[An unusual development following anti-tuberculous treatment: Obstructive inflammatory granuloma]. / Une séquelle peu fréquente après traitement antituberculeux : l'obstruction granulomateuse inflammatoire.

Tuberculosis is a disease that is still a too frequent. Its treatment depends on prolonged, multi-antibiotic, chemotherapy. Progress following treatment is generally good but there is the possibility of parenchymatous or pleural sequelae such as bronchial stenosis due to post tuberculous bronchial fibrosis or bronchiolithiasis. On the other hand, bronchial obstruction after treatment by an inflammatory granuloma is rare. It causes wheezing dyspnoea. In this case, relapse of the tuberculosis was feared, possibly with the development of multi-drug resistance. Treatment with corticosteroids allowed a rapid improvement.

[Per-partum risk factors of neonatal acidemia in planned vaginal delivery for fetuses in breech presentation]. / Facteurs de risque per-partum d'acidose néonatale en cas de tentative d'accouchement voie basse chez les fœtus en présentation podalique.

OBJECTIVES: Delivery mode of term breech presentation is debated because of higher rate of neonatal acidosis (pH<7.15) in planned vaginal delivery than in planned caesarean section. The objective was to evaluate per-partum risk factors of neonatal acidosis in vaginal delivery for podalic fetuses. METHODS: It was a single-centre, case-control retrospective study that included planned vaginal delivery in singleton term breech presentation between 2012 and 2016. The "case" group defined by neonatal pH≤7.10 and the "control" group defined by neonatal pH≥7.20 were matched. The maternal, labor, and neonatal characteristics were noted. RESULTS: One hundred and thirty-two patients were included: each of 44 patients in "case" group, has been matched according to breech type (legs position) to 2 patients in the "control" group, so 88. In multivariate analysis, significant risk factors identified were oxytocin use [ORa=5.663 (95% CI=1.844-17.397)], "high risk" fetal heart rate (FHR) abnormalities according to FIGO classification [ORa=10.997 (95% CI=1.864-64.866)] and FHR abnormalities during expulsion, Melchior 2 [ORa=8.088 (95% CI=1.192-54.875)] and Melchior 4 [ORa=12.705 (95% CI=1.157-139.541)]. CONCLUSIONS: These risk factors of neonatal acidemia have to be known to improve the labor management in case of breech planned vaginal delivery.

Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models.

Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro - in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds.

Modelling the exposure to chemicals for risk assessment: a comprehensive library of multimedia and PBPK models for integration, prediction, uncertainty and sensitivity analysis - the MERLIN-Expo tool.

MERLIN-Expo is a library of models that was developed in the frame of the FP7 EU project 4FUN in order to provide an integrated assessment tool for state-of-the-art exposure assessment for environment, biota and humans, allowing the detection of scientific uncertainties at each step of the exposure process. This paper describes the main features of the MERLIN-Expo tool. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (i) the integration of multimedia (MM) models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic (PBPK) models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (ii) the incorporation of a set of functionalities for uncertainty/sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (iii) the integration of human and wildlife biota targets with common fate modelling in the environment. MERLIN-Expo is composed of a library of fate models dedicated to non biological receptor media (surface waters, soils, outdoor air), biological media of concern for humans (several cultivated crops, mammals, milk, fish), as well as wildlife biota (primary producers in rivers, invertebrates, fish) and humans. These models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Standardized documentation for each model and training material were prepared to support an accurate use of the tool by end-users. One of the objectives of the 4FUN project was also to increase the confidence in the applicability of the MERLIN-Expo tool through targeted realistic case studies. In particular, we aimed at demonstrating the feasibility of building complex realistic exposure scenarios and the accuracy of the modelling predictions through a comparison with actual measurements.

BK/TD models for analyzing in vitro impedance data on cytotoxicity.

