Browsing by Author "Ferreira, T"
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- Biomarkers and Genetic Modulators of Cerebral Vasculopathy in Sub-Saharan Ancestry Children With Sickle Cell AnemiaPublication . Silva, M; Vargas, S; Coelho, A; Ferreira, E; Mendonça, J; Vieira, L; Maia, R; Dias, A; Ferreira, T; Morais, A; Soares, IM; Lavinha, J; Silva, R; Kjöllerström, P; Faustino, PWe investigated biomarkers and genetic modulators of the cerebral vasculopathy (CV) subphenotype in pediatric sickle cell anemia (SCA) patients of sub-Saharan African ancestry. We found that one VCAM1 promoter haplotype (haplotype 7) and VCAM1 single nucleotide variant rs1409419_T were associated with stroke events, stroke risk, as measured by time-averaged mean of maximum velocity in the middle cerebral artery, and with high serum levels of the hemolysis biomarker lactate dehydrogenase. Furthermore, VCAM-1 ligand coding gene ITGA4 variants rs113276800_A and rs3770138_T showed a positive association with stroke events. An additional positive relationship between a genetic variant and stroke risk was observed for ENPP1 rs1044498_A. Conversely, NOS3 variants were negatively associated with silent cerebral infarct events (VNTR 4b_allele and haplotype V) and CV globally (haplotype VII). The -alpha3.7kb-thal deletion did not show association with CV. However, it was associated with higher red blood cell and neutrophil counts, and lower mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width. Our results underline the importance of genetic modulators of the CV sub-phenotype and their potential as SCA therapeutic targets. We also propose that a biomarker panel comprising biochemical, hematological, imaging and genetic data would be instrumental for CV prediction, and prevention.
- Bombas de Efluxo em Pseudomonas Aeruginosa. Importância Clínica na TerapêuticaPublication . Caneiras, C; Marcos, C; Ferreira, T; Hanscheid, T; Melo-Cristino, J; Duarte, AAs infecções severas causadas por Pseudomonas Aeruginosa têm assumido na última década um papel de destaque, dado tratar-se de um microrganismo de difícil erradicação e com elevada resistência intrínseca e adquirida. Em P. aeruginosa foram caracterizados sete sistemas de bombas de efluxo, os quais contribuem para o desenvolvimento de fenótipos de multiresistência às classes de antibióticos clinicamente mais relevantes. Dado que a terapêutica seleccionada pode actuar como indutora e originar eventos mutacionais que promovem a hiperexpressão das bombas de efluxo, o tratamento destas infecções constitui um grande desafio terapêutico e impõe um conhecimento actualizado desta temática. Esta revisão foi assim desenvolvida com o intuito de rever a contribuição da hiperexpressão dos sistemas de bombas de efluxo em P.aeruginosa, na multirresistência aos antibióticos. Pretendeu-se também avaliar a possibilidade da utilização destes sistemas como alvos terapêuticos de modo a restabelecer a susceptibilidade aos antibióticos disponíveis.
- Cateter Ciático Popliteu: Uma Aposta Segura?Publication . Silva, B; Pinto, N; Ferreira, TO bloqueio contínuo de nervos periféricos (BCNP), descrito inicialmente em 1946 (1), consiste na colocação e utilização de um cateter percutâneo adjacente a um ou vários nervos periféricos para administração de anestésico local. A utilização de cateteres perineurais permite prologar a analgesia associada a técnica single shot, que dura, habitualmente, 24 horas. Apesar de bem estudado para analgesia no pos-operatório, o BCNP tem actualmente várias indicações descritas como tratamento de soluços(2), de vasospasmo associado a Doença de Raynaud (3), simpaticectomia e vasodilatação após cirurgia vascular (4), reimplantação de membros amputados(5), analgesia em trauma(6) e tratamento de dor cronica (7). Apesar de estar provado que no tratamento da dor pós-operatória o uso de cateteres perineurais permite uma analgesia mais eficaz comparativamente a analgesia com opióides sistémicos (reduzindo assim a incidência de complicações associadas ao uso destes) (8) e que melhora, a curto prazo, outcomes funcionais após cirurgia da extremidade, não esta evidenciado o beneficio desta técnica regional a longo prazo (9,10,11). Considerando a eficácia da técnica loco-regional para o tratamento da dor neuropática associada a doença arterial periférica (12,13) e a segurança associada ao bloqueio de nervo periférico (8,9,10,11), relata-se um caso de utilização desta técnica num doente para tratamento da agudização de dor crónica secundária a um agravamento da isquémia do membro inferior.
