Explore the vast range of titles available.

Polycyclic aromatic hydrocarbons (PAHs) are associated with occupational exposure and urban atmospheric pollution. Determination of the genotoxic properties of these compounds is thus of outmost importance. For this purpose a variety of cellular models have been widely used. Reliable results can however only be obtained with models reflecting the specific sensitivity of different organs towards PAHs. In this work, we compared the response to benzo[a]pyrene in cell lines from human lungs (A549) and bladder (T24); two important target organs for PAHs-induced cancer. Human hepatocytes (HepG2) were used as a reference, although liver is not a concern for PAHs carcinogenesis. Adducts arising from the ultimate diol-epoxide metabolite of B[a]P, BPDE, were found to be produced in a dose-dependent manner in HepG2. BPDE DNA adducts were not detected in T24 and in A549 their formation was found to be most efficient at the lowest concentration studied (0.2 µM). These results are probably explained by differences in induction and activity of phase I metabolization enzymes, as well as by proteins eliminating the B[a]P epoxide in A549. In addition to BPDE adducts, oxidative DNA damage, namely strand breaks and oxidized purines were measured and found to be produced only in minute amounts in all three cell lines. In summary, our results emphasize the large differences in the response of cells originating from different organs. Our data also point out the importance of carefully selecting the doses used in in vitro toxicological experiments. The example of A549 shows that working at high doses may lead to an underestimation of the risk. Finally, the choice of method for evaluating genotoxicity appears to be of crucial importance. The comet assay does not seem to be the best method for a compound like B[a]P which induces stable adducts causing limited oxidative damage.

Background Acute uncomplicated cystitis (AUC) is an ideal target of optimization for antibiotic therapy in primary care. Because surveillance networks on urinary tract infections (UTI) mix complicated and uncomplicated UTI, reliable epidemiological data on AUC lack. Whether the antibiotic choice should be guided by a rapid urine test (RUT) for leukocytes and nitrites has not been extensively studied in daily practice. The aim of this primary care study was to investigate local epidemiology and RUT-daily use to determine the optimal strategy. Methods General practitioners included 18–65 years women with symptoms of AUC, performed a RUT and sent urines for analysis at a central laboratory. Different treatment strategies were simulated based on RUT and resistance results. Results Among 347 enrolled patients, 78% had a positive urine culture. Escherichia coli predominated (71%) with high rates of susceptibility to nitrofurantoin (100%), fosfomycin (99%), ofloxacin (97%), and even pivmecillinam (87%) and trimethoprim-sulfamethoxazole (87%). Modelization showed that the systematic use of RUT would reduce by 10% the number of patients treated. Fosfomycin for patients with positive RUT offered a 90% overall bacterial coverage, compared to 98% for nitrofurantoin. 95% for ofloxacin, 86% for trimethoprim-sulfamethoxazole and 78% for pivmecillinam. Conclusion Local epidemiology surveillance data not biased by complicated UTI demonstrates that the worldwide increase in antibiotic resistance has not affected AUC yet. Fosfomycin first line in all patients with positive RUT seems the best treatment strategy for AUC, combining good bacterial coverage with expected low toxicity and limited effect on fecal flora. Trial registration The current study was registered at clinicaltrials.gov ( NCT00958295 )

Polycyclic aromatic hydrocarbons (PAHs) are associated with occupational exposure and urban atmospheric pollution. Determination of the genotoxic properties of these compounds is thus of outmost importance. For this purpose a variety of cellular models have been widely used. Reliable results can however only be obtained with models reflecting the specific sensitivity of different organs towards PAHs. In this work, we compared the response to benzo[a]pyrene in cell lines from human lungs (A549) and bladder (T24); two important target organs for PAHs-induced cancer. Human hepatocytes (HepG2) were used as a reference, although liver is not a concern for PAHs carcinogenesis. Adducts arising from the ultimate diol-epoxide metabolite of B[a]P, BPDE, were found to be produced in a dose-dependent manner in HepG2. BPDE DNA adducts were not detected in T24 and in A549 their formation was found to be most efficient at the lowest concentration studied (0.2 µM). These results are probably explained by differences in induction and activity of phase I metabolization enzymes, as well as by proteins eliminating the B[a]P epoxide in A549. In addition to BPDE adducts, oxidative DNA damage, namely strand breaks and oxidized purines were measured and found to be produced only in minute amounts in all three cell lines. In summary, our results emphasize the large differences in the response of cells originating from different organs. Our data also point out the importance of carefully selecting the doses used in in vitro toxicological experiments. The example of A549 shows that working at high doses may lead to an underestimation of the risk. Finally, the choice of method for evaluating genotoxicity appears to be of crucial importance. The comet assay does not seem to be the best method for a compound like B[a]P which induces stable adducts causing limited oxidative damage.Polycyclic aromatic hydrocarbons (PAHs) are associated with occupational exposure and urban atmospheric pollution. Determination of the genotoxic properties of these compounds is thus of outmost importance. For this purpose a variety of cellular models have been widely used. Reliable results can however only be obtained with models reflecting the specific sensitivity of different organs towards PAHs. In this work, we compared the response to benzo[a]pyrene in cell lines from human lungs (A549) and bladder (T24); two important target organs for PAHs-induced cancer. Human hepatocytes (HepG2) were used as a reference, although liver is not a concern for PAHs carcinogenesis. Adducts arising from the ultimate diol-epoxide metabolite of B[a]P, BPDE, were found to be produced in a dose-dependent manner in HepG2. BPDE DNA adducts were not detected in T24 and in A549 their formation was found to be most efficient at the lowest concentration studied (0.2 µM). These results are probably explained by differences in induction and activity of phase I metabolization enzymes, as well as by proteins eliminating the B[a]P epoxide in A549. In addition to BPDE adducts, oxidative DNA damage, namely strand breaks and oxidized purines were measured and found to be produced only in minute amounts in all three cell lines. In summary, our results emphasize the large differences in the response of cells originating from different organs. Our data also point out the importance of carefully selecting the doses used in in vitro toxicological experiments. The example of A549 shows that working at high doses may lead to an underestimation of the risk. Finally, the choice of method for evaluating genotoxicity appears to be of crucial importance. The comet assay does not seem to be the best method for a compound like B[a]P which induces stable adducts causing limited oxidative damage.

