Biological monitoring of chemical exposure : toxicokinetic differences due to age and sex

Human biomonitoring is a widely used method in the assessment of occupational exposure to chemical substances and recommended biological limits are published periodically for interpretation and decision-making. However, it is increasingly recognized that a large variability is associated with biological monitoring, making interpretation less efficient than assumed. In order to improve the applicability of biological monitoring, specific factors responsible for this variability should be identified and their contribution quantified. Among these factors, age and sex are easily identifiable, and present knowledge about pharmaceutical chemicals suggests that they play an important role on the toxicokinetics of occupational chemical agents, and therefore on the biological monitoring results.The aim of the present research project was to assess the influence of age and sex on biological indicators corresponding to organic solvents. This has been done experimentally and by toxicokinetic computer simulation. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile.Age differences were identified by numerical simulations using a general toxicokinetic model from a previous study which was applied to 14 chemicals, representing 21 specific biological entities, with, among others, toluene, phenol, lead and mercury. These models were runn with the modified parameters, indicating in some cases important differences due to age. The expected changes are mostly of the order of 10-20 %, but differences up to 50 % were observed in some cases. These differences appear to depend on the chemical and on the biological entity considered.Sex differences were quantified by controlled human exposures, which were carried out in a 12 m3 exposure chamber for three organic solvents separately: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. The human volunteer groups were composed 12 of ten young men and fifteen young women, the latter subdivided into those with and without hormonal contraceptive. They were exposed during six hours at rest and at half of the threshold limit value. The kinetics of the parent compounds (organic volatiles) and their metabolite(s) were followed in blood, urine and expired air over time. Analyses of the solvent and their metabolites were performed by using headspace gas chromatography, CYP2E1 genotypes by using PCR-based RFLP methods. Experimental data were used to calibrate the toxicokinetic models developed for the three solvents. The results obtained for the different biomarkers of exposure mainly showed an effect on the urinary levels of several biomarkers among women due to the use of hormonal contraceptive, with an increase of about 50 % in the metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Simulations showed that it is possible to use simple toxicokinetic tools in order to predict internal exposure when exposed to organic solvents. Our study suggests that not only physiological differences but also exogenous sex hormones could influence CYP2E1 enzyme activity. The variability among the urinary biological indicators levels gives evidence of an interindividual susceptibility, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Kernel-based Mapping of Meteorological Fields in Complex Orography

Due to the advances in sensor networks and remote sensing technologies, the acquisition and storage rates of meteorological and climatological data increases every day and ask for novel and efficient processing algorithms. A fundamental problem of data analysis and modeling is the spatial prediction of meteorological variables in complex orography, which serves among others to extended climatological analyses, for the assimilation of data into numerical weather prediction models, for preparing inputs to hydrological models and for real time monitoring and short-term forecasting of weather.In this thesis, a new framework for spatial estimation is proposed by taking advantage of a class of algorithms emerging from the statistical learning theory. Nonparametric kernel-based methods for nonlinear data classification, regression and target detection, known as support vector machines (SVM), are adapted for mapping of meteorological variables in complex orography.With the advent of high resolution digital elevation models, the field of spatial prediction met new horizons. In fact, by exploiting image processing tools along with physical heuristics, an incredible number of terrain features which account for the topographic conditions at multiple spatial scales can be extracted. Such features are highly relevant for the mapping of meteorological variables because they control a considerable part of the spatial variability of meteorological fields in the complex Alpine orography. For instance, patterns of orographic rainfall, wind speed and cold air pools are known to be correlated with particular terrain forms, e.g. convex/concave surfaces and upwind sides of mountain slopes.Kernel-based methods are employed to learn the nonlinear statistical dependence which links the multidimensional space of geographical and topographic explanatory variables to the variable of interest, that is the wind speed as measured at the weather stations or the occurrence of orographic rainfall patterns as extracted from sequences of radar images. Compared to low dimensional models integrating only the geographical coordinates, the proposed framework opens a way to regionalize meteorological variables which are multidimensional in nature and rarely show spatial auto-correlation in the original space making the use of classical geostatistics tangled.The challenges which are explored during the thesis are manifolds. First, the complexity of models is optimized to impose appropriate smoothness properties and reduce the impact of noisy measurements. Secondly, a multiple kernel extension of SVM is considered to select the multiscale features which explain most of the spatial variability of wind speed. Then, SVM target detection methods are implemented to describe the orographic conditions which cause persistent and stationary rainfall patterns. Finally, the optimal splitting of the data is studied to estimate realistic performances and confidence intervals characterizing the uncertainty of predictions.The resulting maps of average wind speeds find applications within renewable resources assessment and opens a route to decrease the temporal scale of analysis to meet hydrological requirements. Furthermore, the maps depicting the susceptibility to orographic rainfall enhancement can be used to improve current radar-based quantitative precipitation estimation and forecasting systems and to generate stochastic ensembles of precipitation fields conditioned upon the orography.

