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Macheras E.,Service de Microbiologie Hygiene | Macheras E.,University of Versailles | Roux A.-L.,Laboratoire Of Microbiologie | Roux A.-L.,University of Versailles | And 16 more authors.
Journal of Clinical Microbiology | Year: 2011

Mycobacterium abscessus, Mycobacterium bolletii, and Mycobacterium massiliense (Mycobacterium abscessus sensu lato) are closely related species that currently are identified by the sequencing of the rpoB gene. However, recent studies show that rpoB sequencing alone is insufficient to discriminate between these species, and some authors have questioned their current taxonomic classification. We studied here a large collection of M. abscessus (sensu lato) strains by partial rpoB sequencing (752 bp) and multilocus sequence analysis (MLSA). The final MLSA scheme developed was based on the partial sequences of eight housekeeping genes: argH, cya, glpK, gnd, murC, pgm, pta, and purH. The strains studied included the three type strains (M. abscessus CIP 104536 T, M. massiliense CIP 108297T, and M. bolletii CIP 108541T) and 120 isolates recovered between 1997 and 2007 in France, Germany, Switzerland, and Brazil. The rpoB phylogenetic tree confirmed the existence of three main clusters, each comprising the type strain of one species. However, divergence values between the M. massiliense and M. bolletii clusters all were below 3% and between the M. abscessus and M. massiliense clusters were from 2.66 to 3.59%. The tree produced using the concatenated MLSA gene sequences (4,071 bp) also showed three main clusters, each comprising the type strain of one species. The M. abscessus cluster had a bootstrap value of 100% and was mostly compact. Bootstrap values for the M. massiliense and M. bolletii branches were much lower (71 and 61%, respectively), with the M. massiliense cluster having a fuzzy aspect. Mean (range) divergence values were 2.17% (1.13 to 2.58%) between the M. abscessus and M. massiliense clusters, 2.37% (1.5 to 2.85%) between the M. abscessus and M. bolletii clusters, and 2.28% (0.86 to 2.68%) between the M. massiliense and M. bolletii clusters. Adding the rpoB sequence to the MLSA-concatenated sequence (total sequence, 4,823 bp) had little effect on the clustering of strains. We found 10/120 (8.3%) isolates for which the concatenated MLSA gene sequence and rpoB sequence were discordant (e.g., M. massiliense MLSA sequence and M. abscessus rpoB sequence), suggesting the intergroup lateral transfers of rpoB. In conclusion, our study strongly supports the recent proposal that M. abscessus, M. massiliense, and M. bolletii should constitute a single species. Our findings also indicate that there has been a horizontal transfer of rpoB sequences between these subgroups, precluding the use of rpoB sequencing alone for the accurate identification of the two proposed M. abscessus subspecies. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source

Adamzik M.,Universitatsklinikum Essen | Schafer S.,Universitatsklinikum Essen | Frey U.H.,Universitatsklinikum Essen | Becker A.,Universitatsklinikum Essen | And 9 more authors.
Anesthesiology | Year: 2013

Background: Because the nuclear factor-κB (NF-κB) coupled pathway is believed to amplify inflammation prevailing in sepsis, the authors tested the hypotheses that the insertion-deletion polymorphism (-94ins/delATTG) (1) alters nuclear translocation of nuclear factor-κB and activator protein-1 (NF-κB1) in monocytes after lipopolysaccharide stimulation; (2) affects lipopolysaccharide-induced NF-κB1 messenger RNA expression, tumor necrosis factor α concentrations, and tissue factor activity; and (3) may be associated with increased 30-day mortality in patients with sepsis. METHODS: Nuclear translocation of NF-κB1 in monocytes after lipopolysaccharide stimulation from healthy blood donors was performed with immunofluorescence staining (n = 5 each). Lipopolysaccharide-induced NF-κB1 messenger RNA expression was measured with real-time polymerase chain reaction (PCR; n = 60), tumor necrosis factor α concentrations with a multiplexing system kit (n = 60), and tissue factor activity with thromboelastometry (n = 105). In a prospective study, multivariate proportional hazard analysis tested 30-day mortality in patients with sepsis (n = 143). METHODS AND RESULTS: The homozygous deletion genotype compared with the homozygous insertion genotype was associated with a nearly twofold increase in nuclear translocation of NF-κB1 (P = 0.001), a threefold difference in NF-κB1 messenger RNA expression (P = 0.001), and a twofold increase in tissue factor expression (P = 0.021). The deletion allele in adults with severe sepsis was tested as an independent prognostic factor for 30-day mortality (hazard ratio, 2.3; 95% CI, 1.13-4.8; P = 0.022). Mortality was 25% for homozygous insertion genotypes but 41% for combined heterozygous deletion/homozygous deletion genotypes (P = 0.034). CONCLUSION: The deletion allele of the NFκB1 insertion-deletion (-94ins/delATTG) polymorphism is associated with increased 30-day mortality in patients with severe sepsis and increased reaction of the innate immune system. Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Source

