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Traulle S.,Center Hospitalo University dAmiens | Extramiana F.,University Paris Diderot | Denjoy I.,French Institute of Health and Medical Research | Narayanan K.,French Institute of Health and Medical Research | And 3 more authors.
Europace | Year: 2014

AimsTo evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF).Methods and resultsIn two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 μmol/L) and enroled in a specific follow-up (mean 6.6 ± 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 ± 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 ± 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 ± 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications.ConclusionOur long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up. © The Author 2013.


Dupont H.,CHU Amiens Picardie | Dupont H.,University of Picardie Jules Verne | Gaillot O.,Lille University Hospital Center | Goetgheluck A.-S.,Laboratoire Of Biologie Medicale | And 11 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2016

An interregional surveillance program was conducted in the northwestern part of France to determine the prevalence of carbapenem-nonsusceptible Enterobacteriaceae (CNSE) isolates and their susceptibility to ceftazidime-avibactam and aztreonam-avibactam combinations. Nonduplicate CNSE clinical isolates were prospectively collected from six hospitals between June 2012 and November 2013. MICs of ceftazidime and aztreonam, alone or combined with a fixed concentration of avibactam (4 μg/ml), and those of carbapenems (comparator agents) were determined. MICs of ertapenem in combination with phenylalanine arginine-naphthylamide dihydrochloride (PAβN) were also determined to assess active efflux. Genes encoding carbapenemases, plasmid-mediated AmpC enzymes, extended-spectrum β-lactamases (ESBLs), and major outer membrane proteins (OMPs) were amplified and sequenced. OMPs were also extracted for SDS-PAGE analysis. Among the 139 CNSE isolates, mainly Enterobacter spp. and Klebsiella pneumoniae, 123 (88.4%) were ertapenem nonsusceptible, 12 (8.6%) exhibited reduced susceptibility to all carbapenems, and 4 Proteeae isolates (2.9%) were resistant to imipenem. Carbapenemase production was detected in only two isolates (producing OXA-48 and IMI-3). In contrast, OMP deficiency, in association with AmpCs and/or ESBLs (mainly CTX-M-9, SHV-12, and CTX-M-15), was largely identified among CNSE isolates. The ceftazidime-avibactam and aztreonam-avibactam combinations exhibited potent activity against CNSE isolates (MIC50/MIC90, 1/1 μg/ml and 0.5/0.5 μg/ml, respectively) compared to that of ceftazidime and aztreonam alone (MIC50/MIC90, 512/512 μg/ml and 128/512 μg/ml, respectively). This study reveals the in vitro activity of ceftazidime-avibactam and aztreonam-avibactam combinations against a large collection of porin-deficient enterobacterial isolates that are representative of the CNSE recovered in the northern part of France. Copyright © 2015, American Society for Microbiology. All Rights Reserved.


PubMed | Center Hospitalier Of Beauvais, Center Hospitalo University dAmiens, Laboratoire Of Biologie Medicale, Lille University Hospital Center and 3 more.
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2016

