A general model to predict individual exposure to solar UV by using ambient irradiance data

Excessive exposure to solar ultraviolet (UV) is the main cause of skin cancer. Specific prevention should be further developed to target overexposed or highly vulnerable populations. A better characterisation of anatomical UV exposure patterns is however needed for specific prevention. To develop a regression model for predicting the UV exposure ratio (ER, ratio between the anatomical dose and the corresponding ground level dose) for each body site without requiring individual measurements. A 3D numeric model (SimUVEx) was used to compute ER for various body sites and postures. A multiple fractional polynomial regression analysis was performed to identify predictors of ER. The regression model used simulation data and its performance was tested on an independent data set. Two input variables were sufficient to explain ER: the cosine of the maximal daily solar zenith angle and the fraction of the sky visible from the body site. The regression model was in good agreement with the simulated data ER (R(2)=0.988). Relative errors up to +20% and -10% were found in daily doses predictions, whereas an average relative error of only 2.4% (-0.03% to 5.4%) was found in yearly dose predictions. The regression model predicts accurately ER and UV doses on the basis of readily available data such as global UV erythemal irradiance measured at ground surface stations or inferred from satellite information. It renders the development of exposure data on a wide temporal and geographical scale possible and opens broad perspectives for epidemiological studies and skin cancer prevention.

In utero exposure to immunosuppressive drugs.

The number of pregnant women receiving immunosuppressants for anti-rejection therapy or autoimmune diseases is increasing. All immunosuppressive drugs cross the placenta, raising questions about the long-term outcome of the children exposed in utero. There is no higher risk of congenital anomalies. However, an increased incidence of prematurity, intrauterine growth retardation (IUGR) and generally low birth weight has been reported, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporine, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes.

The fourth transmembrane segment of the Na,K-ATPase alpha subunit: a systematic mutagenesis study.

The Na,K-ATPase is a major ion-motive ATPase of the P-type family responsible for many aspects of cellular homeostasis. To determine the structure of the pathway for cations across the transmembrane portion of the Na,K-ATPase, we mutated 24 residues of the fourth transmembrane segment into cysteine and studied their function and accessibility by exposure to the sulfhydryl reagent 2-aminoethyl-methanethiosulfonate. Accessibility was also examined after treatment with palytoxin, which transforms the Na,K-pump into a cation channel. Of the 24 tested cysteine mutants, seven had no or a much reduced transport function. In particular cysteine mutants of the highly conserved "PEG" motif had a strongly reduced activity. However, most of the non-functional mutants could still be transformed by palytoxin as well as all of the functional mutants. Accessibility, determined as a 2-aminoethyl-methanethiosulfonate-induced reduction of the transport activity or as inhibition of the membrane conductance after palytoxin treatment, was observed for the following positions: Phe(323), Ile(322), Gly(326), Ala(330), Pro(333), Glu(334), and Gly(335). In accordance with a structural model of the Na,K-ATPase obtained by homology modeling with the two published structures of sarcoplasmic and endoplasmic reticulum calcium ATPase (Protein Data Bank codes 1EUL and 1IWO), the results suggest the presence of a cation pathway along the side of the fourth transmembrane segment that faces the space between transmembrane segments 5 and 6. The phenylalanine residue in position 323 has a critical position at the outer mouth of the cation pathway. The residues thought to form the cation binding site II ((333)PEGL) are also part of the accessible wall of the cation pathway opened by palytoxin through the Na,K-pump.

New developments and applications in modelling occupational exposure to airborne contaminants