Gebhardt F.E.,Institute For Medizinische Mikrobiologie | Wantia N.,Institute For Medizinische Mikrobiologie
Medizinische Klinik - Intensivmedizin und Notfallmedizin | Year: 2013

There are numerous guidelines for the prevention of hospital-acquired infections; however, adherence to these guidelines is only limited. The bundle concept was developed to facilitate the implementation by prioritizing certain measures. A bundle contains 3-5 evidence-based key interventions. The bundle concept has been successfully applied to reduce central catheter-related bloodstream infections and ventilation-associated pneumonia whereby only strict compliance can help to reduce infections; therefore, the right implementation strategy is essential. This means accurate planning, delegation of responsibilities, education, control of compliance and infection surveillance. © 2013 Springer-Verlag Berlin Heidelberg. Source

Desel C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Werninghaus K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Ritter M.,TU Munich | Jozefowski K.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 9 more authors.
PLoS ONE | Year: 2013

Successful vaccination against intracellular pathogens requires the generation of cellular immune responses. Trehalose-6,6-dibehenate (TDB), the synthetic analog of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM), is a potent adjuvant inducing strong Th1 and Th17 immune responses. We previously identified the C-type lectin Mincle as receptor for these glycolipids that triggers the FcRγ-Syk-Card9 pathway for APC activation and adjuvanticity. Interestingly, in vivo data revealed that the adjuvant effect was not solely Mincle-dependent but also required MyD88. Therefore, we dissected which MyD88-dependent pathways are essential for successful immunization with a tuberculosis subunit vaccine. We show here that antigen-specific Th1/Th17 immune responses required IL-1 receptor-mediated signals independent of IL-18 and IL-33-signaling. ASC-deficient mice had impaired IL-17 but intact IFNγ responses, indicating partial independence of TDB adjuvanticity from inflammasome activation. Our data suggest that the glycolipid adjuvant TDB triggers Mincle-dependent IL-1 production to induce MyD88-dependent Th1/Th17 responses in vivo. © 2013 Desel et al. Source

Schubert A.,Universitatsklinikum Ulm | Ehlert K.,Universitatsklinikum Munster | Schuler-Luettmann S.,Institute For Medizinische Mikrobiologie | Gentner E.,Universitatsklinikum Ulm | And 2 more authors.
BMC Infectious Diseases | Year: 2013

Background: Human cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients. The use of antiviral agents is limited by toxicity and evolving resistance in immunocompromised patients with ongoing viral replication during therapy. Here, we present the first documented case of genotypic resistance against maribavir in a bone marrow transplant (BMT) recipient.Case presentation: The female 13-year-old patient was suffering from a refractory cytopenia. Ganciclovir, foscarnet, cidofovir, leflunomide and maribavir, an inhibitor of the cytomegalovirus UL97 protein, were administered to treat a therapy-resistant cytomegalovirus infection. Viral mutations conferring resistance against nucleotide and pyrophosphate analogs as well as maribavir (MBV) have evolved sequentially. Particularly, impressive was the fast emergence of multiple mutations T409M, H411Y and H411N conferring maribavir resistance after less than 6 weeks.Conclusion: We describe the fast emergence of cytomegalovirus variants with different maribavir resistance associated mutations in a bone marrow transplant recipient treated with MBV 400 mg p.o. twice per day. The results suggest that a high virus load permitted a selection of several but distinct therapy-resistant HCMV mutants. Since a phase II study with MBV is intended for the treatment of resistant or refractory HCMV infections in transplant recipients this has to be kept in mind in patients with high viral loads during therapy (NCT01611974). © 2013 Schubert et al.; licensee BioMed Central Ltd. Source

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