- Disclosing Azole Resistance Mechanisms in Resistant Candida Glabrata Strains Encoding Wild-Type or Gain-of-Function CgPDR1 Alleles Through Comparative Genomics and TranscriptomicsPublication . Salazar, SB; Pinheiro, MJ; Sotti-Novais, D; Soares, AR; Lopes, MM; Ferreira, T; Rodrigues, V; Fernandes, F; Mira, NPThe pathogenic yeast Candida glabrata is intrinsically resilient to azoles and rapidly acquires resistance to these antifungals, in vitro and in vivo. In most cases azole-resistant C. glabrata clinical strains encode hyperactive CgPdr1 variants, however, resistant strains encoding wild-type CgPDR1 alleles have also been isolated, although remaining to be disclosed the underlying resistance mechanism. In this study, we scrutinized the mechanisms underlying resistance to azoles of 8 resistant clinical C. glabrata strains, identified along the course of epidemiological surveys undertaken in Portugal. Seven of the strains were found to encode CgPdr1 gain-of-function variants (I392M, E555K, G558C, and I803T) with the substitutions I392M and I803T being herein characterized as hyper-activating mutations for the first time. While cells expressing the wild-type CgPDR1 allele required the mediator subunit Gal11A to enhance tolerance to fluconazole, this was dispensable for cells expressing the I803T variant indicating that the CgPdr1 interactome is shaped by different gain-of-function substitutions. Genomic and transcriptomic profiling of the sole azole-resistant C. glabrata isolate encoding a wild-type CgPDR1 allele (ISTB218) revealed that under fluconazole stress this strain over-expresses various genes described to provide protection against this antifungal, while also showing reduced expression of genes described to increase sensitivity to these drugs. The overall role in driving the azole-resistance phenotype of the ISTB218 C. glabrata isolate played by these changes in the transcriptome and genome of the ISTB218 isolate are discussed shedding light into mechanisms of resistance that go beyond the CgPdr1-signalling pathway and that may alone, or in combination, pave the way for the acquisition of resistance to azoles in vivo.
- Genetic Modulators of Fetal Hemoglobin Expression and Ischemic Stroke Occurrence in African Descendant Children With Sickle Cell AnemiaPublication . Nicolau, M; Vargas, S; Silva, M; Coelho, A; Ferreira, E; Mendonça, J; Vieira, L; Kjöllerström, P; Maia, R; Silva, R; Dias, A; Ferreira, T; Morais, A; Soares, IM; Lavinha, J; Faustino, PSickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.
- Invasive and Subcutaneous Infections Caused by Filamentous Fungi: Report from a Portuguese Multicentric Surveillance ProgramPublication . Veríssimo, C; Toscano, C; Ferreira, T; Abreu, G; Simões, H; Diogo, J; Carvalho, D; Santiago, F; Lima, A; Queirós, AM; Sabino, RInvasive fungal infections (IFI) have significantly increased over the past years due to advances in medical care for the at-risk immunocompromised population. IFI are often difficult to diagnose and manage, and can be associated with substantial morbidity and mortality. This study aims to contribute to understanding the etiology of invasive and subcutaneous fungal infections, their associated risk factors, and to perceive the outcome of patients who developed invasive disease, raising awareness of these infections at a local level but also in a global context. A laboratory surveillance approach was conducted over a seven-year period and included: (i) cases of invasive and subcutaneous fungal infections caused by filamentous/dimorphic fungi, confirmed by either microscopy or positive culture from sterile samples, (ii) cases diagnosed as probable IFI according to the criteria established by EORTC/MSG when duly substantiated. Fourteen Portuguese laboratories were enrolled. Cases included in this study were classified according to the new consensus definitions of invasive fungal diseases (IFD) published in 2020 as follows: proven IFI (N = 31), subcutaneous fungal infection (N = 23). Those proven deep fungal infections (N = 54) totalized 71.1% of the total cases, whereas 28.9% were classified as probable IFI (N = 22). It was possible to identify the etiological fungal agent in 73 cases (96%). Aspergillus was the most frequent genera detected, but endemic dimorphic fungi represented 14.47% (N = 11) of the total cases. Despite the small number of cases, a high diversity of species were involved in deep fungal infections. This fact has implications for clinical and laboratory diagnosis, and on the therapeutic management of these infections, since different species, even within the same genus, can present diverse patterns of susceptibility to antifungals.