Apport de la pH-impédancemétrie au diagnostic du reflux gastro- oesophagien et de la dysphagie [Advantages of pH-impedance monitoring in gastroesophageal reflux and dysphagia investigations]

Les manifestations ORL du reflux gastro-œsophagien sont fréquentes. La pH-impédancemétrie permet d’évaluer des reflux acides ou non acides et de déterminer leur extension proximale. A la lumière de deux patients de notre collectif, nous observons une corrélation entre reflux non acide et symptômes ORL dans le premier cas et une suppression acide insuffisante dans le deuxième cas. Ces résultats nous orientent vers un traitement spécifique complémentaire aux inhibiteurs de la pompe à protons. La pH-impédancemétrie détecte les reflux aussi bien acides que non acides, et analyse la concordance entre les symptômes et les épisodes de reflux. Elle permet ainsi une meilleure compréhension des manifestations ORL du reflux gastro-œsophagien et une prise en charge thérapeutique mieux adaptée. ENT symptoms of gastro-esophageal reflux are frequent. pH-impedance can detect acid and non-acid reflux and measure their proximal extension. The technique identifies the refluxate by changes in impedance. We discuss 2 clinical situations where correlation of symptoms could be explained by a non-acid reflux in the first case, and a lack of acid suppression in the second case, respectively. These results lead to a specific additional treatment to proton pump inhibitors (PPI). This technology provides a better understanding of the pathogenesis of reflux laryngitis, and affords the prescription of PPI on a proven diagnosis. Detection of non-acid reflux leads to an optimized medical treatment.

Monitoring and failure mechanism interpretation of an unstable slope in Southern Switzerland based on terrestrial laser scanner

We present the application of terrestrial laser scanning (TLS) for the monitoring and characterization of an active landslide area in Val Canaria (Ticino, Southern Swiss Alps). At catchment scale, the study area is affected by a large Deep Seated Gravitational Slope Deformation (DSGSD) area presenting, in the lower boundary, several retrogressive landslides active since the 1990s. Due to its frequent landslide events this area was periodically monitored by TLS since 2006. Periodic acquisitions provided new information on 3D displacements at the bottom of slope and the detection of centimetre to decimetre level scale changes (e.g. rockfall and pre-failure deformations). In October 2009, a major slope collapse occured at the bottom of the most unstable area. Based on the comparison between TLS data before and after the collapse, we carried out a detailed failure mechanism analysis and volume calculation.

Effect of Video Camera-Based Remote Roadway Condition Monitoring on Snow Removal-Related Maintenance Operations. 2014

Remote monitoring through the use of cameras is widely utilized for traffic operation, but has not been utilized widely for roadway maintenance operations. The Utah Department of Transportation (UDOT) has implemented a new remote monitoring system, referred to as a Cloud-enabled Remote Video Streaming (CRVS) camera system for snow removal-related maintenance operations in the winter. The purpose of this study was to evaluate the effectiveness of the use of the CRVS camera system in snow removal-related maintenance operations. This study was conducted in two parts: opinion surveys of maintenance station supervisors and an analysis on snow removal-related maintenance costs. The responses to the opinion surveys mostly displayed positive reviews of the use of the CRVS cameras. On a scale of 1 (least effective) to 5 (most effective), the average overall effectiveness given by the station supervisors was 4.3. An expedition trip for this study was defined as a trip that was made to just check the roadways if snow-removal was necessary. The average of the responses received from surveys was calculated to be a 33 percent reduction in expedition trips. For the second part of this study, an analysis was performed on the snow removal-related maintenance cost data provided by UDOT to see if the installation of a CRVS camera had an effect in reducing expedition trips. This expedition cost comparison was performed for 10 sets of maintenance stations within Utah. It was difficult to make any definitive inferences from the comparison of expedition costs over the years for which precipitation and expedition cost data were available; hence a statistical analysis was performed using the Mixed Model ANOVA. This analysis resulted in an average of 14 percent higher ratio of expedition costs at maintenance stations with a CRVS camera before the installation of the camera compared to the ratio of expedition costs after the installation of the camera. This difference was not proven to be statistically significant at the 95 percent confident level, but indicated that the installation of CRVS cameras was on the average helpful in reducing expedition costs and may be considered practically significant. It is recommended that more detailed and consistent maintenance cost records be prepared for accurate analysis of cost records for this type of study in the future.

Ambulatory blood pressure monitoring in the elderly hypertensive patient.