The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. In the present study, we built mechanistic biokinetic/toxicodynamic (BK/TD) models to analyze the time course of cell viability in cytotoxicity assay using impedance. These models account for the fate of the tested compounds during the assay. BK/TD models were applied to analyze HepaRG cell viability, after single (48 h) and repeated (4 weeks) exposures to three hepatotoxic compounds (coumarin, isoeugenol and benzophenone-2). The BK/TD models properly fit the data used for their calibration that was obtained for single or repeated exposure. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data. We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity.

In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes.

In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis-Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin's metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3 µL/min/10(6) cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.

Determination of cis-permethrin, trans-permethrin and associated metabolites in rat blood and organs by gas chromatography-ion trap mass spectrometry.

An analytical method was developed to measure cis-permethrin and trans-permethrin in different biological rat matrices and fluids (whole blood, red blood cells, plasma, brain, liver, muscle, testes, kidneys, fat and faeces). The method was also suitable for the simultaneous quantification of their associated metabolites [cis-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis-DCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (trans-DCCA) and 3-phenoxybenzoic acid (3-PBA)] in blood (whole blood, red blood cells, plasma) and liver. The target analytes were derivatised in samples using a methanolic/hydrochloric acid solution and then extracted with toluene. The analysis was performed by gas chromatography, and detection using ion trap tandem mass spectrometry. The selectivity obtained for complex matrices such as rat organs allowed the use of a purification step to be avoided for most of the matrices investigated. In the case of fat, where permethrin is suspected to accumulate, a dedicated purification step was developed. In fluids, the limits of quantification were at the 50 ng/mL level for the parent compounds and 3-PBA and at 25 ng/mL for cis-DCCA and trans-DCCA. For solid matrices excluding fat, the limits of quantification ranged from 50 ng/g for muscle to 100 ng/g for brain and testes for both cis-permethrin and trans-permethrin. The extraction recoveries ranged primarily between 80 and 120% for the matrix tested. The stability of blood samples was tested through the addition of 1% v/v formic acid. The methods developed were applied in a toxicokinetic study in adult rats. cis-Permethrin and the metabolites were detected in all corresponding matrices, whereas trans-permethrin was detected only in blood, plasma and faeces.

Exposure assessment of phthalates in French pregnant women: results of the ELFE pilot study.

The ubiquitous use of phthalate esters in plastics, building material, medical devices, personal care products and food packaging materials results in a widespread exposure of general population. This study reports measurement of urinary concentration of phthalate metabolites in France and provides a first assessment of the exposure of French pregnant women to this chemical class. For the majority of the phthalate metabolites, concentrations measured in urine were similar to those reported in previous studies except for two phthalates that were characterized by high concentrations of metabolites if compared to previous European and American studies: DiNP (Di-iso-nonylphthalate) and DEHP (Di(2-ethylhexyl)phthalate). In a second part of the study, a pharmacokinetic model was used in order to gain understanding on exposure to DEHP. A high concentration of the primary metabolite of DEHP, MEHP (Mono(2-ethylhexyl)phthalate), was thus identified probably because of a very recent exposure to perfusion materials at the hospital. Pharmacokinetics modelling highlighted that gathering data on the time gap between exposure and biomonitoring is an essential information requirement for reconstructing the dose of non persistent pollutants. Information about exposure pathway is also crucial for conducting effective reverse dosimetry.

Measurement of protection factor of respiratory protective devices toward nanoparticles.

The use of nanoparticles in industry has increased spectacularly over the past few years. Additionally, nanoscale particles seem to be the cause of new professional exposure situations. Due to their size, these particles may build up within the respiratory tract and may even reach the nervous system via the nasal passages; for this reason, it is generally recommended to wear respiratory protective devices (RPDs) in situations where collective protection is impossible to implement or inadequate. Here, we present the test bench ETNA designed to study the efficiency of RPDs in the presence of nanoparticles. The results of the efficiency measurement of two RPDs for two positions (sealed and unsealed) on a Sheffield head, for two inhalation configurations (constant flow and cyclic flow), and for two different particle size distributions of NaCl aerosol (one centered on 13 nm and the other on 59 nm) are presented below. The measurements indicate that when the leaks are negligible at the interface mask/head, the efficiency of RPD is greater for nanoparticles. For major leaks, the device's protection factor changes independently of the size of the particles. Furthermore, no trends with respect to the effect of the respiration type (constant-flow and cyclic-flow tests) have been shown on the device's protection factor.