- Invasive Bacterial Infections in Children With Sickle Cell Disease: 2014–2019Publication . Gaschignard, J; Koehl, B; Rees, DC; Rincón-López, E; Vanderfaeillie, A; Pascault, A; Allali, S; Cela, E; Odièvre, MH; Hau, I; Oliveira, M; Guillaumat, C; Brousse, V; de Montalembert, M; Navarro Gómez, ML; Beldjoudi, N; Bardon-Cancho, EJ; Epalza, C; Benkerrou, M; Gaschignard, J; Koehl, B; Pascault, A; Brousse, V; Allali, S; de Montalembert, M; Odièvre, MH; Hau, I; Guillaumat, C; Blais, S; Runel-Belliard, C; Pellegrino, B; Malric, A; Guitton, C; Gouraud, F; Petras, M; Bensaid, P; Basmaci, R; Eyssette-Guereau, S; Pham, LL; Bardon-Cancho, EJ; Cela, E; Gómez, ML; Rincon-Lopez, E; Ruiz-Llobet, A; Adan, R; Puyo, PV; Recasens, V; Epalza, C; Perez-Alonso, V; Torrent, M; Gomez, AB; Vázquez, A; Rodríguez, RP; Alfaridi, H; Almaghrabi, R; Hoyoux, M; Vanderfaeillie, A; Ferreira, T; Rees, DBackground: Children with sickle cell disease (SCD) are at a high risk of invasive bacterial infections (IBI). Universal penicillin prophylaxis and vaccination, especially against Streptococcus pneumoniae, have deeply changed its epidemiology. Analysis of IBI in children with SCD in a post-13-valent pneumococcal vaccine era is limited. Methods: Twenty-eight pediatric hospitals from 5 European countries retrospectively collected IBI episodes in SCD children aged 1 month to 18 years between 2014 and 2019. IBI was defined as a positive bacterial culture or polymerase chain reaction from a normally sterile fluid: blood, cerebrospinal, joint, or pleural fluid and deep surgical specimen. Results: We recorded 169 IBI episodes. Salmonella spp. was the main isolated bacteria (n = 44, 26%), followed by Streptococcus pneumonia (Sp; n = 31, 18%) and Staphylococcus aureus (n = 20, 12%). Salmonella prevailed in osteoarticular infections and in primary bacteremia (45% and 23% of episodes, respectively) and Sp in meningitis and acute chest syndrome (88% and 50%, respectively). All Sp IBI occurred in children ≤10 years old, including 35% in children 5 to 10 years old. Twenty-seven (17%) children had complications of infection and 3 died: 2 because of Sp, and 1 because of Salmonella. The main risk factors for a severe IBI were a previous IBI and pneumococcal infection (17 Sp/51 cases). Conclusions: In a post-13-valent pneumococcal vaccine era, Salmonella was the leading cause of bacteremia in IBI in children with SCD in Europe. Sp came second, was isolated in children ≤10 years old, and was more likely to cause severe and fatal cases.