In this retrospective analysis, we assessed the usefulness of ambulatory blood pressure monitoring in the evaluation of elderly hypertensive patients. Thirty-eight untreated and 31 treated hypertensives aged 70 years or more had a systolic blood pressure greater than or equal to 160 mmHg and/or a diastolic blood pressure greater than or equal to 95 mmHg in the clinic. All 69 patients underwent blood pressure monitoring during their customary daily activities using a portable semi-automatic blood pressure recorder (Remier M2000). The mean of all blood pressures obtained with this device was taken as the ambulatory recorded blood pressure. Recorded blood pressures were greater than or equal to 160 mmHg systolic and greater than or equal to 90 mmHg diastolic in 17 untreated and 17 treated patients. In these patients, the introduction of antihypertensive therapy, or its modification, markedly reduced blood pressure during a 4-8 month follow-up. A further 21 untreated and 14 treated patients had recorded blood pressures of less than 160/90 mmHg. The treatment status of these patients was left unchanged for 4-8 months of follow-up. Nevertheless, office blood pressure in these groups, with no change in treatment, decreased significantly during the observation period. At the last visit to the outpatient clinic, there was no significant difference in blood pressure between the four subgroups of patients. Thus, ambulatory blood pressure monitoring appears to be useful in the elderly hypertensive patient in detecting those patients whose blood pressure is elevated only in the clinic. Blood pressure profiles obtained outside the clinic may therefore be useful in making therapeutic decisions in the aged hypertensive.

Optimal culture incubation time in orthopedic device-associated infections: a retrospective analysis of prolonged 14-day incubation.

Accurate diagnosis of orthopedic device-associated infections can be challenging. Culture of tissue biopsy specimens is often considered the gold standard; however, there is currently no consensus on the ideal incubation time for specimens. The aim of our study was to assess the yield of a 14-day incubation protocol for tissue biopsy specimens from revision surgery (joint replacements and internal fixation devices) in a general orthopedic and trauma surgery setting. Medical records were reviewed retrospectively in order to identify cases of infection according to predefined diagnostic criteria. From August 2009 to March 2012, 499 tissue biopsy specimens were sampled from 117 cases. In 70 cases (59.8%), at least one sample showed microbiological growth. Among them, 58 cases (82.9%) were considered infections and 12 cases (17.1%) were classified as contaminations. The median time to positivity in the cases of infection was 1 day (range, 1 to 10 days), compared to 6 days (range, 1 to 11 days) in the cases of contamination (P < 0.001). Fifty-six (96.6%) of the infection cases were diagnosed within 7 days of incubation. In conclusion, the results of our study show that the incubation of tissue biopsy specimens beyond 7 days is not productive in a general orthopedic and trauma surgery setting. Prolonged 14-day incubation might be of interest in particular situations, however, in which the prevalence of slow-growing microorganisms and anaerobes is higher.

Optimal CD8 T cell responsiveness is controlled within a defined TCR affinity window

Protective immune responses relyon TCR-mediated recognition of antigenspresented by MHC molecules. Tcells directed against tumor antigensare thought to express TCRs of loweraffinity/avidity than pathogen-specificT lymphocytes. An attractivestrategy to improve anti-tumor T cellresponses is to adoptively transferCD8+ T cells engineered with TCRsof optimized affinity. However, themechanisms that control optimal Tcell activation and responsiveness remainpoorly defined. We aim at characterizingTCR-pMHC binding parametersand downstream signalingevents that regulate T cell functionalityby using an in silico designedpanel of tumor antigen-specific TCRsof incremental affinity for pMHC(Kd100 M- 15 nM).We found that optimalT cell responses (cytokine secretionand target cell killing) occurredwithin a well-defined window ofTCR-pMHC binding affinity (5 M-1 M), while drastic functional declinewas detected in T cells expressingvery low and very high TCRaffinities,which was not caused by any increasein apoptosis. Whole-genomemicroarray analysis revealed that Tcells with optimal TCR affinitieshighly up-regulated transcription ofgenes typical of T cell activation (i.e.IFN-, NF-B and TNFR), while reducedexpression was detected in Tcells of very low or very high TCR affinity.Strikingly, hierarchical clusteringshowed that the latter two variantsclustered together with the un-stimulatedcontrol Tcells.Yet, despite commonclustering, several genes seemedto be differentially expressed, suggestingthat the mechanisms involvedin this "unresponsiveness state" maydiffer between those two variants. Finally,calcium influx assays also demonstratedattenuated responses in Tcells of very high TCR affinity. Ourresults indicate that optimal T cellfunction is tightly controlled within adefinedTCRaffinity window throughvery proximal TCR-mediated mechanisms,possibly at the TCR-pMHCbinding interface. Uncovering themechanisms regulating optimal/maximalT cell function is essential to understandand promote therapeutic designlike adoptive T cell therapy.