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BackgroundCOVID-19 severity is mainly related to lung impairment. However, preexisting patient characteristics and biomarkers at admission associated with this event are not precisely known.MethodsWe report 205 patients admitted for a proven COVID-19 in our institution between March 7 and April 22, 2020, particularly their comorbidities, respiratory severity, immune profile, and metabolic profile.FindingsMedian age was 70 years [interquartile range (IQR) 25-75: 60;79]; 115 (56·1%) patients were men. Oxygen supplementation of >2L/min was required in 107 patients (52·2%) after a median time of 8 days [IQR: 6;10] after the first symptoms; 67 (32·7%) patients were admitted to the intensive care unit (ICU), almost exclusively due to severe hypoxia. Patients requiring >2L/min oxygen therapy and/or ICU admission were older and more frequently males, with a significantly higher body mass index (BMI), a significantly higher total cholesterol (TC) / HDL cholesterol ratio, and higher triglycerides. They also had higher plasma levels of C-reactive protein (CRP) and interleukin 6 (IL-6); IL-6 >20 ng/L and CRP >70 mg/L were significantly associated with ICU admission and/or (for patients with a decision of limitation of life-support therapy) death. Higher BMI and TC/HDL-c ratio were associated with higher CRP and IL-6 levels. Steroid therapy was performed in 61 patients; while its clinical impact was inconclusive due to heterogeneous situations, IL-6 levels decreased significantly more in these patients.InterpretationSevere COVID-19 mostly relates to late-onset pneumonia associated with preexisting metabolic syndrome markers and a surge in inflammatory markers, allowing the early identification of at-risk patients.FundingThis work was supported by Foundation University of Grenoble Alpes.

Studies characterizing associations between phenols, phthalates and thyroid hormones during pregnancy produce inconsistent results. This divergence may be partly attributable to false positives due to multiple comparison testing of large numbers of chemicals, and measurement error as studies rely on small numbers of biospecimens despite high intra-individual variability in urinary chemical metabolite concentrations.This study employsA two-tiered approach was implemented:The ToxCast/Tox21 screening reduced the chemical set from 16 to 13 and the associated number of statistical comparisons by 19%. Parabens were negatively associated with free triiodothyronine (T3) and the T3/T4 (total thyroxine) ratio. Monobenzyl phthalate was positively associated with total T4 and negatively with the T3/T4 ratio. Effect modification by iodine status was detected for several compounds (among themFor these chemicals, screening for compounds with an increased likelihood for thyroid-related effects and relying on repeated urine samples to assess exposures improved the overall performance of multichemical analyses of thyroid disruption. This approach may improve future evaluations of human data for the thyroid pathway with implication for fetal health and may serve as a model for evaluating other toxicity outcomes. https://doi.org/10.1289/EHP10239.

We introduced an aptamer switch design that relies on the ability of post-transition/transition metal ions to trigger, through their coordination to nucleobases, substantial DNA destabilization. In the absence of molecular target, the addition of one such metal ion to usual aptamer working solutions promotes the formation of an alternative, inert DNA state. Upon exposure to the cognate compound, the equilibrium is shifted towards the competent DNA form. The switching process was preferentially activated by metal ions of intermediate base over phosphate complexation preference ( i.e. Pb 2+ , Cd 2+ ) and operated with diversely structured DNA molecules. This very simple aptamer switch scheme was applied to the detection of small organics using the fluorescence anisotropy readout mode. We envision that the approach could be adapted to a variety of signalling methods that report on changes in the surface charge density of DNA receptors.

