The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications

Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homeostatic effects of flow-activated transcription factor Krüppel-like factor 2 (KLF2) are compromised in PAH. Here we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodeling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice. This study shows that reduced KLF2 signaling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling

The OSCAR code: modelling and simulation of the corrosion product behaviour under nucleate boiling conditions in PWRs

International audienceThe PWR primary circuit materials are subject to general corrosion leading to metallic elements (mainly Fe, Ni, Cr, Mn, Co) transfer and subsequent ion precipitation and particle deposition processes on the primary circuit surfaces. When deposited on fuel rods, these species are activated by neutron flux. Thus, crud erosion and dissolution processes result in primary coolant activities. During a normal operating cycle in an EDF PWR, the volume activities in the coolant are relatively stable (usually about 10-30 Bq.g-1 in Co-58). During some cycles (depending on fuel management), a significant increase in Co-58 and Cr-51 volume activities can be observed (10 to 100 times the ordinary volume activities). This increase in volume activities is due to local sub-cooled nucleate boiling on the hottest parts of some fuel assemblies. Indeed, it is well known that nucleate boiling enhances the deposition and precipitation processes. Crud growth in boiling conditions is related to different phenomena: Enrichment: concentration increases at crud-coolant interface, Boiling deposition by vaporisation: fluid vaporization at wall results in particle deposition and ion precipitation. As the crud growth, boiling occurs in the crud itself, so do the ion precipitation and deposition of the small particles. Boiling deposition by trapping: some of the small particles trapped at the interface bubble/fluid make deposit when a bubble leaves the wall. Enhanced erosion: turbulences generated by bubbles collapsing close to the wall and spalling above a certain deposit thickness enhance erosion; it results in the release of particle agglomerates.These phenomena have been modelled in the OSCAR V1.3 code. In this article, we present the modelling of these mass transfer mechanisms in boiling conditions and we show that the crud amount on fuel rods and the volume activities in the primary coolant in case of boiling calculated by OSCAR are in accordance with the experimental feedback on French PWRs

Modelling of crud growth phenomena on PWR fuel rods under nucleate boiling conditions

International audiencePWR primary circuit materials undergo general corrosion leading to a release of metallic element release and subsequent process of particle deposition and ion precipitation on the primary circuit surfaces. The species accumulated on fuel rods are activated by neutron flux. Consequently, crud erosion and dissolution induce primary coolant contamination. In French PWRs, 58 Co volume activity is generally low and almost constant (< 30 MBq.m-3) throughout an ordinary operating cycle. In some specific cases, a significant increase in volume activity is observed after the middle of a cycle (100-1000 MBq.m-3 for 58 Co) when conditions for nucleate boiling are locally reached in certain fuel assemblies. Indeed, it is well known that nucleate boiling intensifies the deposition process. The thickness of the crud layer can reach some micrometers in non-boiling areas, whereas it can reach 100 micrometers in boiling areas

The OSCAR code: modelling and simulation of the corrosion product behaviour under nucleate boiling conditions in PWRs

International audienceThe PWR primary circuit materials are subject to general corrosion leading to metallic elements (mainly Fe, Ni, Cr, Mn, Co) transfer and subsequent ion precipitation and particle deposition processes on the primary circuit surfaces. When deposited on fuel rods, these species are activated by neutron flux. Thus, crud erosion and dissolution processes result in primary coolant activities. During a normal operating cycle in an EDF PWR, the volume activities in the coolant are relatively stable (usually about 10-30 Bq.g-1 in Co-58). During some cycles (depending on fuel management), a significant increase in Co-58 and Cr-51 volume activities can be observed (10 to 100 times the ordinary volume activities). This increase in volume activities is due to local sub-cooled nucleate boiling on the hottest parts of some fuel assemblies. Indeed, it is well known that nucleate boiling enhances the deposition and precipitation processes. Crud growth in boiling conditions is related to different phenomena: Enrichment: concentration increases at crud-coolant interface, Boiling deposition by vaporisation: fluid vaporization at wall results in particle deposition and ion precipitation. As the crud growth, boiling occurs in the crud itself, so do the ion precipitation and deposition of the small particles. Boiling deposition by trapping: some of the small particles trapped at the interface bubble/fluid make deposit when a bubble leaves the wall. Enhanced erosion: turbulences generated by bubbles collapsing close to the wall and spalling above a certain deposit thickness enhance erosion; it results in the release of particle agglomerates.These phenomena have been modelled in the OSCAR V1.3 code. In this article, we present the modelling of these mass transfer mechanisms in boiling conditions and we show that the crud amount on fuel rods and the volume activities in the primary coolant in case of boiling calculated by OSCAR are in accordance with the experimental feedback on French PWRs

Modelling of crud growth phenomena on PWR fuel rods under nucleate boiling conditions

International audiencePWR primary circuit materials undergo general corrosion leading to a release of metallic element release and subsequent process of particle deposition and ion precipitation on the primary circuit surfaces. The species accumulated on fuel rods are activated by neutron flux. Consequently, crud erosion and dissolution induce primary coolant contamination. In French PWRs, 58 Co volume activity is generally low and almost constant (< 30 MBq.m-3) throughout an ordinary operating cycle. In some specific cases, a significant increase in volume activity is observed after the middle of a cycle (100-1000 MBq.m-3 for 58 Co) when conditions for nucleate boiling are locally reached in certain fuel assemblies. Indeed, it is well known that nucleate boiling intensifies the deposition process. The thickness of the crud layer can reach some micrometers in non-boiling areas, whereas it can reach 100 micrometers in boiling areas

Is 5 days of oral fluoroquinolone enough for acute uncomplicated pyelonephritis? The DTP randomized trial

International audienceThe treatment duration of acute uncomplicated pyelonephritis (AUP) is still under debate. As shortening treatment duration could be a means to reduce antimicrobial resistance, we aimed to establish whether 5 days of antibiotic treatment is non-inferior to 10 days in patients with AUP. We performed an open-label prospective randomized trial comparing 5 days to 10 days of fluoroquinolone treatment for AUP. The inclusion criteria were: female patients aged ≥18 years with clinical signs of urinary tract infection, fever >38 °C, and positive urinalysis. Patients were randomized to either 5 or 10 days of fluoroquinolone treatment. Outcome was cure at day 10 and day 30 after the end of treatment. One hundred patients were randomized and 12 were excluded after randomization. The mean ± standard deviation (SD) age was 31.8 ± 11 years old and the mean ± SD temperature was 38.6 ± 0.7 °C. The main bacterium involved was Escherichia coli (n = 86; 97.7%) and 3 (3.4%) patients had a positive blood culture. In the post-hoc analysis, clinical cure 10 days after the end of the treatment was 28/30 (93.3%) in the 5-day arm and 36/38 (94.7%) in the 10-day arm (p = 1.00). At day 30, the clinical cure rate was 23/23 (100%) in the 5-day arm and 20/20 (100%) in the 10-day arm (p = 1.00). The microbiological cure rate was 20/23 (87.0%) in the 5-day arm and 16/20 (80.0%) in the 10-day arm (p = 1.00). The efficacy of 5 days of fluoroquinolone treatment does not seem different from 10 days of treatment for AUP