An interregional surveillance program was conducted in the northwestern part of France to determine the prevalence of carbapenem-nonsusceptible Enterobacteriaceae (CNSE) isolates and their susceptibility to ceftazidime-avibactam and aztreonam-avibactam combinations. Nonduplicate CNSE clinical isolates were prospectively collected from six hospitals between June 2012 and November 2013. MICs of ceftazidime and aztreonam, alone or combined with a fixed concentration of avibactam (4 g/ml), and those of carbapenems (comparator agents) were determined. MICs of ertapenem in combination with phenylalanine arginine-naphthylamide dihydrochloride (PAN) were also determined to assess active efflux. Genes encoding carbapenemases, plasmid-mediated AmpC enzymes, extended-spectrum -lactamases (ESBLs), and major outer membrane proteins (OMPs) were amplified and sequenced. OMPs were also extracted for SDS-PAGE analysis. Among the 139 CNSE isolates, mainly Enterobacter spp. and Klebsiella pneumoniae, 123 (88.4%) were ertapenem nonsusceptible, 12 (8.6%) exhibited reduced susceptibility to all carbapenems, and 4 Proteeae isolates (2.9%) were resistant to imipenem. Carbapenemase production was detected in only two isolates (producing OXA-48 and IMI-3). In contrast, OMP deficiency, in association with AmpCs and/or ESBLs (mainly CTX-M-9, SHV-12, and CTX-M-15), was largely identified among CNSE isolates. The ceftazidime-avibactam and aztreonam-avibactam combinations exhibited potent activity against CNSE isolates (MIC50/MIC90, 1/1 g/ml and 0.5/0.5 g/ml, respectively) compared to that of ceftazidime and aztreonam alone (MIC50/MIC90, 512/512 g/ml and 128/512 g/ml, respectively). This study reveals the in vitro activity of ceftazidime-avibactam and aztreonam-avibactam combinations against a large collection of porin-deficient enterobacterial isolates that are representative of the CNSE recovered in the northern part of France.


Mammeri H.,Center Hospitalo University dAmiens | Guillon H.,Center Hospitalo University dAmiens | Eb F.,Center Hospitalo University dAmiens | Nordmann P.,University Paris - Sud
Antimicrobial Agents and Chemotherapy | Year: 2010

The CMY-2, ACT-1, DHA-1, ACC-1, and FOX-1 enzymes are representative of five plasmid-mediated AmpC (pAmpC) β-lactamase clusters. Resistance to imipenem has been reported in Enterobacteriaceae as a result of pAmpC expression combined with decreased outer membrane permeability. The aim of this study was to determine the role of different pAmpCs in carbapenem resistance and to define the structure/activity relationship supporting carbapenemase activity. The ampC genes encoding the five pAmpCs and the chromosomal AmpC of Escherichia coli EC6, which was used as a reference cephalosporinase, were cloned and introduced into wild-type E. coli TOP10 and OmpC/OmpF porin-deficient E. coli HB4 strains. The MICs of β-lactams for the recombinant strains revealed that CMY-2, ACT-1, and DHA-1 β-lactamases conferred a high level of resistance to ceftazidime and cefotaxime once expressed in E. coli TOP10 and reduced significantly the susceptibility to imipenem once expressed in E. coli HB4. In contrast, FOX-1 and ACC-1 enzymes did not confer resistance to imipenem. Biochemical analysis showed that CMY-2 β-lactamase and, to a lesser extent, ACT-1 exhibited the highest catalytic efficiency toward imipenem and showed low K m values. A modeling study revealed that the large R2 binding site of these two enzymes may support the carbapenemase activity. Therefore, CMY-2-type, ACT-1-type, and DHA-1-type β-lactamases may promote the emergence of carbapenem resistance in porin-deficient clinical isolates. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Dahyot S.,Center Hospitalo University dAmiens | Dahyot S.,University of Picardie Jules Verne | Broutin I.,University of Paris Descartes | De Champs C.,Center Hospitalo University Of Reims | And 6 more authors.
FEMS Microbiology Letters | Year: 2013

Only a few plasmid-borne AmpC (pAmpC) β-lactamases, such as CMY-2, can account for carbapenem resistance in Enterobacteriaceae in combination with outer membrane impermeability. The aim of this study was to elucidate the contribution of Asn-346, which is well conserved among carbapenem-hydrolyzing pAmpCs, to the hydrolysis spectrum of CMY-2. Site-directed mutagenesis experiments were carried out to replace Asn-346 with glycine, alanine, valine, glutamate, aspartate, serine, threonine, glutamine, tyrosine, isoleucine, lysine, and histidine. The recombinant plasmids were transferred into wild-type and porin-deficient Escherichia coli strains. Asn-346 replacement reduced significantly the MICs of all β-lactams, except the Asn-346-Ile substitution that increased the MICs of cephalosporins, whereas it decreased those of carbapenems. The biochemical characterization, along with a molecular modeling study, showed that the size and the polarity of the side chain at position 346 assisted substrate binding and turnover. This study shows for the first time that the amino acid at position 346 contributes to the β-lactamase activity of cephalosporinases. Asparagine and isoleucine residues, which are well conserved at position 346 among AmpC-type enzymes, modulate their hydrolysis spectrum in an opposing sense. Ile-346 confers higher level of cephalosporins resistance, whereas Asn-346 confers carbapenem resistance in combination with outer membrane impermeability. © 2013 Federation of European Microbiological Societies.


