[Allergic Broncho-Pulmonary Aspergillosis (ABPA) in cystic fibrosis: Mechanisms, diagnosis and therapeutic options]. / Aspergillose bronchopulmonaire allergique (ABPA) et mucoviscidose : mécanismes, diagnostic et alternatives thérapeutiques.

INTRODUCTION: Fungal aspergillosis colonization and allergic bronchopulmonary aspergillosis (ABPA) can have a strong impact on the prognosis in cystic fibrosis (CF). We conducted round table discussions involving French experts from pediatric and adult centers caring for patients with CF, microbiologists, radiologists and pharmacists. The aim was to explore the current state of knowledge on: the pathophysiological mechanisms of Aspergillus and other micromycetes infections in CF (such as Scedosporium sp.), and on the clinico-biological diagnosis of ABPA. In perspective, the experts explored the role of imaging in the diagnosis of APBA, specifically CT and MRI; as well as the role of bronchoscopy in the management. We also reviewed the therapeutic management, including different corticosteroid regimens, antifungals and anti-IgE antibodies. CONCLUSION: The diagnosis of ABPA in CF should be based on more standardized biological assays and imaging to optimize treatment and follow-up.

Diagenetic production, accumulation and sediment-water exchanges of methylmercury in contrasted sediment facies of Lake Titicaca (Bolivia).

Monomethylmercury (MMHg) concentrations in aquatic biota from Lake Titicaca are elevated although the mercury (Hg) contamination level of the lake is low. The contribution of sediments to the lake MMHg pool remained however unclear. In this work, seven cores representative of the contrasted sediments and aquatic ecotopes of Lake Titicaca were sliced and analyzed for Hg and redox-sensitive elements (Mn, Fe, N and S) speciation in pore-water (PW) and sediment to document early diagenetic processes responsible for MMHg production and accumulation in PW during organic matter (OM) oxidation. The highest MMHg concentrations (up to 12.2 ng L-1 and 90% of THg) were found in subsurface PWs of the carbonate-rich sediments which cover 75% of the small basin and 20% of the large one. In other sediment facies, the larger content of OM restricted MMHg production and accumulation in PW by sequestering Hg in the solid phase and potentially also by decreasing its bioavailability in the PW. Diagenetically reduced S and Fe played a dual role either favoring or restricting the availability of Hg for biomethylation. The calculation of theoretical diffusive fluxes suggests that Lake Titicaca bottom sediments are a net source of MMHg, accounting for more than one third of the daily MMHg accumulated in the water column of the Lago Menor. We suggest that in the context of rising anthropogenic pressure, the enhancement of eutrophication in high altitude Altiplano lakes may increase these MMHg effluxes into the water column and favor its accumulation in water and biota.

Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

Economical optimization of a breeding scheme by selective phenotyping of the calibration set in a multi-trait context: application to bread making quality.

KEY MESSAGE: Trait-assisted genomic prediction approach is a way to improve genetic gain by cost unit, by reducing budget allocated to phenotyping or by increasing the program's size for the same budget. This study compares different strategies of genomic prediction to optimize resource allocation in breeding schemes by using information from cheaper correlated traits to predict a more expensive trait of interest. We used bread wheat baking score (BMS) calculated for French registration as a case study. To conduct this project, 398 lines from a public breeding program were genotyped and phenotyped for BMS and correlated traits in 11 locations in France between 2000 and 2016. Single-trait (ST), multi-trait (MT) and trait-assisted (TA) strategies were compared in terms of predictive ability and cost. In MT and TA strategies, information from dough strength (W), a cheaper trait correlated with BMS (r = 0.45), was evaluated in the training population or in both the training and the validation sets, respectively. TA models allowed to reduce the budget allocated to phenotyping by up to 65% while maintaining the predictive ability of BMS. TA models also improved the predictive ability of BMS compared to ST models for a fixed budget (maximum gain: + 0.14 in cross-validation and + 0.21 in forward prediction). We also demonstrated that the budget can be further reduced by approximately one fourth while maintaining the same predictive ability by reducing the number of phenotypic records to estimate BMS adjusted means. In addition, we showed that the choice of the lines to be phenotyped can be optimized to minimize cost or maximize predictive ability. To do so, we extended the mean of the generalized coefficient of determination (CDmean) criterion to the multi-trait context (CDmulti).