Cet article concerne un fragment d’inscription inédit, découvert en 2018 dans le secteur de l’Antiquaille, sur la colline de Fourvière à Lyon. Joint à un fragment déjà connu (CIL XIII, 1809), il permet de reconstituer une partie de la carrière du chevalier romain M. Aemilius Laetus, également attesté à Lyon par une dédicace à Silvain (CIL XIII, 1779). Celle-ci ayant été découverte à l’Antiquaille, on peut envisager une même localisation originelle pour les deux monuments. Le dossier épigraphique révèle que Laetus fut promu au poste d’a studiis dans la chancellerie impériale, après avoir assumé deux procuratèles provinciales, dont celle de Lyonnaise et d’Aquitaine. Il s’inscrit bien dans la série des titulaires connus de ce poste important, qu’il a dû occuper entre le règne d'Hadrien et le début du iiie s. The article is devoted to the study of a fragment of an unpublished inscription that was discovered in 2018 during an archaeological survey carried out at 1, rue de l’Antiquaille, located on the Fourvière hill in Lyon. It completes a second fragment discovered in 1892 at the bottom of this hill, at rue Saint-Jean (CIL XIII 1809). The combination of the two pieces, which originally belonged to a honorary monument erected by unknown dedicators, makes it possible to understand part of the cursus honorum of M. Aemilius Laetus, a member of the equestrian order, by confirming previous hypotheses. M. Aemilius Laetus is also known in Lyon through a dedication to Silvanus (CIL XIII 1779), which was discovered in the same sector of L’Antiquaille. It may therefore indicate that the honorary monument of the procurator, to which the new fragment belongs, stood in the close vicinity. These inscriptions reveal that Laetus was promoted to the position of a studiis at the imperial chancellery, after occupying two positions as provincial procurator, including that of Lugdunensis and Aquitania. In this regard Laetus fits well into the series of known holders of this important position, between the reign of Hadrian and the beginning of the 3rd c. AD, although the analysis of the text, prosopography or paleography, in the current state does not make it possible to define a more accurate dating.

We describe herein an aptamer-based sensing approach that signal the presence of small-molecule targets when fluorescent DNA probes are challenged with the Ni

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis, as such, efforts to explore new treatments and GBM’s etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)—an in vitro attractive agent for cancer therapy against GBM—was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.

The aim of this study was to assess the validity of the predictive INTERSALT equation using spot urine samples to estimate 24-hour urinary sodium (24-hUNa) excretion and daily sodium intake among the French adult population. Among 193 French adults ("validation sample"), we assessed the validity by comparing predicted 24-hUNa excretion from spot urine and measured 24-hUNa excretion from 24-hour urine collections. Spearman correlation coefficients and Bland-Altman plots were used and we calculated calibration coefficients. In a nationally representative sample of 1,720 French adults ("application sample"), the calibrated predictive equation was then applied to the spot urine Na values to estimate 24-hUNa excretion and daily Na intake. In that sample, predicted Na intake was compared to that estimated from 24-hour dietary recalls. Results were adjusted and corrected using calibration coefficients. In the validation sample, the measured 24-hUNa excretion was on average 14% higher than the predicted 24-hUNa (+ 13% for men and + 16% for women). Correlation between measured and predicted 24-hUNa excretion was moderate (Spearman r = 0.42) and the Bland-Altman plots showed underestimation at lower excretion level and overestimation at higher level. In the application study, estimated daily salt intake was 8.0 g/day using dietary recalls, 8.1 g/day using predicted INTERSALT equation and 9.3 g/day after applying calibration coefficients calculated in the validation study. Despite overall underestimation of 24-hUNa excretion by spot urinary sodium, the use of predictive INTERSALT equation remains an acceptable alternative in monitoring global Na intake/excreted in the French population but its use is not advised at the individual level., SCOPUS: ar.j, info:eu-repo/semantics/published

Resume A l’heure ou la strategie de prevention est un axe majeur de la politique de Sante Publique et ou le depistage neonatal connait sa premiere reorganisation en France depuis 40 ans, il est interessant de visualiser ce programme national exhaustif avec le regard du biologiste, responsable de ces examens de biologie medicale (du pre au post-analytique) et confronte a la reglementation. Cette description de l’organisation du depistage sera rapidement caduque dans la mesure ou une reflexion est en cours avec la Haute Autorite de sante pour inclure de nouvelles pathologies dans le panel propose a chaque enfant.

Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1). If untreated, the disease leads to an important intellectual disability (IQ

Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3μM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-κB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-κB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-κB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents.