Linking fate model in freshwater and PBPK model to assess human internal dosimetry of B(a)P associated with drinking water.

In the present study, we demonstrate an integrated modeling approach for predicting internal tissue concentrations of chemicals by coupling a multimedia environmental model and a generic physiologically based pharmacokinetic (PBPK) model. A case study was designed for a region situated on the Seine river watershed, downstream of the Paris megacity, and for benzo(a)pyrene emitted from industrial zones in the region. In this case study, these two models are linked only by water intake from riverine system for the multimedia model into human body for the PBPK model. The limited monitoring data sets of B(a)P concentrations in bottom sediment and in raw river water, obtained at the downstream of Paris, were used to re-construct long-term daily concentrations of B(a)P in river water. The re-construction of long-term series of B(a)P level played a key role for the intermediate model calibration (conducted in multimedia model) and thus for improving model input to PBPK model. In order to take into account the parametric uncertainty in the model inputs, some input parameters relevant for the multimedia model were given by probability density functions (PDFs); some generic PDFs were updated with site-specific measurements by a Bayesian approach. The results of this study showed that the multimedia model fits well with actual annual measurements in sediments over one decade. No accumulation of B(a)P in the organs was observed. In conclusion, this case study demonstrated the feasibility of a full-chain assessment combining multimedia environmental predictions and PBPK modeling, including uncertainty and sensitivity analyses.

Genetic Fusarium chemotyping as a useful tool for predicting nivalenol contamination in winter wheat.

Fusarium graminearum [teleomorph Gibberella zeae] and Fusarium culmorum together with Fusarium poae are the main species known to produce nivalenol (NIV). The NIV content in wheat (Triticum aestivum L.) harvested in Luxembourg was investigated in 2007 and 2008 at 17 different locations. Species determination and genetic chemotyping of F. graminearum and F. culmorum were used to understand the spatial distribution of NIV producers in wheat from Luxembourg. Three hundred thirteen F. graminearum, 175 F. culmorum and 117 F. poae strains respectively were isolated. Chemotypes of the first two species were determined by PCR and confirmed on a sub-sample of single isolates by LC-MS/MS analysis. The 15-acetylated DON chemotype of F. graminearum was dominant in both years representing 94.2% of the population while the NIV chemotype represented 5.8%. The F. culmorum chemotypes were rather evenly distributed, with 3-acetylated DON and NIV profiles present with similar abundances (53.2% and 46.8%, respectively). NIV presence in wheat flour obtained from the 17 sites was correlated with the number of F. culmorum (NIV chemotype) isolated from 100 seeds, suggesting its primary role in NIV production on grains. The predictive power for identifying NIV contamination in grains based on NIV chemotype presence was confirmed by coupling the isolation procedure with a cut-off value, resulting in the successful identification (100%, p=0.008) of NIV contamination in grains collected from 9 additional experimental sites. In conclusion, the results highlight the importance of chemotyping for improved prediction of toxin contamination in wheat.

First Report of the Nivalenol Chemotype of Fusarium graminearum Causing Head Blight of Wheat in the Grand Duchy of Luxembourg.