A boy with hydroxyurea-refractory sickle cell anemia underwent bone marrow transplantation with autologous hematopoietic stem cells transduced by a lentivirus to express an antisickling β-globin variant. No sickle cell crises occurred in the following 15 months. Sickle cell disease is among the most prevalent inherited monogenic disorders. Approximately 90,000 people in the United States have sickle cell disease, and worldwide more than 275,000 infants are born with the disease annually. 1 , 2 Sickle cell disease was the first disease for which the molecular basis was identified: a single amino acid substitution in “adult” βA-globin (Glu6Val) stemming from a single base substitution (A→T) in the first exon of the human βA-globin gene ( HBB ) was discovered in 1956. 3 Sickle hemoglobin (HbS) polymerizes on deoxygenation, reducing the deformability of red cells. Patients have intensely painful vaso-occlusive . . .

IntroductionIntraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery.We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery.Methods and analysisMulticentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea–vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay.Ethics and disseminationThis trial has been approved by an independent ethics committee (Comité de Protection des Personnes Ouest III–Angers on 23 February 2021). Results will be submitted in international journals for peer reviewing.Trial registration number NCT04940689, EudraCT 2020-002126-90.

One usual way to strengthen a metal is to add alloying elements and to control the size and the density of the precipitates obtained. However, precipitation in multicomponent alloys can take complex pathways depending on the relative diffusivity of solute atoms and on the relative driving forces involved. In Al–Zr–Sc alloys, atomic simulations based on first-principle calculations combined with various complementary experimental approaches working at different scales reveal a strongly inhomogeneous structure of the precipitates: owing to the much faster diffusivity of Sc compared with Zr in the solid solution, and to the absence of Zr and Sc diffusion inside the precipitates, the precipitate core is mostly Sc-rich, whereas the external shell is Zr-rich. This explains previous observations of an enhanced nucleation rate in Al–Zr–Sc alloys compared with binary Al–Sc alloys, along with much higher resistance to Ostwald ripening, two features of the utmost importance in the field of light high-strength materials.

Objectives The principal aim of our study was to establish concordance between post-mortem CT (PMCT) and forensic standard autopsy (SA) in detecting lesions according to different anatomical regions. A secondary aim was to determine the efficacy of PMCT in showing lethal lesions. Methods PMCTs were compared with autopsies in 236 cadavers in different contexts of death. PMCT findings were assessed by two independent radiologists. Results Concordance between PMCT and autopsy was almost perfect in showing skull, basal skull and hyoid bone fractures as well as in detecting facial, vertebral or pelvic fractures. Both examinations were discordant in demonstrating some intracranial injuries, vascular or organ wounds (more findings showed by autopsy), as well in showing free air in anatomical cavities (more findings detected by PMCT). Moreover, PMCT was effective in determining lethal lesions in the context of craniofacial trauma or after a gunshot wound. Concordance between the findings of the two radiologists was almost perfect for each type of lesion. Conclusion PMCT could be considered as effective as SA in determining the cause of death in certain traumatic events. It was also effective in showing lethal lesions and could be a useful tool in reducing the number of SA. Key Points • Post - mortem CT is increasingly performed as an alternative / adjunct to formal autopsy. • More modern CT systems provide greater anatomical scope. • PMCT can usually determine the cause of most deaths following trauma. • Prospective studies are still required to establish an algorithm for forensic CT .

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy, such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and their association with the autophagosome membrane through a conjugation to a lipid, the phosphatidyl-ethanolamine. Contrarily to mammals, C. elegans possesses single homologs of LC3 and GABARAP families, named LGG-2 and LGG-1. Using site-directed mutagenesis, we inhibited the conjugation of LGG-1 to the autophagosome membrane and generated mutants that express only cytosolic forms, either the precursor or the cleaved protein. LGG-1 is an essential gene for autophagy and development in C. elegans , but we discovered that its functions could be fully achieved independently of its localization to the membrane. This study reveals an essential role for the cleaved form of LGG-1 in autophagy but also in an autophagy-independent embryonic function. Our data question the use of lipidated GABARAP/LC3 as the main marker of autophagic flux and highlight the high plasticity of autophagy.

The removal of micropollutants is an important environmental and health issue. Electro-Fenton offers an electrochemical advanced treatment that is particularly effective for the breakdown of aromatic contaminants. Due to the wide variety of chemicals, it is preferable to analyze model contaminants, such as phenol, when optimizing and assessing the efficacy of a novel treatment process. In this study, we therefore made use of innovative types of electrode material and optimized operating parameters (current density and aeration rate) for the removal of phenol by electro-Fenton, with a view to maximize the energy efficiency of the process. By determining the best current density (1.25 mA cm−2), frequency of aeration (continuous) and by using a boron-doped diamond (BDD) anode, it was possible to achieve over 98.5% phenol (1 mM) removal within 1.5 h. BDD further outcompeted platinum as anode material in terms of mineralization rate and yield, and displayed low energy consumption of 0.08 kWh (g-TOC)−1, about one order of magnitude lower than other advanced oxidation processes, such as UV/TiO2 and UV/O3. Furthermore, a carbon cloth anode proved even more cost-effective than BDD if the end goal is the removal of phenol by electro-Fenton instead of complete mineralization.