The development of enantioselective assays and sensors has received much attention for the determination of enantiomeric impurities. Herein, we demonstrated that the previously reported aptamer kissing complex (AKC) assay strategy can be implemented for designing a chiral tool that allows both the simultaneous enantiomer quantification and the enantiopurity analysis. D- and L-arginine vasopressin (AVP) were employed as model enantiomeric targets. The D- and L-AVP engineered aptamers (aptaswitch) were used as recognition units whereas the Fluorescein or Texas Red labelled D- and L-hairpin probes (aptakiss) served as probes of the enantiomer-dependent AKC formation. The orthogonal fluorescence anisotropy signaling scheme at two different emission wavelengths permitted the concomitant sensing of the AVP enantiomers in a single sample, under a high-throughput microplate format. It was also shown that the AKC-based enantioselective sensor allowed the enantiomeric impurity detection at a level as low as 0.01%.

Many similarities between tryptophan (Trp) and phenylalanine (Phe) metabolisms exist. It is possible that a modification of Trp metabolism might be seen in phenylketonuria (PKU). As some of these metabolites have neuroactive properties, they should be consider in neurological impairment seen in this pathology and not totally explained by blood Phe concentrations. One hundred and fifty-one adult PKU patients (mean age 26.8 years) were included for this study. Plasma Trp, kynurenine (KYN), 3-hydroxykynurenic acid (3HK), and kynurenic acid (KA) were analyzed by liquid chromatography coupled with tandem mass spectrometry. KYN and 3HK were significantly lower in PKU patients compared to general population (P < .0001), and KA was significantly enhanced is this population (P = .009). Furthermore, 3HK concentration was significantly different between PKU patients underwent controlled low-Phe diet compared to PKU patients without this diet (P = .0016). In PKU patients with diet, taking AA substitute enable higher plasma 3HK concentration than without (P = .0008) but still not reaching general population level (P < .0001). Although further study has to be done, it is clear that Trp metabolism is modified in adult PKU patients. An exploration of complete Trp metabolism, and not only Trp concentration, is needed in PKU population, but also in other inborn error of metabolism treated with hypoprotidic diet.

Introduction: Giant cell arteritis (GCA) is a systemic vasculitis with important relapses and sometimes severe complications. Serum amyloid A (SAA) is a protein of the acute phase of inflammation and could be involved in the pathophysiology of GCA. The aim of this study is determining if SAA is a marker of disease activity. Methods: Patients with diagnosis or relapse of GCA were included between October 2015 and January 2018 in our center. SAA dosage was realized at baseline then every 3 months for one year. Along the study, patients were separated in 3 groups according to clinical status: active disease, inactive disease or infections. Results: Twenty patients were included: 15 newly diagnosed and 5 relapses. There have been 21 clinical situations with active disease, 46 with inactive disease and 8 infections. SAA level were significantly higher during active disease (84.5, IR: 30.7-220 mg/l) compared with patients in inactive disease (23.85, IR: 14.6-35.3 mg/l), p = 0.01. There were no statistically difference between SAA level in active disease and infections, p = 0.09. Conclusion: We have shown that SAA is a marker of disease activity. The second step is determinate if SAA is more specific than erythrocyte sedimentation rate or C-protein reactive and could be a potential diagnostic test.

Obstructive Sleep Apnea (OSA) is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the OSA-related cardiometabolic alterations. This study aimed at assessing the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and metabolic and inflammatory parameters were assessed such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, NF-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischemia-reperfusion. Circulating lipids, insulin, HOMA-IR, leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver IL-6 and TNF-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in IL-6 but not in TNF- α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partially protect against IH-induced inflammation. This article is protected by copyright. All rights reserved