Late Holocene volcanic and anthropogenic mercury deposition in the western Central Andes (Lake Chungará, Chile).

Volcanism is one of the major natural processes emitting mercury (Hg) to the atmosphere, representing a significant component of the global Hg budget. The importance of volcanic eruptions for local-scale Hg deposition was investigated using analyses of Hg, inorganic elemental tracers, and organic biomarkers in a sediment sequence from Lake Chungará (4520 m a.s.l.). Environmental change and Hg deposition in the immediate vicinity of the Parinacota volcano were reconstructed over the last 2700 years, encompassing the pre-anthropogenic and anthropogenic periods. Twenty eruptions delivering large amounts of Hg (1 to 457 µg Hg m-2 yr-1 deposited at the timescale of the event) were locally recorded. Peaks of Hg concentration recorded after most of the eruptions were attributed to a decrease in sedimentation rate together with the rapid re-oxidation of gaseous elemental Hg and deposition with fine particles and incorporation into lake primary producers. Over the study period, the contribution of volcanic emissions has been estimated as 32% of the total Hg input to the lake. Sharp depletions in primary production occurred at each eruption, likely resulting from massive volcaniclastic inputs and changes in the lake-water physico-chemistry. Excluding the volcanic deposition periods, Hg accumulation rates rose from natural background values (1.9 ±â€¯0.5 µg m-2 yr-1) by a factor of 2.3 during the pre-colonial mining period (1400-900 yr cal. BP), and by a factor of 6 and 7.6, respectively, during the Hispanic colonial epoch (400-150 yr cal. BP) and the industrial era (~140 yr cal. BP to present). Altogether, the dataset indicates that lake primary production has been the main, but not limiting, carrier for Hg to the sediment. Volcanic activity and climate change are only secondary drivers of local Hg deposition relative to the magnitude of regional and global anthropogenic emissions.

Development of a large volume injection method using a programmed temperature vaporization injector - gas chromatography hyphenated to ICP-MS for the simultaneous determination of mercury, tin and lead species at ultra-trace levels in natural waters.

The current EU legislation lays down Environmental Quality Standards (EQS) for 45 priority substances in surface waters; among them levels for (organo)metallic species of Hg, Sn and Pb are set between ng L-1 (for Hg and Sn) and µg L-1 (for Pb). To date, only a few analytical methods can reach these very restrictive limits and there is thus a need for comprehensive methods able to analyze these species down to these levels in natural waters. The aim of this work was to develop an online automated pre-concentration method using large volume injections with a Programmed Temperature Vaporization (PTV) injector fitted with a sorbent packed liner coupled to GC-ICP-MS to further improve the detection limits associated to this well-established method. The influence of several parameters such as the PTV transfer temperature and time, carrier gas flow rate and amount of packing material was investigated. Finally, the maximum volume injected through single or multiple injection modes was optimized to obtain the best compromise between chromatographic resolution and sensitivity. After optimization, very satisfactory results in terms of absolute and methodological detection limits were achieved, down to the pg L-1 level for all species studied. The potential of the method was exemplified by determining the concentrations of organometallic compounds in unpolluted river waters samples from the Adour river basin (SW France) and results were compared with conventional (splitless) GC-ICP-MS. The strength of this analytical method lies in the low detection limits reached for the simultaneous analysis of a wide group of organometallic compounds, and the potential to transfer this method to other gas chromatographic applications with inherent lower sensitivity.

Mercury contamination level and speciation inventory in Lakes Titicaca & Uru-Uru (Bolivia): Current status and future trends.