Head blight caused by Fusarium graminearum is one of the major diseases of wheat (Triticum aestivum L.) in Luxembourg (2) and there is concern for mycotoxins in diseased grain. Isolates of F. graminearum have been assigned to chemotypes based on the particular toxins produced. Ten wheat fields representing different topoclimatological areas of Luxembourg were surveyed in 2007 and 2008 to determine the frequency and distribution of chemotypes. Partially blighted wheat heads were collected, and diseased grains were plated on Fusarium-selective agar (dichloran-chloramphenicol-peptone) for 12 days at 22 ± 2°C with a 12-h light period. Monoconidial isolates of F. graminearum (79 in 2007 and 85 in 2008) were obtained by conidia dilution on 2% water agar and needle selection under a microscope. F. graminearum isolates showed rapid growth on potato dextrose agar, dense aerial mycelium with red pigment deposits in the plate, macroconidia with five to six defined septa, and a basal cell with the typical foot shape. Microconidia were absent. To confirm species identification, a PCR reaction was carried out using the F. graminearum species-specific primers Fg16F (5'-CTCCGGATATGTTGCGTCAA-3') and Fg16R (5'-GGTAGGTATCCGACATGGCAA-3') according to Demeke et al. (1). Chemotype of each isolate was determined according to Ward et al. (4). In particular, PCR primer 12CON (5' CATGAGCATGGTGATGTC-3') coupled with primer 12NF (5'-TCTCCTCGTTGTATCTGG-3') and primer 3CON (5'-TGGCAAAGACTGGTTCAC-3') coupled with primer 3NA (5'-GTGCACAGAATATACGAGC-3') identified the nivalenol chemotype, primer 12CON coupled with primer 12-15F (5'-TACAGCGGTCGCAACTTC-3') and primer 3CON coupled with primer 3D15A (5'-ACTGACCCAAGCTGCCATC-3') identified the 15-acetylated deoxynivalenol (DON) chemotype, while primer 12CON coupled with primer 12-3F (5'-CTTTGGCAAGCCCGTGCA-3') and primer 3CON coupled with primer 3D3A (5'-CGCATTGGCTAACACATG-3') identified 3-acetylated DON chemotype. Reactions were repeated two times and positive controls (provided by Kerry O'Donnell, NRRL collection, Peoria, IL) and a negative control (water) were used in each reaction. Frequency of the nivalenol chemotype was found to be 2.5% in 2007 and 1% in 2008. Interestingly, the nivalenol chemotype was absent in southern Luxembourg. According to this finding, nivalenol was likely to be present at low levels in grain from Reisdorf and Echternach in 2007 (central Luxembourg) and in 2008 from grain of Troisvierges (northern Luxembourg). The remaining isolates in both years belonged to the 15-acetylated DON chemotype and the 3-acetylated DON chemotype was not detected. Compared with a previous report from the Netherlands (3), the nivalenol chemotype in Luxembourg is less frequent and widespread. To our knowledge, this is the first report of the nivalenol chemotype of F. graminearum causing head blight on wheat in Luxembourg. References:(1) T. Demeke et al. Int. J. Food Microbiol. 103:271, 2005. (2) F. Giraud et al. Plant Dis. 92:1587, 2008. (3) C. Waalwijk et al. Eur. J. Plant Pathol. 109:743, 2003. (4) T. J. Ward et al. Fung. Genet. Biol. 45:473, 2008.

[Which supervision and treatment to use in case of exposure to Parvovirus B19 during pregnancy?]. / Quelles surveillance et thérapeutique appliquer en cas de contage avec le Parvovirus B19 en cours de grossesse?

Fifty percent of young women are not immunized against Parvovirus B19 and may be infected during their pregnancy. Because of the scarcity of the foetal complications, the behaviour to be held in case of Parvovirus B19 exposure is badly known. In this view, we realized a review of the literature to answer the questions put by Parvovirus B19 during pregnancy, in particular in case of maternal exposure. About 33% of Parvovirus B19 infections of the pregnant women are complicated by foetal contamination. This foetal infection does not always result in foetal complications. The foetal complications are more frequent before 20 weeks of gestation (11 to 15% of spontaneous abortion and foetal death, 3% of foetal hydrops). After 20 weeks of gestation, it remains 1% of foetal hydrops. Without treatment, they may sometimes lead to foetal death. In the case of Parvovirus B19 exposure, it is advisable to control the maternal serology to know its initial status. According to the result, a weekly ultrasonographic supervision will be proposed to detect foetal anaemia (ascites, pericardial effusion). In the case of foetal hydrops, an in utero transfusion reduce the risk of foetal loss. The long-term outcome of infected foetuses is mostly good. Authors describe a survival without after-effect in 90% of the cases. More ample studies are necessary to evaluate long-term neurodevelopmental outcome of hydropic foetuses.