We report herein a novel sandwich-type enzyme-linked assay for the "signal-on" colorimetric detection of small molecules. The approach (referred to as enzyme-linked aptamer kissing complex assay (ELAKCA)) relied on the kissing complex-based recognition of the target-bound hairpin aptamer conformational state by a specific RNA hairpin probe. The aptamer was covalently immobilized on a microplate well surface to act as target capture element. Upon small analyte addition, the folded aptamer was able to bind to the biotinylated RNA hairpin module through loop-loop interaction. The formed ternary complex was then revealed by the introduction of the streptavidin-horseradish peroxidase conjugate that catalytically converted the 3,3',5,5'-tetramethylbenzidine substrate into a colorimetric product. ELAKCA was successfully designed for two different systems allowing detecting the adenosine and theophylline molecules. The potential practical applicability in terms of biological sample analysis (human plasma), temporal stability, and reusability was also reported. Owing to the variety of both hairpin functional nucleic acids, kissing motifs, and enzyme-based signaling systems, ELAKCA opens up new prospects for developing small molecule sensing platforms of wide applications.

Obstructive sleep apnoea syndrome is characterized by repetitive episodes of upper airway collapse during sleep resulting in chronic intermittent hypoxia (IH). Obstructive sleep apnoea syndrome, through IH, promotes cardiovascular and metabolic disorders. Endothelin-1 (ET-1) secretion is upregulated by IH, and is able to modulate adipocyte metabolism. Therefore, the present study aimed to characterize the role of ET-1 in the metabolic consequences of IH on adipose tissue in vivo and in vitro. Wistar rats were submitted to 14 days of IH-cycles (30 s of 21% FiO2 and 30 s of 5% FiO2 ; 8 h day(-1) ) or normoxia (air-air cycles) and were treated or not with bosentan, a dual type A and B endothelin receptor (ETA-R and ETB-R) antagonist. Bosentan treatment decreased plasma free fatty acid and triglyceride levels, and inhibited IH-induced lipolysis in adipose tissue. Moreover, IH induced a 2-fold increase in ET-1 transcription and ETA-R expression in adipose tissue that was reversed by bosentan. In 3T3-L1 adipocytes, ET-1 upregulated its own and its ETA-R transcription and this effect was abolished by bosentan. Moreover, ET-1 induced glycerol release and inhibited insulin-induced glucose uptake. Bosentan and BQ123 inhibited these effects. Bosentan also reversed the ET-1-induced phosphorylation of hormone-sensitive lipase (HSL) on Ser(660) . Finally, ET-1-induced lipolysis and HSL phosphorylation were also observed under hypoxia. Altogether, these data suggest that ET-1 is involved in IH-induced lipolysis in Wistar rats, and that upregulation of ET-1 production and ETA-R expression by ET-1 itself under IH could amplify its effects. Moreover, ET-1-induced lipolysis could be mediated through ETA-R and activation of HSL by Ser(660) phosphorylation.

The article aims at studying the relationship between young men of Gallia Narbonensis – a province well known for its early adhesion to Roman culture – and cohortes praetoriae, which were closely linked to the imperial power. Up to here, this relationship was seen with a Roman eye, so the focus was put on “ recruiting soldiers” rather than on “ joining the army”. Time has come for a more anthropological approach, dealing with individual and familial expectations, human relationships and networks, considered at the municipal, provincial and imperial levels. In the broader perspective of a collective work on local élites in Gallia Narbonensis, the study tries to assess the meaning of service in the imperial guard, regarding social mobility, as well as cultural and political integration., L’étude cherche à cerner le rapport de la jeunesse masculine de Gaule Narbonnaise – une province publique de l’Occident romain, réputée pour son adhésion précoce et profonde au modèle romain – à un corps militaire singulier parce que très étroitement associé au pouvoir impérial. Longtemps envisagées depuis Rome – comme en témoigne le recours bien établi à la notion de «recrutement » , qui revient à se placer du côté de l’armée – ces relations sont désormais l’objet d’une approche bilatérale, moins institutionnelle et plus anthropologique. Elle requiert d’être attentif aux aspirations individuelles et familiales, aux interactions humaines et aux réseaux, mais aussi aux contextes municipal, provincial et impérial, qui entraient tous en jeu pour définir le sens du service dans la garde prétorienne. Tout en s’appliquant à éclairer ces diverses logiques, l’étude s’inscrit dans le cadre d’une réflexion collective sur les élites de Gaule Narbonnaise. Elle cherche donc à déterminer en quelle mesure un service militaire professionnel, accompli dans la plus prestigieuse des unités de l’armée romaine impériale, pouvait initier, accompagner ou prolonger des mécanismes d’ascension sociale et d’intégration culturelle et politique., Faure Patrice. Les provinciaux de Gaule Narbonnaise et la garde prétorienne. In: Revue archéologique de Narbonnaise, tome 49, 2016. pp. 85-111.