Résumé: L'évaluation de l'exposition aux nuisances professionnelles représente une étape importante dans l'analyse de poste de travail. Les mesures directes sont rarement utilisées sur les lieux même du travail et l'exposition est souvent estimée sur base de jugements d'experts. Il y a donc un besoin important de développer des outils simples et transparents, qui puissent aider les spécialistes en hygiène industrielle dans leur prise de décision quant aux niveaux d'exposition. L'objectif de cette recherche est de développer et d'améliorer les outils de modélisation destinés à prévoir l'exposition. Dans un premier temps, une enquête a été entreprise en Suisse parmi les hygiénistes du travail afin d'identifier les besoins (types des résultats, de modèles et de paramètres observables potentiels). Il a été constaté que les modèles d'exposition ne sont guère employés dans la pratique en Suisse, l'exposition étant principalement estimée sur la base de l'expérience de l'expert. De plus, l'émissions de polluants ainsi que leur dispersion autour de la source ont été considérés comme des paramètres fondamentaux. Pour tester la flexibilité et la précision des modèles d'exposition classiques, des expériences de modélisations ont été effectuées dans des situations concrètes. En particulier, des modèles prédictifs ont été utilisés pour évaluer l'exposition professionnelle au monoxyde de carbone et la comparer aux niveaux d'exposition répertoriés dans la littérature pour des situations similaires. De même, l'exposition aux sprays imperméabilisants a été appréciée dans le contexte d'une étude épidémiologique sur une cohorte suisse. Dans ce cas, certains expériences ont été entreprises pour caractériser le taux de d'émission des sprays imperméabilisants. Ensuite un modèle classique à deux-zone a été employé pour évaluer la dispersion d'aérosol dans le champ proche et lointain pendant l'activité de sprayage. D'autres expériences ont également été effectuées pour acquérir une meilleure compréhension des processus d'émission et de dispersion d'un traceur, en se concentrant sur la caractérisation de l'exposition du champ proche. Un design expérimental a été développé pour effectuer des mesures simultanées dans plusieurs points d'une cabine d'exposition, par des instruments à lecture directe. Il a été constaté que d'un point de vue statistique, la théorie basée sur les compartiments est sensée, bien que l'attribution à un compartiment donné ne pourrait pas se faire sur la base des simples considérations géométriques. Dans une étape suivante, des données expérimentales ont été collectées sur la base des observations faites dans environ 100 lieux de travail différents: des informations sur les déterminants observés ont été associées aux mesures d'exposition des informations sur les déterminants observés ont été associé. Ces différentes données ont été employées pour améliorer le modèle d'exposition à deux zones. Un outil a donc été développé pour inclure des déterminants spécifiques dans le choix du compartiment, renforçant ainsi la fiabilité des prévisions. Toutes ces investigations ont servi à améliorer notre compréhension des outils des modélisations ainsi que leurs limitations. L'intégration de déterminants mieux adaptés aux besoins des experts devrait les inciter à employer cet outil dans leur pratique. D'ailleurs, en augmentant la qualité des outils des modélisations, cette recherche permettra non seulement d'encourager leur utilisation systématique, mais elle pourra également améliorer l'évaluation de l'exposition basée sur les jugements d'experts et, par conséquent, la protection de la santé des travailleurs. Abstract Occupational exposure assessment is an important stage in the management of chemical exposures. Few direct measurements are carried out in workplaces, and exposures are often estimated based on expert judgements. There is therefore a major requirement for simple transparent tools to help occupational health specialists to define exposure levels. The aim of the present research is to develop and improve modelling tools in order to predict exposure levels. In a first step a survey was made among professionals to define their expectations about modelling tools (what types of results, models and potential observable parameters). It was found that models are rarely used in Switzerland and that exposures are mainly estimated from past experiences of the expert. Moreover chemical emissions and their dispersion near the source have also been considered as key parameters. Experimental and modelling studies were also performed in some specific cases in order to test the flexibility and drawbacks of existing tools. In particular, models were applied to assess professional exposure to CO for different situations and compared with the exposure levels found in the literature for similar situations. Further, exposure to waterproofing sprays was studied as part of an epidemiological study on a Swiss cohort. In this case, some laboratory investigation have been undertaken to characterize the waterproofing overspray emission rate. A classical two-zone model was used to assess the aerosol dispersion in the near and far field during spraying. Experiments were also carried out to better understand the processes of emission and dispersion for tracer compounds, focusing on the characterization of near field exposure. An experimental set-up has been developed to perform simultaneous measurements through direct reading instruments in several points. It was mainly found that from a statistical point of view, the compartmental theory makes sense but the attribution to a given compartment could ñó~be done by simple geometric consideration. In a further step the experimental data were completed by observations made in about 100 different workplaces, including exposure measurements and observation of predefined determinants. The various data obtained have been used to improve an existing twocompartment exposure model. A tool was developed to include specific determinants in the choice of the compartment, thus largely improving the reliability of the predictions. All these investigations helped improving our understanding of modelling tools and identify their limitations. The integration of more accessible determinants, which are in accordance with experts needs, may indeed enhance model application for field practice. Moreover, while increasing the quality of modelling tool, this research will not only encourage their systematic use, but might also improve the conditions in which the expert judgments take place, and therefore the workers `health protection.

Progesterone down-regulates the open probability of the amiloride-sensitive epithelial sodium channel via a Nedd4-2-dependent mechanism.