Aquatic ecosystems of the Bolivian Altiplano (∼3800 m a.s.l.) are characterized by extreme hydro-climatic constrains (e.g., high UV-radiations and low oxygen) and are under the pressure of increasing anthropogenic activities, unregulated mining, agricultural and urban development. We report here a complete inventory of mercury (Hg) levels and speciation in the water column, atmosphere, sediment and key sentinel organisms (i.e., plankton, fish and birds) of two endorheic Lakes of the same watershed differing with respect to their size, eutrophication and contamination levels. Total Hg (THg) and monomethylmercury (MMHg) concentrations in filtered water and sediment of Lake Titicaca are in the lowest range of reported levels in other large lakes worldwide. Downstream, Hg levels are 3-10 times higher in the shallow eutrophic Lake Uru-Uru than in Lake Titicaca due to high Hg inputs from the surrounding mining region. High percentages of MMHg were found in the filtered and unfiltered water rising up from <1 to ∼50% THg from the oligo/hetero-trophic Lake Titicaca to the eutrophic Lake Uru-Uru. Such high %MMHg is explained by a high in situ MMHg production in relation to the sulfate rich substrate, the low oxygen levels of the water column, and the stabilization of MMHg due to abundant ligands present in these alkaline waters. Differences in MMHg concentrations in water and sediments compartments between Lake Titicaca and Uru-Uru were found to mirror the offset in MMHg levels that also exist in their respective food webs. This suggests that in situ MMHg baseline production is likely the main factor controlling MMHg levels in fish species consumed by the local population. Finally, the increase of anthropogenic pressure in Lake Titicaca may probably enhance eutrophication processes which favor MMHg production and thus accumulation in water and biota.

Association mapping for phenology and plant architecture in maize shows higher power for developmental traits compared with growth influenced traits.

Plant architecture, phenology and yield components of cultivated plants have repeatedly been shaped by selection to meet human needs and adaptation to different environments. Here we assessed the genetic architecture of 24 correlated maize traits that interact during plant cycle. Overall, 336 lines were phenotyped in a network of 9 trials and genotyped with 50K single-nucleotide polymorphisms. Phenology was the main factor of differentiation between genetic groups. Then yield components distinguished dents from lower yielding genetic groups. However, most of trait variation occurred within group and we observed similar overall and within group correlations, suggesting a major effect of pleiotropy and/or linkage. We found 34 quantitative trait loci (QTLs) for individual traits and six for trait combinations corresponding to PCA coordinates. Among them, only five were pleiotropic. We found a cluster of QTLs in a 5 Mb region around Tb1 associated with tiller number, ear row number and the first PCA axis, the latter being positively correlated to flowering time and negatively correlated to yield. Kn1 and ZmNIP1 were candidate genes for tillering, ZCN8 for leaf number and Rubisco Activase 1 for kernel weight. Experimental repeatabilities, numbers of QTLs and proportion of explained variation were higher for traits related to plant development such as tillering, leaf number and flowering time, than for traits affected by growth such as yield components. This suggests a simpler genetic determinism with larger individual QTL effects for the first category.

Dent and Flint maize diversity panels reveal important genetic potential for increasing biomass production.

KEY MESSAGE: Genetic and phenotypic analysis of two complementary maize panels revealed an important variation for biomass yield. Flowering and biomass QTL were discovered by association mapping in both panels. The high whole plant biomass productivity of maize makes it a potential source of energy in animal feeding and biofuel production. The variability and the genetic determinism of traits related to biomass are poorly known. We analyzed two highly diverse panels of Dent and Flint lines representing complementary heterotic groups for Northern Europe. They were genotyped with the 50 k SNP-array and phenotyped as hybrids (crossed to a tester of the complementary pool) in a western European field trial network for traits related to flowering time, plant height, and biomass. The molecular information revealed to be a powerful tool for discovering different levels of structure and relatedness in both panels. This study revealed important variation and potential genetic progress for biomass production, even at constant precocity. Association mapping was run by combining genotypes and phenotypes in a mixed model with a random polygenic effect. This permitted the detection of significant associations, confirming height and flowering time quantitative trait loci (QTL) found in literature. Biomass yield QTL were detected in both panels but were unstable across the environments. Alternative kinship estimator only based on markers unlinked to the tested SNP increased the number of significant associations by around 40% with a satisfying control of the false positive rate. This study gave insights into the variability and the genetic architectures of biomass-related traits in Flint and Dent lines and suggests important potential of these two pools for breeding high biomass yielding hybrid varieties.

Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock.