International audience; Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM.

BACKGROUND Pomegranate peel extract (PPE) contains several compounds with antioxidative properties. PPE added to foods may interact with endogenous antioxidants and promote health. However, little is known about the biochemical mechanisms by which PPE exerts their actions on tissues of biological systems in vivo. The purpose of this study was to determine the effects of PPE on activities of antioxidant enzymes. Mice were used to investigate the effects of PPE on plasma levels of malondialdehyde (MDA), tissue MDA content and activities of superoxide dismutase 1 (SOD1), SOD2 and glutathione peroxidase (GPX) in the small intestine, liver and skeletal muscle – different tissues involved in the digestion, absorption and metabolism of dietary nutrients. Control mice were fed a standard diet, whereas treated mice were fed for 40 days with the standard diet containing 5% or 10% PPE. RESULTS Mice fed the 10% PPE diet exhibited lower plasma MDA concentrations, reduced content of MDA in the small intestine and liver and higher levels of SOD1 and GPX activities in the small intestine compared to mice fed the control diet. CONCLUSIONS These findings demonstrate that intake of PPE in diet attenuates small intestine lipid peroxidation and strengthens the first line of small intestine antioxidant defense by enhancing enzymatic antioxidative pathways. PPE is worthy of further study as a therapeutic approach to prevent peroxidative stress-induced gut pathogenesis. © 2015 Society of Chemical Industry

Many methods for routine total plasma/serum 25-hydroxyvitamin D (25OHD) measurements are available from automated immunoassays to the most specific LC–MS/MS techniques. These last ones are nowadays numerous, still perfectible but more powerful than immunoassays in specific illnesses. We presented a robust method for simple quantification of 25-hydroxyvitamin D 2 (25OHD 2 ) and 25-hydroxyvitamin D 3 (25OHD 3 ) in human plasma by LC–APCI-MS/MS. This method is reliable and easy to perform for clinical measurements as we report a 4-year of clinical laboratory use. A brief off-line sample pretreatment (protein precipitation with addition of the internal standard) was realized then the supernatant was loaded into 96-well plates and analyzed by an online SPE-LC/MS/MS method on an APCI mode. 25OHD 2 and 25OHD 3 were both measured. The chromatographic system was thought and optimized for providing a dedicated line for this measurement on a shared instrument. The linearity was tested up to 380 nmol/L for both 25OHD 2 and 25OHD 3 . The limit of quantification (LOQ) was 7 and 8 nmol/L for 25OHD 3 and 25OHD 2 , respectively. Routine imprecision and bias were found in agreement with recommended limits for routine testing, CV ≤ 10% and bias ≤ 5%. Since July 2010, our participation to DEQAS was successfully validated. This simple robust online SPE-LC/MS/MS method is suitable for routine measurement of 25OHD 2 and 25OHD 3 in human adult plasma. The assay operates for 4 years and has performed more than 40,000 patient samples on a shared instrument.

SummaryBackground Decreased sleep duration and altered sleep quality are risk factors for obesity in youth. Structured exercise training has been shown to increase sleep duration and improve sleep quality. Objectives This study aimed at evaluating the impact of exercise training for improving sleep duration, sleep quality and physical activity in obese adolescents (OB). Methods Twenty OB (age: 14.5 ± 1.5 years; body mass index: 34.0 ± 4.7 kg m−2) and 20 healthy-weight adolescents (HW) completed an overnight polysomnography and wore an accelerometer (SenseWear Bodymedia) for 7 days. OB participated in a 12-week supervised exercise-training programme consisting of 180 min of exercise weekly. Exercise training was a combination of aerobic exercise and resistance training. Results Sleep duration was greater in HW compared with OB (P