Overview of the current use of levosimendan in France: a prospective observational cohort study

Abstract Background Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results The patients included ( n = 602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock ( n = 250, 41.5%), decompensated heart failure ( n = 127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment ( n = 86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation ( n = 82, 13.6%). They received 0.18 ± 0.07 µg/kg/min levosimendan over 26 ± 8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied

Intermolecular interactions of the extended recognition site of VIM-2 metallo-β-lactamase with 1,2,4-triazole-3-thione inhibitors. Validations of a polarizable molecular mechanics potential by ab initio QC

peer reviewedAbstract Molecular dynamics on the complexes of inhibitors with Zn-metalloproteins are a privileged area of applications of polarizable molecular mechanics potentials. With which accuracy could these reproduce the QC intermolecular interaction energies in the two mono-zinc cores and in the dizinc core, toward full-fledged MD simulations on the entire protein complexes? We considered the complexes of the extended recognition site of a Zn-dependent metallo-β-lactamase, VIM-2, produced by bacteria responsible for nosocomial infections, with five newly synthesized inhibitors sharing an original dizinc binding group, 1,2,4-triazole-3-thione (TZT). We considered the energy-minimized structures of each of the five VIM-2 complexes obtained with the SIBFA potential. Energy decomposition analyses (EDA) at the HF level enabled to compare the QC and the SIBFA ΔE values and their contributions in the zinc cores, with and without TZT, totaling 30 complexes. With one exception, the ΔE(QC) values were reproduced with relative errors <1.5\%. We next considered the complex of the entire inhibitors with an extended model of VIM-2 recognition site, totaling up to 280 atoms. ΔE(SIBFA) could closely reproduce ΔE(QC). EDA analyses were resumed on the complexes of each inhibitor arm with its interacting VIM-2 residues. As a last step, EDA results at correlated levels were analyzed for the mono- and dizinc sites enabling comparisons with dispersion-augmented ΔE(SIBFA) and correlated multipoles and polarizabilities. Closely reproducing ΔE(QC) and the contrasting trends of its individual contributions should enable for dependable free energy perturbation studies and comparisons to recent experimental ΔG values, limiting as much as possible the reliance on error compensations

Plant defensins harbour 4 di-sulfide bridges, they are expressed in the endoplasmic reticulum and in Golgi vesicles, and they confer zinc tolerance. What is the mechanism by which defensins can induce zinc tolerance ?

International audienc

Molecular structure of bacterial biofilms involved in iron biocorrosion

International audienceTo a better knowledge of iron biocorrosion mechanisms occurring in different applications (nuclear context, petroleum industry, cultural heritage,…), it is crucial to define which bacteria are active and their role. Despite a wide literature on the influence of bacteria on iron corrosion rates, most often considering a single metabolic group (Iron-Reducing Bacteria IRB, Sulfate-Reducing Bacteria SRB), the role of each species in a population involving various metabolisms possibly affecting corrosion remains unknown. At the same time, it is also essential to identify the corrosion products and to be able to link them to a possible bacterial activity. Our study is then devoted to the local diagnostic of the action of bacterial strains in iron corrosion. An innovative methodology for diagnosing the active bacterial strains in iron corrosion at the micrometric scale was developed by using vibrational techniques such as Attenuated Total Reflection Infra-Red ATR-IR and μRaman spectroscopies. The first step was the setup of a preparation protocol and its optimization for the characterization of bacteria by ATR-IR to obtain the vibrational fingerprint of bacterial strains performing metabolisms already identified in the nuclear context (IRB, SRB and sulfate-oxidizing bacteria SOB). The spectral fingerprint was also determined for iron coupons corroded in the presence of each strain. The question of the ability to discriminate the strains, whether planktonic or in biofilm, by their vibrational fingerprint was resolved. Indeed, the discrimination of the three bacterial strains was possible in the spectral region around 1000 cm-1. Furthermore, the strains evidenced spectra differences according to their growth mode: for strains in planktonic form, the most intense bands of the IR spectrum were those of amide I and II while for the ones in biofilm form, these were the bands of exopolysaccharides (compounds excreted by bacteria when they form biofilms) in the region around 1000 cm-1. These results allow discrimination by the ATR-IR spectrum of different bacterial strains in planktonic or in biofilm form. Since both the three strains but also their form (planktonic or biofilm) were distinguishable by their IR spectrum, experiments were conducted on iron coupons corroded with the bacterial consortium. The objective was to determine the active strains and to couple this information with the nature of the corrosion products. This diagnostic tool for bacterial signature determination can be transposed to a variety of corrosion problems providing significant benefits

Escherichia coli response to uranyl exposure at low pH and associated protein regulations.

Better understanding of uranyl toxicity in bacteria is necessary to optimize strains for bioremediation purposes or for using bacteria as biodetectors for bioavailable uranyl. In this study, after different steps of optimization, Escherichia coli cells were exposed to uranyl at low pH to minimize uranyl precipitation and to increase its bioavailability. Bacteria were adapted to mid acidic pH before exposure to 50 or 80 µM uranyl acetate for two hours at pH≈3. To evaluate the impact of uranium, growth in these conditions were compared and the same rates of cells survival were observed in control and uranyl exposed cultures. Additionally, this impact was analyzed by two-dimensional differential gel electrophoresis proteomics to discover protein actors specifically present or accumulated in contact with uranium.Exposure to uranium resulted in differential accumulation of proteins associated with oxidative stress and in the accumulation of the NADH/quinone oxidoreductase WrbA. This FMN dependent protein performs obligate two-electron reduction of quinones, and may be involved in cells response to oxidative stress. Interestingly, this WrbA protein presents similarities with the chromate reductase from E. coli, which was shown to reduce uranyl in vitro

Cell survival after exposure to uranyl at acidic pH.

<p>Numbering of Colony Forming Units from the <i>E. coli</i> culture in LB-Mes pH 5.5, and in the exposure LB 1/10 Glucose medium at pH 2.7 before (T0) and after exposure for 2 hours to 50 µM sodium acetate, 50 µM of uranyl acetate, and 80 µM of uranyl acetate.</p

Uranyl concentrations in the supernatants and in the cell pellets.

<p>Uranyl concentrations in the supernatants and in the cell pellets.</p

Schematic view of <i>E. coli</i> cells exposure to uranium and details of the optimized analysis protocol.

<p>Schematic view of <i>E. coli</i> cells exposure to uranium and details of the optimized analysis protocol.</p