To assess the risk of acute kidney injury (AKI) attributable to aminoglycosides (AGs) in patients with severe sepsis or septic shock, we performed a retrospective cohort study in one medical intensive care unit (ICU) in France. Patients admitted for severe sepsis/septic shock between November 2008 and January 2010 were eligible. A propensity score for AG administration was built using day 1 demographic and clinical characteristics. Patients still on the ICU on day 3 were included. Patients with renal failure before day 3 or endocarditis were excluded. The time window for assessment of renal risk was day 3 to day 15, defined according to the RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification. The AKI risk was assessed by means of a propensity-adjusted Cox proportional hazards regression analysis. Of 317 consecutive patients, 198 received AGs. The SAPS II (simplified acute physiology score II) score and nosocomial origin of infection favored the use of AGs, whereas a preexisting renal insufficiency and the neurological site of infection decreased the propensity for AG treatment. One hundred three patients with renal failure before day 3 were excluded. AGs were given once daily over 2.6 ± 1.1 days. AKI occurred in 16.3% of patients in a median time of 6 (interquartile range, 5 to 10) days. After adjustment to the clinical course and exposure to other nephrotoxic agents between day 1 and day 3, a propensity-adjusted Cox proportional hazards regression analysis showed no increased risk of AKI in patients receiving AGs (adjusted relative risk = 0.75 [0.32 to 1.76]). In conclusion, in critically septic patients presenting without early renal failure, aminoglycoside therapy for less than 3 days was not associated with an increased risk of AKI.

Refining thermodynamic constants for mercury(II)-sulfides in equilibrium with metacinnabar at sub-micromolar aqueous sulfide concentrations.

An important issue in mercury (Hg) biogeochemistry is to explore the influence of aqueous Hg(II) forms on bacterial uptake, and subsequent methyl mercury formation, under iron(III) and sulfate reducing conditions. The success of this is dependent on relevant information on the thermodynamic stability of Hg-sulfides. In the present study, we determined the solubility of a commercially available HgS(s) phase, which was shown by X-ray diffraction to be a mixture of 83% metacinnabar and 17% cinnabar. At aqueous sulfide concentrations between 0.060 and 84 µM, well below levels in previous studies, we report a solubility product (log Ksp ± SE) of -36.8 ± 0.1 (HgS(s) + H(+) = Hg(2+) + HS(-), I = 0, T = 25 °C, pH 6-10, n = 20) for metacinnabar. This value is 0.7 log units higher than previous estimates. Complementing our data with data from Paquette and Helz (1997), we took advantage of a large data set (n = 65) covering a wide range of aqueous sulfide (0.06 µM-140 mM) and pH (1-11). On the basis of this, we report refined formation constants (±SE) for the three aqueous Hg(II)-sulfide species proposed by Schwarzenbach and Widmer (1963): Hg(2+) + 2HS(-) = Hg(SH)2(0); log K = 39.1 ± 0.1, Hg(2+) + 2HS(-) = HgS2H(-) + H(+); log K = 32.5 ± 0.1, Hg(2+) + 2HS(-) = HgS2(2-) + 2H(+); log K = 23.2 ± 0.1. Our refined log K values differ from previous estimates by 0.2-0.6 log units. Furthermore, at the low sulfide concentrations in our study we could rule out the value of -10.0 for the reaction HgS(s) + H2O = HgOHSH(aq) as reported by Dyrssén and Wedborg (1991). By establishing a solubility product for the most environmentally relevant HgS(s) phase, metacinnabar, and extending the range of aqueous sulfide concentrations to sub-micromolar levels, relevant for soils, sediments, and waters, this study decreases the uncertainty in stability constants for Hg-sulfides, thereby improving the basis for understanding the bioavailability and mobility of Hg(II) in the environment.

Treatment of advanced gastrointestinal stromal tumors in patients over 75 years old: clinical and pharmacological implications.