Activation of the mitogen-activated protein (MAP) kinase cascade by progesterone in Xenopus oocytes leads to a marked down-regulation of activity of the amiloride-sensitive epithelial sodium channel (ENaC). Here we have studied the signaling pathways involved in progesterone effect on ENaC activity. We demonstrate that: (i) the truncation of the C termini of the alphabetagammaENaC subunits results in the loss of the progesterone effect on ENaC; (ii) the effect of progesterone was also suppressed by mutating conserved tyrosine residues in the Pro-X-X-Tyr (PY) motif of the C termini of the beta and gamma ENaC subunits (beta(Y618A) and gamma(Y628A)); (iii) the down-regulation of ENaC activity by progesterone was also suppressed by co-expression ENaC subunits with a catalytically inactive mutant of Nedd4-2, a ubiquitin ligase that has been previously demonstrated to decrease ENaC cell-surface expression via a ubiquitin-dependent internalization/degradation mechanism; (iv) the effect of progesterone was significantly reduced by suppression of consensus sites (beta(T613A) and gamma(T623A)) for ENaC phosphorylation by the extracellular-regulated kinase (ERK), a MAP kinase previously shown to facilitate the binding of Nedd4 ubiquitin ligases to ENaC; (v) the quantification of cell-surface-expressed ENaC subunits revealed that progesterone decreases ENaC open probability (whole cell P(o), wcP(o)) and not its cell-surface expression. Collectively, these results demonstrate that the binding of active Nedd4-2 to ENaC is a crucial step in the mechanism of ENaC inhibition by progesterone. Upon activation of ERK, the effect of Nedd4-2 on ENaC open probability can become more important than its effect on ENaC cell-surface expression.

Ganciclovir Exposure under a 450 mg Daily Dosage of Valganciclovir for the Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients.

Background: It is suggested that a low dose of valganciclovir can be equally effective than a standard dose for cytomegalovirus (CMV) prophylaxis after kidney transplantation. The aim of our study was to determine the ganciclovir exposure observed under a routine daily dosage of 450 mg valganciclovir in kidney transplant recipients with a wide range of renal function. Methods: In this prospective study, kidney transplant recipients with a GFR MDRD above 25 mL/min at risk for CMV (donor or recipient seropositive for CMV) received a dose of valganciclovir (450 mg daily) prophylaxis for 3 months. Ganciclovir levels at trough (Ctrough) and at peak (C3h) were measured monthly. Ganciclovir exposure (AUC0-24) was estimated using Bayesian non-linear mixed-effect modelling (NONMEM) and compared between 3 groups of patients according to their kidney function: GFRMDRD 26-39 mL/min (Group 1), GFRMDRD 40-59 mL/min (Group 2) and GFRMDRD 60-90 mL/min (Group 3). CMV DNAemia was assessed during and after prophylaxis using PCR. Results: Thirty-six patients received 450 mg daily of valganciclovir for 3 months. Median ganciclovir C3h was 3.9 mg/L (range: 1.3-7.1) and Ctrough was 0.4 mg/L (range 0.1-2.7). Median (range) AUC0-24 of ganciclovir was 59.3 mg.h/L (39.0-85.3) in Group 1 patients, 35.8 mg.h/L (24.9-55.8) in Group 2 patients and 29.6 mg.h/L (22.0- 43.2) in Group 3 patients (p<0.001). Anemia was more common in Group 1 patients compared to patients on the other groups (p=0.01). No differences in other adverse events according to ganciclovir exposure were observed. CMV DNAemia was not detected during prophylaxis. After discontinuing prophylaxis, CMV DNAemia was seen in 8/34 patients (23.5%) and 4/36 patients (11%) developed CMV disease. Conclusion: A routine dosage of valganciclovir achieved plasma levels of ganciclovir in patients with GFR>60 mL/min similar to those previously reported using oral ganciclovir. A daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Multimodel inference and multimodel averaging in empirical modeling of occupational exposure levels.

Empirical modeling of exposure levels has been popular for identifying exposure determinants in occupational hygiene. Traditional data-driven methods used to choose a model on which to base inferences have typically not accounted for the uncertainty linked to the process of selecting the final model. Several new approaches propose making statistical inferences from a set of plausible models rather than from a single model regarded as 'best'. This paper introduces the multimodel averaging approach described in the monograph by Burnham and Anderson. In their approach, a set of plausible models are defined a priori by taking into account the sample size and previous knowledge of variables influent on exposure levels. The Akaike information criterion is then calculated to evaluate the relative support of the data for each model, expressed as Akaike weight, to be interpreted as the probability of the model being the best approximating model given the model set. The model weights can then be used to rank models, quantify the evidence favoring one over another, perform multimodel prediction, estimate the relative influence of the potential predictors and estimate multimodel-averaged effects of determinants. The whole approach is illustrated with the analysis of a data set of 1500 volatile organic compound exposure levels collected by the Institute for work and health (Lausanne, Switzerland) over 20 years, each concentration having been divided by the relevant Swiss occupational exposure limit and log-transformed before analysis. Multimodel inference represents a promising procedure for modeling exposure levels that incorporates the notion that several models can be supported by the data and permits to evaluate to a certain extent model selection uncertainty, which is seldom mentioned in current practice.

