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- Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individualsPublication . Bettencourt, B.F.; Rocha, F.L.; Alves, H.; Amorim, R.; Caetano Lopes, J.; Vieira Sousa, E.; Pimentel Santos, F.; Lima, M.; Porto, G.; Branco, J.C.; Fonseca, J.E.; Bruges Armas, J.OBJECTIVE: The association of non-MHC genes with AS has been recently suggested. We aimed to investigate the association of the ERAP1, IL23R and TNFSF15 regions and the susceptibility to and protection from AS in HLA-B27-positive individuals. METHODS: A total of 200 unrelated AS patients and 559 healthy unrelated subjects, all HLA-B27 positive, were tested. Twenty single nucleotide polymorphisms (SNPs) were investigated in and near IL23R (nine SNPs), in ERAP1 (five SNPs) and in TNFSF15 (six SNPs). RESULTS: ERAP1 rs30187 [odds ratio (OR) = 1.5, P = 4.7 × 10(-3)] had the strongest association with AS susceptibility. A protective effect was found in three of the ERAP1 SNPs: rs17482078 (OR = 0.7, P = 2.8 × 10(-2)), rs10050860 (OR = 0.7, P = 2.3 × 10(-2)), rs2287987 (OR = 0.6, P = 1.3 × 10(-2)). The ERAP1 haplotype rs17482078/rs10050860/rs30187/rs2287987-CCTT showed an association with AS susceptibility (P = 6.8 × 10(-3)) and a protective effect was identified in rs17482078/rs10050860/rs30187/rs2287987-TTCC (P = 3.1 × 10(-2)). Significant association with AS susceptibility was found in one IL23R marker (rs1004819, P = 4.3 × 10(-2), OR = 1.3). No associations were observed in the TNFSF15 region. CONCLUSION: The identification of a new protection haplotype in ERAP1 and the lack of association of the TNFSF15 region can provide new insights into the understanding of the mechanisms underlying the susceptibility to and protection from AS.
- Haemophilus influenzae invasive disease in children – preliminary results from the Portuguese Study GroupPublication . Bajanca-Lavado, Maria Paula; Betencourt, Célia; Cunha, Florbela; Gonçalo-Marques, José; Portuguese Study Group of Invasive Haemophilus influenzae Disease of The Pediatric Infectious Disease SocietyIntroduction: Haemophilus influenzae (H. influenzae) can cause life-threatening infections especially in children. Although six capsular serotypes (a-f) have been identified to date, H. influenzae serotype b (Hib) has long been a major cause of morbidity and mortality. The Hib conjugate vaccine was introduced in the Portuguese Immunization Program in June 2000 and lead to a dramatically decrease of invasive disease. The National Reference Laboratory for Bacterial Respiratory Infections, based at the National Institute of Health in Lisbon, is the reference laboratory for H. influenzae. In the beginning of 2010, the Pediatric Infectious Disease Society and our Laboratory started a surveillance study on invasive H. influenzae infections in paediatric age, with the participation of 30 Hospitals all over Portugal. Material and Methods: From January 2010 to December 2012 we received 28 strains from patients under 18 years old. Twenty-four strains were isolated from blood, three from cerebrospinal fluid, and one from a net joint fluid. Twenty two isolates (78.6%) were from pre-school children (≤5 years old). Males accounted for 78.6% of the cases. β-lactamase production was determined with nitrocefin. Minimum inhibitory concentrations (MIC) was determined for 13 antibiotics by a microdilution assay, according to CLSI guidelines. Serotyping was performed by PCR. MLST was performed for strains isolated after 2011. Results and Discussion: Serotype characterization showed that the majority of the cases (75%) were due to non-capsulated strains (NC). Of the 7 capsulated strains, five were serotype b (two vaccine failures) and two serotypes a and f respectively. Two strains were β-lactamase producers (7.1%). All other strains were susceptible to all antibiotics tested, except for trimethoprim-sulfamethoxazole with 22.2% of resistance. According to other studies MLST also revealed a great diversity among NC strains: 8 different STs in 11 strains. Comparing the results of this surveillance with our first studies, in pre-vaccine era, we are facing a change in the epidemiology of H. influenzae invasive disease with NC, fully susceptible strains, being responsible for invasive disease in Portugal.
- Characterization of ampicillin resistance mechanisms in clinical Haemophilus influenzae strains isolated in Portugal between 2009 and 2012Publication . Guilherme, Elsa; Bajanca-Lavado, Maria PaulaIntroduction: Haemophilus influenzae (Hi) is mainly responsible for respiratory infections and empirical therapy is used most of times. Ampicillin resistance is a problem of concern since some strains have diminished susceptibility to β-lactams through a non-enzymatic mechanism that involves decreased affinity of β-lactams for altered penicillin-binding proteins (PBPs). Strains exhibiting this resistance mechanism are referred as β-lactamase-negative ampicillin resistant (BLNAR). The aim of this study is to characterize ampicillin resistance mechanisms in clinical isolates of Hi in Portugal. Material and Methods: Two hundred and thirty-five isolates chosen according to their ampicillin MICs: 139 BLNAR (MIC≥1mg/L), 33 susceptible strains (BLNAS; MIC<1mg/L) and 63 β-lactamase producers (BLPAR) were analyzed. The ftsI gene encoding PBP3 was amplified and sequenced. MIC was determined for 13 antibiotics by a microdilution assay, according to CLSI guidelines. Results and Discussion: Of the 235 Hi isolates 199 had mutations in the ftsI transpeptidase domain as follow: 136 gBLNAR out of 139 BLNAR strains (98%) and 44 gBLPACR out of 63 BPLAR strains (70%). Of note, 19 out of 33 BLNAS (58%) presented mutations being designated as gBLNAR. Among gBLNAR and gBLPACR strains there were 43 different mutation patterns, that were included in the six previously described groups and subgroups (I, IIa, IIb, IIc, IId, III-like). The most common amino acid substitutions were located near KTG motif: N526K (160/199, 80.4%), V547I (140/199, 70.4%) and N569S (131/199, 65.8%). Strains with mutations were less susceptible to the β-lactam antibiotics studied. Comparing these results with previously ones, performed in our laboratory (between 2001 and 2008) we are assisting to an increase of susceptible strains (ampicillin MIC≤2mg/L) as well as resistant strains (beta-lactamase producers) with mutations in the ftsI gene, being so called gBLNAR and gBLPACR. CLSI breakpoints alone can’t characterize these strains as susceptible or resistant in the susceptibility tests performed routinely in the laboratory. In this way, a continuous research on breakpoints and methodologies to better define strains of this kind is of crucial importance. In conclusion, we emphasize the importance of continuing surveillance studies of this nature as essential tools to define trends in the antibiotic resistance of Hi.