Lefrere J.-J.,Sanguine | Lefrere J.-J.,Center hospitalo University dAmiens | Berche P.,University of Paris Descartes
Annales Medico-Psychologiques | Year: 2010

During the First World War, Dr Edgar Berillon (1859-1948) developed a theory according to which the French and German physical and physiological characteristics are very different. His theories were seriously considered by the scientific and medical community of the time, especially as they contributed to the general propaganda against the enemy. This scientificopatriotic delirium was presented in several publications, the content of which appear both grotesque and false today. © 2010 Elsevier Masson SAS.


Lefrere J.-J.,Sanguine | Lefrere J.-J.,Center hospitalo University dAmiens | Berche P.,University of Paris Descartes
Annales d'Endocrinologie | Year: 2010

Pioneer in the field of hormone therapy, Charles-Edward Brown-Séquard (1817-1894) tried to stop the effects of aging on his contemporaries by injecting animal testicle extracts. His therapy was very popular in the last years of the 19th century. He even had followers in the following century, amongst whom Serge Voronoff (1866-1951), who grafted monkey testicles in replacement of human ones, or Paul Niehans (1882-1971) who practiced therapy using calf embryo cells in Switzerland. © 2010 Elsevier Masson SAS.


Guillon H.,Center Hospitalo University dAmiens | Guillon H.,University of Picardie Jules Verne | Tande D.,University of Western Brittany | Mammeri H.,Center Hospitalo University dAmiens | Mammeri H.,University of Picardie Jules Verne
Antimicrobial Agents and Chemotherapy | Year: 2011

Escherichia coli isolate MEV, responsible for a bloodstream infection, was resistant to penicillins, cephalosporins, and ertapenem. Molecular and biochemical characterization revealed the production of a novel, chromosome-borne, extended-spectrum AmpC (ESAC) β-lactamase with a Ser-282 duplication and increased carbapenemase activity. This study demonstrates for the first time that chromosome-borne ESAC β-lactamases can contribute to the emergence of ertapenem resistance in E. coli clinical isolates. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Lefrere J.-J.,Sanguine | Lefrere J.-J.,Center hospitalo University dAmiens | Berche P.,University of Paris Descartes
Transfusion Clinique et Biologique | Year: 2010

The discovery of ABO blood group was a major step in mastering transfusion therapy. Karl Landsteiner (1868-1843) was the author of this discovery. This paper retraces the hard career of this American scientist of Austrian origin, and describes the circumstances that led his research to the discoveries, which were turning points in the history of the immunology. © 2009 Elsevier Masson SAS. All rights reserved.


Jaulin P.,rue de Bellechasse | Lefrere J.-J.,Sanguine | Lefrere J.-J.,Center hospitalo University dAmiens
Transfusion Clinique et Biologique | Year: 2010

The pioneers of blood transfusion first appeared in the 17th century, mainly in France and England, through animal experimentation, followed by some attempts in the healthy or sick. In France, the names of Dom Robert and Jean-Baptiste Denis belong to the beginning of the adventure of transfusion. Transfusions were then made with a total lack of knowledge of immunological danger. Following the death of a transfused patient, a death most likely related to acute intravascular hemolysis, the practice of transfusion was prohibited, on both sides of the Channel, by decision of Parliament. © 2010 Elsevier Masson SAS.

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