- Profiling Persistent Asthma Phenotypes in Adolescents: A Longitudinal Diagnostic Evaluation from the INSPIRERS StudiesPublication . Amaral, R; Jácome, C; Almeida, R; Pereira, AM; Alves-Correia, M; Mendes, S; Rodrigues, JC; Carvalho, J; Araújo, L; Costa, A; Silva, A; Teixeira, MF; Ferreira-Magalhães, M; Alves, RR; Moreira, AS; Fernandes, RM; Ferreira, R; Leiria-Pinto, P; Neuparth, N; Bordalo, D; Todo Bom, A; Cálix, MJ; Ferreira, T; Gomes, J; Vidal, C; Mendes, A; Vasconcelos, MJ; Silva, PM; Ferraz, J; Morête, A; Pinto, CS; Santos, N; Loureiro, CC; Arrobas, A; Marques, ML; Lozoya, C; Lopes, C; Cardia, F; Loureiro, CC; Câmara, R; Vieira, I; Silva, S; Silva, E; Rodrigues, N; Fonseca, JAWe aimed to identify persistent asthma phenotypes among adolescents and to evaluate longitudinally asthma-related outcomes across phenotypes. Adolescents (13-17 years) from the prospective, observational, and multicenter INSPIRERS studies, conducted in Portugal and Spain, were included (n = 162). Latent class analysis was applied to demographic, environmental, and clinical variables, collected at a baseline medical visit. Longitudinal differences in clinical variables were assessed at a 4-month follow-up telephone contact (n = 128). Three classes/phenotypes of persistent asthma were identified. Adolescents in class 1 (n = 87) were highly symptomatic at baseline and presented the highest number of unscheduled healthcare visits per month and exacerbations per month, both at baseline and follow-up. Class 2 (n = 32) was characterized by female predominance, more frequent obesity, and uncontrolled upper/lower airways symptoms at baseline. At follow-up, there was a significant increase in the proportion of controlled lower airway symptoms (p < 0.001). Class 3 (n = 43) included mostly males with controlled lower airways symptoms; at follow-up, while keeping symptom control, there was a significant increase in exacerbations/month (p = 0.015). We have identified distinct phenotypes of persistent asthma in adolescents with different patterns in longitudinal asthma-related outcomes, supporting the importance of profiling asthma phenotypes in predicting disease outcomes that might inform targeted interventions and reduce future risk.
- Recurrent Klebsiella Pneumoniae Infection Causing Transcatheter Aortic Valve Implantation (TAVI)-Related EndocarditisPublication . Tosatto, V; Cruz, C; Ferreira, T; Moreira Marques, T; Boattini, M; Almeida, A; Barata Moura, RThe authors report the case of an 86-year-old woman presenting with recurrent Klebsiella pneumoniae bacteraemia. She had severe aortic stenosis submitted to a recent transcatheter aortic valve implantation (TAVI). Initially, Klebsiella pneumoniae bacteraemia from a urinary source was diagnosed. Following another 4 episodes of bacteraemia with the same agent, the source was ultimately found to be a periprosthetic abscess. Considering the patient's unsuitability for surgery, a decision was made for life-long antimicrobial therapy. This approach has been successful in preventing recurrences or complications. Endocarditis is one of the most severe complications seen following TAVI, often carrying a poor prognosis. Even though Klebsiella spp. are common pathogens for healthcare-associated infections among the elderly, they are seldom the causative agent for endocarditis. Being the first reported case of TAVI-related Klebsiella endocarditis, it was successfully managed using a medical approach.
- A Sífilis Congénita Ainda Existe! Análise Retrospectiva de 12 Anos de uma Grande MaternidadePublication . Jacinto, S; Henriques, M; Ferreira, T; Carvalhosa, G; Costa, T; Valido, AMObjectivos: Estudar a prevalência, factores de risco, evolução clínica e abordagem terapêutica da sífilis congénita em recém-nascidos (RN) de risco, nascidos numa maternidade de referência com apoio perinatal diferenciado. Método: Realizou-se um estudo transversal para cálculo de prevalência à nascença de sífilis congénita, entre Janeiro de 1993 e Dezembro de 2004, através de recolha de dados registados nos processos clínicos das mães e respectivos RN. De acordo com os critérios definidos pelo Centers for Disease Control and Prevention (CDC) em 1989, os RN filhos de mãe com VDRL e/ou TPHA positivo foram divididos em três grupos de risco. Resultados: Foram identificados 467 recém-nascidos, verificando-se que a prevalência de risco de sífilis congénita à nascença se tem mantido ao longo dos anos (5,6‰). A maioria dos recém-nascidos (65%) enquadra-se no grupo de maior risco. Dezanove RN (4%) apresentaram sífilis congénita sintomática ao nascimento, a maioria pertencente ao grupo de maior risco. Outros factores de risco encontrados foram a gravidez não-vigiada, em 30% das mães, toxicodependência em 9%, coinfecção por vírus da hepatite B em 5%, por vírus da hepatite C em 4,7% e por vírus de imunodeficiência humana em 3,4% dos casos. Em alguns casos existia mais do que um factor de risco associado. Conclusões: Verificou-se que a prevalência de risco de sífilis congénita não sofreu grandes variações ao longo dos doze anos, pelo que a sífilis continua a constituir um problema de Saúde Pública em Portugal, com custos económicos e sociais.