Data about the patterns of care and the specific outcome of elderly patients with advanced gastrointestinal stromal tumors (GISTs) are almost nonexistent. Between 2001 and 2009, 44 patients ≥75 years old with advanced GISTs started first-line imatinib (400 mg/day) in seven participating institutions. Clinical data were collected by reviewing medical records and were entered in a comprehensive database. During the same period, 160 patients with advanced GIST (136 patients <75 years old, 24 patients ≥75 years old) had access to an imatinib blood level testing program. Imatinib plasma concentration (patient dose 400 mg/day) tests were centralized in a single laboratory. Median age was 78 years old (range 75-86). Thirty-six patients (82 %) experienced at least one adverse event (Table 2). Drug-related adverse events were mainly of grades 1 and 2 and were medically manageable. Permanent dose reduction (200-300 mg/day) was required for 20 patients (45.5 %) and was significantly more frequent for patients with performance status (PS) ≥2: 33.5 versus 8.5 %, p = 0.04. Eight patients (18 %) required imatinib interruption for intolerance. Median PFS was 34.4 months (95 % CI 11.5-57.4) (Fig. 1). Median overall survival (OS) was 50.3 months (95 % CI 37-63.5). Performance status <2 was the sole pre-therapeutic factor associated with improved OS. No correlation was found between comorbidities and tolerance or outcome. Imatinib trough plasma concentrations increase with age, although this correlation did not reach statistical significance. First-line imatinib is a feasible and effective treatment in patients with advanced GISTs ≥75 years. Aging seems to have only a moderate impact on imatinib pharmacokinetics. Overall survival is similar to that of younger patients. Comorbidities did not result in increased incidence of toxicity. Careful follow-up regarding tolerance issues should be considered in elderly patients with poor PS.

Investigations into the differential reactivity of endogenous and exogenous mercury species in coastal sediments.

Stable isotopic tracer methodologies now allow the evaluation of the reactivity of the endogenous (ambient) and exogenous (added) Hg to further predict the potential effect of Hg inputs in ecosystems. The differential reactivity of endogenous and exogenous Hg was compared in superficial sediments collected in a coastal lagoon (Arcachon Bay) and in an estuary (Adour River) from the Bay of Biscay (SW France). All Hg species (gaseous, aqueous, and solid fraction) and ancillary data were measured during time course slurry experiments under variable redox conditions. The average endogenous methylation yield was higher in the estuarine (1.2 %) than in the lagoonal sediment (0.5 %), although both methylation and demethylation rates were higher in the lagoonal sediment in relation with a higher sulfate-reducing activity. Demethylation was overall more consistent than methylation in both sediments. The endogenous and exogenous Hg behaviors were always correlated but the exogenous inorganic Hg (IHg) partitioning into water was 2.0-4.3 times higher than the endogenous one. Its methylation was just slightly higher (1.4) in the estuarine sediment while the difference in the lagoonal sediment was much larger (3.6). The relative endogenous and exogenous methylation yields were not correlated to IHg partitioning, demonstrating that the bioavailable species distributions were different for the two IHg pools. In both sediments, the exogenous IHg partitioning equaled the endogenous one within a week, while its higher methylation lasted for months. Such results provide an original assessment approach to compare coastal sediment response to Hg inputs.

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy.

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).

Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial.

BACKGROUND: Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-ß signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. OBJECTIVES: We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. METHODS: We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. RESULTS: Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. CONCLUSIONS: This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome.

The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.

An experimental approach to investigate mercury species transformations under redox oscillations in coastal sediments.

This work describes a laboratory experiment designed to unravel mercury species reactivity in superficial coastal sediments oscillating between oxic and anoxic conditions. The experimental set-up has been applied to a sediment slurry from the Arcachon Bay (France) to follow the evolution of both naturally occurring (i.e. endogenous) and isotopically enriched added mercury species (i.e. exogenous, ¹99IHg and ²°¹MMHg) at environmental levels. The transformation and partition between the different phases (aqueous, solid and gaseous) of the endogenous and exogenous mercury species (inorganic Hg (IHg), monomethyl Hg (MMHg), elemental Hg (Hg°) and dimethyl Hg (DMHg)) have been investigated by isotopic speciation methods throughout the experiment. The results demonstrate that the experimental approach is able to promote sediment redox oscillations and to simultaneously follow the biogeochemical fate of naturally occurring or added mercury species. Experimentally driven redox transition events were found to significantly enhance the aqueous Hg species concentrations, while the MMHg burden is not greatly affected. Indeed, during the anoxic-oxic transition, while aqueous endogenous IHg and MMHg exhibited a two-fold increase, aqueous exogenous IHg and MMHg increased 7 and 4 times, respectively. Transient increases of the net IHg methylation were recorded during the redox transitions with the largest increase of the MMHg contents (factor 1.8) observed during the oxic-anoxic transition. High resolution in situ redox experiments have not been performed up to now, therefore the developed experimental set-up provides novel insights in both the influence of redox conditions on Hg methylation/demethylation and adsorption/desorption processes and kinetics in superficial sediments.