra estudada, 106 casos de anomalia gastrintestinal e 36 de defeito da parede abdominal anterior, representou 5% (142/2717) do total de admissões da unidade e 25% (142/566) de todos os recém-nascidos com anomalia(s) congénita(s). A anomalia congénita "per si" foi o motivo do internamento em 123 (87%) casos. Foram identificados possíveis factores de risco em oito (6%) casos e o diagnóstico pré-natal correcto foi efectuado em 37 (26%) casos.Em nove (6%) casos verificou-se associação a anomalia cromossómica. Foram também, identificados dois síndromas, três casos de associação VATER e uma sequência malformativa. O tempo de internamento médio foi de 17,6 dias. Faleceram nove (6%) recém-nascidos. Conclusões: as anomalias congénitas gastrintestinais e da parede abdominal representam um grupo de patologias com importância significativa numa unidade de cuidados intensivos neonatais, não apenas pelas elevadas frequência, morbilidade e mortalidade, mas também pela complexidade de alguns casos exigindo apoio multidisciplinar. O diagnóstico pré-natal é de fundamental importância, permitindo propor, nalguns casos, a interrupção da gestação ou orientar o parto para centros com cuidados perinatais diferenciados.ABSTRACT Introduction: congenital anomalies of the gastrointestinal tract and anterior abdominal wall, a frequently observed group of diseases in neonatal intensive care units, contribute to high morbidity and mortality among newborn infants. Objectives: to characterize and estimate the contribution of these anomalies to the admission to a neonatal intensive care unit. Population and methods:a retrospective chart review was carried out in 142 newborns, presenting with congenital anomalies of the gastrointestinal tract or anterior abdominal wall, admitted to Hospital de São João Neonatal Intensive Care Unit, between 01/01/97 and 31/ 12/01. Results: a total of 106 gastrointestinal and 36 anterior abdominal wall defects were reviewed, representing 5% (142/2717) of the overall admissions and 25% (142/566) of the newborns presenting with a congenital anomaly. The anomaly was directly related to the hospitalization in 123 (87%) of the cases. Possible risk factors were identified in eight (6%) newborns and correct prenatal diagnosis was carried out in 37 (26%) pregnancies. Nine (6%) cases were associated with a chromosomal anomaly. Two syndromes, three VATER association and a sequence were identified. Mean hospitalization length was 17,6 days and nine (6%) newborns died. Conclusions: congenital anomalies of the gastrointestinal tract and anterior abdominal wall represent a group of diseases of great concern in neonatology, not only because of their frequency, morbidity and mortality rates, but also because of the complexity of some cases, imposing a multidisciplinary approach. Prenatal diagnosis is of great importance, making pregnancy interruption possible in some cases, or to direct births into a secondary or tertiary care center.
- Effects of highly conserved major histocompatibility complex (MHC) extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areasPublication . Costa, M.; Cruz, E.; Barton, J.; Thorstensen, K.; Morais, S.; da Silva, B.; Pinto, J.; Vieira, C.; Vieira, J.; Acton, R.; Porto, G.Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+)T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+) T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8(+) T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+) T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8(+) T-lymphocyte numbers.
- Encefalopatia multiquística - a propósito de dois casos clínicosPublication . Pereira, B.; Pereira, C.A.; Pinto, J.; Santos, M.Introdução: A encefalopatia multiquística é uma entidade rara, em que o parênquima cerebral é substituído por quistos de vários tamanhos. Tem sido associada a múltiplas causas: transfusão feto-fetal em gravidez gemelar monozigótica, encefalopatia neonatal, infeções do sistema nervoso central, acidente vascular cerebral, trauma, hipotensão materna severa, entre outras. O fator comum que liga todas estas situações é a ocorrência de hipóxia cerebral grave. O seu diagnóstico baseia-se em exames de neuroimagem, sendo a ecografia transfontanelar o exame de primeira linha. É uma patologia de mau prognóstico que, na maioria dos casos, evolui para disfunção neurológica severa progressiva até à morte. Casos clínicos: Os autores apresentam dois casos clínicos de encefalopatia multiquística, ambos de apresentação neonatal precoce mas distinta. Discussão/Conclusão: O conhecimento desta entidade, dos seus fatores de risco e da sua importante morbimortalidade infantil, são essenciais para o seu reconhecimento precoce e abordagem adequada.
- O Laboratório de exploração funcional respiratória no lactentePublication . Borrego, L.; Pinto, P.; Neuparth, N.; Pinto, J.
- 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.
