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- Multilocus Sequencing Typing of Invasive Haemophilus influenzae strains Isolated in Portugal in the Pre-vaccination Period (1989-2001)Publication . Veiga, Elisabete; Gomes, Sandra; Bettencourt, Célia; Bajanca-Lavado, Maria PaulaIntroduction: Haemophilus influenzae can cause life-threatening infections in children and adults, such as pneumonia, bacteremia, and meningitis, despite de availability of the H. influenzae type b vaccine. Six capsular types, a-f, have been identified to date. Non-capsulated (NC) H. influenzae have also been described. Multilocus Sequencing Typing (MLST) is a powerful method that allows a precise and unambiguous characterization of H. influenzae genotypes. Aim: Identification of the major genotypes that characterize Portuguese invasive H. influenzae strains in the years before the implementation of the Hib vaccine (1989-2001). Comparison of results from this study with the ones from our previous published study with isolates from pos-vaccination period (2002-2010). Methods: Seventy invasive H. influenzae strains (38 Hib, 31 NC, 1 f) were randomly selected for analysis, isolated during 1989-2001 from cerebrospinal fluid (n=24), blood (n=43) and pleural fluid (n=3). Thirty-six strains (51.4%) were isolated from pre-school children. Capsular status was identified by PCR amplification of bexA gene and capsular type was determined by amplification of capsule-specific genes (for serotypes a-f) using primers and conditions described in the literature. MLST was performed by sequencing internal fragments of the 7 housekeeping genes (adk, atpG, frdB, fucK, mdh, pgi and recA). Sequences were analyzed and submitted to the MLST website (http://haemophilus.mlst.net) for assignment of the sequence type (ST). Phylogenetic estimations were conducted through MEGA5 by using the neighbor-joining method. Results: Thirty-four (89.5%) of the 38 Hib isolates analyzed were assigned to CC6, 4 of which were new STs, while 4 were single strains of different STs. Of the 31 NC isolates, 26 (83.9%) were single strains of different STs (12 new STs), 4 strains belong to CC395 and CC396 (2 strains each), and 1 was identified as CC6. The isolate type f was characterized as ST124. Discussion and conclusions: In this study we observed a high diversity of NC strains, in opposite to Hib clonality. Despite of the great decline of serotype b in the pos-vaccination period, with a concomitant increase of NC and non–b isolates, no significant differences were observed in the MLST characterization of pre-vaccination isolates. Of the 16 Hib studied, all but one were characterized as CC6 (94.7%). Among the 67 NC isolates, 42 (62.7%) were single strains of different STs; the remaining isolates were of 6 different CCs. In conclusion, there are no differences in molecular typing of H. influenzae strains isolated in the pre and pos-vaccination period, in our country. The majority of episodes of invasive disease occurring in Portugal are now due to fully susceptible, highly diverse, non-capsulated strains. Given the evolving dynamics of this pathogen and the increase in non-type b capsulated isolates, continuous surveillance is needed.
- Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and its Specific Treatment with Alirocumab, a PCSK9 Monoclonal AntibodyPublication . Hopkins, P.N.; Defesche, J.; Fouchier, S.W.; Bruckert, E.; Luc, G.; Cariou, B.; Sjouke, B.; Leren, T.P.; Harada-Shiba, M.; Mabuchi, H.; Rabès, J.P.; Carrié, A.; van Heyningen, C.; Carreau, V.; Farnier, M.; Teoh, Y.P.; Bourbon, M.; Kawashiri, M.A.; Nohara, A.; Soran, H.; Marais, A.D.; Tada, H.; Abifadel, M.; Boileau, C.; Chanu, B.; Katsuda, S.; Kishimoto, I.; Lambert, G.; Makino, H.; Miyamoto, Y.; Pichelin, M.; Yagi, K.; Yamagishi, M.; Zair, Y.; Mellis, S.; Yancopoulos, G.D.; Stahl, N.; Mendoza, J.; Du, Y.; Hamon, S.; Krempf, M.; Swergold, G.D.BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: -We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing four different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) >70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: Among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset 49.4 years) and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: In PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared to placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary endpoint). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: -PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk for premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and appears to be well tolerated in these patients. Clinical Trial Registration-www.clinicaltrials.gov; Unique Identifier: NCT01604824