Biodistribution Study of the Anaesthetic Sodium Phenobarbital Labelled with Technetium-99m in Swiss Mice Infected with Schistosoma mansoni Sambon, 1907

Technetium-99m (99mTc) is a radionuclide that has negligible enviromnental impact, is easily available, inexpensive and can be used as a radioactive tracer in biological experiences. In order to know the mode of action of sodium phenobarbital in moving adult Schistosoma mansoni worms from mesenteric veins to the liver, we labelled sodium phenobarbital (PBBT) with 99mTc and a biodistribution study in infected and non-infected Swiss mice was performed. The PBBT was incubated with stannous chloride used as reducing agent and with 99mTc, as sodium pertechnetate. The radioactivity labelling (%) was determined by paper ascending chromatography perfomed with acetone (solvent). The 99mTc-PBBT was administered by intraperitoneal route to Swiss mice infected eight weeks before. The animals were perfused after diferent periods of time (0,1,2,3,4 hr) when blood, spleen, liver, portal vein, mesenteric veins, stomach, kidneys and adult worms were isolated. The radioactivity present in these samples was counted in a well counter and the percentage was determined. The radioactivity was mainly taken up by the blood, kidney, liver and spleen. No radioactivity was found on the adult worms. We concluded that the worm shift was due to an action on the host of the sodium phenobarbital

Human mercury exposure associated with small-scale gold mining in Burkina Faso.

PURPOSE: In Burkina Faso, gold ore is one of the main sources of income for an important part of the active population. Artisan gold miners use mercury in the extraction, a toxic metal whose human health risks are well known. The aim of the present study was to assess mercury exposure as well as to understand the exposure determinants of gold miners in Burkinabe small-scale mines.METHODS: The examined gold miners' population on the different selected gold mining sites was composed by persons who were directly and indirectly related to gold mining activities. But measurement of urinary mercury was performed on workers most susceptible to be exposed to mercury. Thus, occupational exposure to mercury was evaluated among ninety-three workers belonging to eight different gold mining sites spread in six regions of Burkina Faso. Among others, work-related exposure determinants were taken into account for each person during urine sampling as for example amalgamating or heating mercury. All participants were medically examined by a local medical team in order to identify possible symptoms related to the toxic effect of mercury.RESULTS: Mercury levels were high, showing that 69% of the measurements exceeded the ACGIH (American Conference of Industrial Hygienists) biological exposure indice (BEI) of 35 µg per g of creatinine (µg/g-Cr) (prior to shift) while 16% even exceeded 350 µg/g-Cr. Basically, unspecific but also specific symptoms related to mercury toxicity could be underlined among the persons who were directly related to gold mining activities. Only one-third among the studied subpopulation reported about less than three symptoms possibly associated to mercury exposure and nearly half of them suffered from at least five of these symptoms. Ore washers were more involved in the direct handling of mercury while gold dealers in the final gold recovery activities. These differences may explain the overexposure observed in gold dealers and indicate that the refining process is the major source of exposure.CONCLUSIONS: This study attests that mercury exposure still is an issue of concern. North-South collaborations should encourage knowledge exchange between developing and developed countries, for a cleaner artisanal gold mining process and thus for reducing human health and environmental hazards due to mercury use.

Calibration of surface contamination monitors for the detection of iodine incorporation in the thyroid gland.

In Switzerland, individuals exposed to the risk of activity intake are required to perform regular monitoring. Monitoring consists in a screening measurement and is meant to be performed using commonly available laboratory instruments. More particularly, iodine intake is measured using a surface contamination monitor. The goal of the present paper is to report the calibration method developed for thyroid screening instruments. It consists of measuring the instrument response to a known activity located in the thyroid gland of a standard neck phantom. One issue of this procedure remains that the iodine radioisotopes have a short half-life. Therefore, the adequacy and limitations to simulate the short-lived radionuclides with so-called mock radionuclides of longer half-life were also evaluated. In light of the results, it has been decided to use only the appropriate iodine sources to perform the calibration.