- Miosite orbitária numa criançaPublication . Fraga, J.; Sá, A.; Cândido, C.; Pinto, J.; Dias, F.Introdução: A doença inflamatória orbitária caracteriza-se por um processo inflamatório, de etiologia desconhecida, que pode atingir qualquer estrutura da órbita. Apresentamos um caso clínico da forma que envolve os músculos extraoculares (miosite orbitária). Caso clínico: Criança do sexo masculino com nove anos de idade, sem antecedentes patológicos de relevo, que iniciou subitamente dor ocular à direita, acompanhada de edema palpebral homolateral. À observação, apresentava proptose, edema palpebral moderado com rubor local, limitação da elevação da pálpebra e da elevação e abdução do olho direito, com diplopia. A investigação efectuada sugeriu o diagnóstico de miosite orbitária, tendo iniciado terapêutica com corticóide sistémico com resolução do quadro. Discussão: O presente caso descreve uma entidade nosológica rara em idade pediátrica, habitualmente benigna, mas que se não reconhecida e tratada precocemente, pode originar sequelas da mobilidade ocular. ABSTRACT Background: Orbital inflammatory disease is characterized by an inflammatory process of unknown etiology, which may affect any structure of the orbit. We describe a case report of inflammation of the extraocular muscles (orbital myositis). Case report: A previously healthy nine year-old male, with negative paste medical history, presented with right eye pain and homolateral eyelid swelling of sudden onset. On physical examination there was proptosis, eyelid edema with moderate local redness, and diplopia with limitation in the elevation of the eyelid and of abduction and elevation of the eye. The investigation suggested the diagnosis of orbital myositis. Intravenous corticosteroid therapy was started with clinical improvement. Discussion: This case report reports a rare, usually benign, entity in children, which if not early recognized and treated may cause persistent eye motility dysfunction.
- Non-Transferrin-Bound Iron (NTBI) Uptake by T Lymphocytes: Evidence for the Selective Acquisition of Oligomeric Ferric Citrate SpeciesPublication . Arezes, J.; Costa, M.; Vieira, I.; Dias, V.; Kong, X.; Fernandes, R.; Vos, M.; Carlsson, A.; Rikers, Y.; Porto, G.; Rangel, M.; Hider, R.; Pinto, J.Iron is an essential nutrient in several biological processes such as oxygen transport, DNA replication and erythropoiesis. Plasma iron normally circulates bound to transferrin. In iron overload disorders, however, iron concentrations exceed transferrin binding capacity and iron appears complexed with low molecular weight molecules, known as non-transferrin-bound iron (NTBI). NTBI is responsible for the toxicity associated with iron-overload pathologies but the mechanisms leading to NTBI uptake are not fully understood. Here we show for the first time that T lymphocytes are able to take up and accumulate NTBI in a manner that resembles that of hepatocytes. Moreover, we show that both hepatocytes and T lymphocytes take up the oligomeric Fe3Cit3 preferentially to other iron-citrate species, suggesting the existence of a selective NTBI carrier. These results provide a tool for the identification of the still elusive ferric-citrate cellular carrier and may also open a new pathway towards the design of more efficient iron chelators for the treatment of iron overload disorders.
- 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.
- A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron.Publication . Porto, G.; Roetto, A.; Daraio, F.; Pinto, J.; Almeida, S.; Bacelar, C.; Nemeth, E.; Ganz, T.; Camaschella, C.Blood. 2005 Oct 15;106(8):2922-3. A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron. Porto G, Roetto A, Daraio F, Pinto JP, Almeida S, Bacelar C, Nemeth E, Ganz T, Camaschella C. PMID: 16204153 [PubMed - indexed for MEDLINE]Free Article Publication Types, MeSH Terms, SubstancesPublication Types: Letter Research Support, Non-U.S. Gov't MeSH Terms: Antimicrobial Cationic Peptides/genetics* Antimicrobial Cationic Peptides/urine Glycine/genetics* Hemochromatosis/genetics Homozygote* Humans Iron/pharmacology* Mutation/genetics Portugal Promoter Regions, Genetic/genetics* Transcription, Genetic/genetics* Up-Regulation/drug effects* Substances: Antimicrobial Cationic Peptides hepcidin Glycine Iron LinkOut - more resourcesFull Text Sources: HighWire Press EBSCO Other Literature Sources: COS Scholar Universe Medical: Genetics Home Reference - HAMP Gene - Genetics Home Reference Molecular Biology Databases: IRON - HSDB GLYCINE - HSDB
- The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysisPublication . Slogrove, A.; Schomaker, M.; Davies, M.; Williams, P.; Balkan, S.; Ben-Farhat, J.; Calles, N.; Chokephaibulkit, K.; Duff, C.; Eboua, T.; Kekitiinwa-Rukyalekere, A.; Maxwell, N.; Pinto, J.; Seage, G.; Teasdale, C.; Wanless, S.; Warszawski, J.; Wools-Kaloustian, K.; Yotebieng, M.; Timmerman, V.; Collins, I.; Goodall, R.; Smith, C.; Patel, K.; Paul, M.; Gibb, D.; Vreeman, R.; Abrams, E.; Hazra, R.; Van Dyke, R.; Bekker, L.; Mofenson, L.; Vicari, M.; Essajee, S.; Penazzato, M.; Anabwani, G.; Q Mohapi, E.; N Kazembe, P.; Hlatshwayo, M.; Lumumba, M.; Goetghebuer, T.; Thorne, C.; Galli, L.; van Rossum, A.; Giaquinto, C.; Marczynska, M.; Marques, L.; Prata, F.; Ene, L.; Okhonskaia, L.; Rojo, P.; Fortuny, C.; Naver, L.; Rudin, C.; Le Coeur, S.; Volokha, A.; Rouzier, V.; Succi, R.; Sohn, A.; Kariminia, A.; Edmonds, A.; Lelo, P.; Ayaya, S.; Ongwen, P.; Jefferys, L.; Phiri, S.; Mubiana-Mbewe, Mw.; Sawry, S.; Renner, L.; Sylla, M.; Abzug, M.; Levin, M.; Oleske, J.; Chernoff, M.; Traite, S.; Purswani, M.; Chadwick, E.; Judd, A.; Leroy, V.Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.