Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.

The difficulty in mimicking nervous system complexity and cell-cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent brain cell culture models, consisting of both neurons and glial cells organized in 2 or 3 dimensions to mimic the brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D cell model, together with a greater alteration of neurotoxicity markers. After 14days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure.

A web-based tool to aid the identification of chemicals potentially posing a health risk through percutaneous exposure

Occupational hygiene practitioners typically assess the risk posed by occupational exposure by comparing exposure measurements to regulatory occupational exposure limits (OELs). In most jurisdictions, OELs are only available for exposure by the inhalation pathway. Skin notations are used to indicate substances for which dermal exposure may lead to health effects. However, these notations are either present or absent and provide no indication of acceptable levels of exposure. Furthermore, the methodology and framework for assigning skin notation differ widely across jurisdictions resulting in inconsistencies in the substances that carry notations. The UPERCUT tool was developed in response to these limitations. It helps occupational health stakeholders to assess the hazard associated with dermal exposure to chemicals. UPERCUT integrates dermal quantitative structure-activity relationships (QSARs) and toxicological data to provide users with a skin hazard index called the dermal hazard ratio (DHR) for the substance and scenario of interest. The DHR is the ratio between the estimated 'received' dose and the 'acceptable' dose. The 'received' dose is estimated using physico-chemical data and information on the exposure scenario provided by the user (body parts exposure and exposure duration), and the 'acceptable' dose is estimated using inhalation OELs and toxicological data. The uncertainty surrounding the DHR is estimated with Monte Carlo simulation. Additional information on the selected substances includes intrinsic skin permeation potential of the substance and the existence of skin notations. UPERCUT is the only available tool that estimates the absorbed dose and compares this to an acceptable dose. In the absence of dermal OELs it provides a systematic and simple approach for screening dermal exposure scenarios for 1686 substances.

Immunologic work up of subjects who didn't respond appropriately to a rabies post exposure prophylaxis

Background New recommendations for rabies postexposure prophylaxis (rPEP) were published by the Centers for Disease Control and Prevention and the World Health Organization in 2010. In view of these new recommendations, the adequacy of rPEP among patients consulting the travel clinic of the University Hospital of Lausanne has been investigated and 6,8% of patients have been identified as non-responders with the new rPEP regimen. In this study we have selected the non-responders for a complete immunologic work up. Method Clinical and paraclinical immunologic investigations have been done to the non- responders patients. Those investigations have been conducted to look for an increased susceptibility to infections and an immunodeficiency. The investigations included a clinical evaluation, a full blood count, measurement of the immunoglobulin levels, a numeration of the subpopulations of the lymphocytes, a HIV test and an evaluation of the humoral response to tetanus, pneumococcal, and hepatitis B vaccinations. A lymphocyte proliferation assay with rabies antigen was performed to assess the cellular immune response. Results 9 subjects with rabies antibody titers ≤0,5 IU/ml after an rPEP with 4 doses were included in this study (=non-responders). 8/9 of these non-responders had an unremarkable medical history. 9/9 of them had normal paraclinical tests that did not suggest an immunodeficiency. The results of the lymphocyte proliferation assay with rabies antigen showed a significant correlation between the level of the humoral and cellular response. Conclusion These results suggest that a 4 dose intramuscular rPEP elicits in some patients a relatively poor humoral and cellular response, even in the absence of any immunosuppression. A serology on day 21 of the rPEP seems therefore useful to identify the patients who don't respond appropriately. Those non-responders should receive additional doses until they reach an antibody titer above 0.5 IU/ml.

Virus Infections in Early Childhood, Cow’s Milk Formula Exposure and Genetic Predisposition in the Development of Diabetes-Associated Autoimmunity

Varhaislapsuuden virusinfektioiden, lehmänmaitopohjaisen äidinmaitovastikeen ja geneettisen alttiuden merkitys diabetekseen liittyvän autoimmuniteetin kehittymisessä Tyypin 1 diabetes on autoimmuunisairaus, joka syntyy haiman insuliinia tuottavien beta-solujen tuhouduttua elimistön oman immuunipuolustusjärjestelmän hyökkäyksen seurauksena. Sekä perimän että ympäristötekijöiden arvellaan vaikuttavan tautiprosessiin, mutta taudin tarkkaa syntymekanismia ei tunneta. Tutkimuksen tarkoituksena oli selvittää varhaislapsuuden ympäristötekijöiden vaikutusta beta-soluautoimmuniteetin syntyyn, erityispaino tutkimuksessa oli ympäristötekijöiden yhteisvaikutuksessa sekä geneettisten riskitekijöiden ja ympäristötekijöiden vuorovaikutuksessa. Varhaislapsuudessa sairastettu sytomegalovirus- tai enterovirusinfektio ei lisännyt beta-soluautoimmuniteetin riskiä lapsilla, joilla on geneettisesti kohonnut riski sairastua tyypin 1 diabetekseen. Ennen puolen vuoden ikää sairastettu rotavirusinfektio lisäsi hieman tyypin 1 diabetekseen liittyvän autoimmuniteetin riskiä. Tarkemmassa analyysissa varhaislapsuuden enterovirusinfektio osoittautui kuitenkin autovasta-aineiden muodostumisen riskitekijäksi niiden lasten joukossa, jotka olivat saaneet lehmänmaitopohjaista äidinmaidon vastiketta ensimmäisten elinkuukausien aikana. Tämä löydös viittaa enterovirusinfektion ja lehmänmaitopohjaisen vastikkeen yhteisvaikutukseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Löydösten mukaan PTPN22 geenin C1858T polymorfismi vaikuttaa CD4+ T solujen aktivaatioon ja proliferaatiovasteeseen, 1858T alleeliin liittyy alentunut T-soluresepto-rivälitteinen aktivaatio. 1858T alleelin kantajuuteen liittyy lisäksi lisääntynyt autovasta-aineiden ja kliinisen diabeteksen ilmaantuvuus. Tämä yhteys rajoittui yksilöihin, jotka olivat altistuneet lehmänmaitopohjaiselle vastikkeelle ennen kuuden kuukauden ikää. Tulosten mukaan sekä ympäristötekijöiden väliset yhteisvaikutukset että perimä vaikuttavat yksittäisen ympäristötekijän merkitykseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Nämä yhteisvaikutukset ympäristötekijöiden kesken ja perimän ja ympäristötekijöiden välillä selittävät aiemmin julkaistujen tulosten ristiriittaisuutta tutkimuksissa, joissa on analysoitu vain yhden ympäristötekijän vaikutusta diabeteksen ilmaantuvuuteen.

Analytical challenges in breath analysis and its application to exposure monitoring

There is an increasing interest in the use of breath analysis for monitoring human physiology and exposure to toxic substances or environmental pollutants. This review focuses on the current status of the sampling procedures, collection devices and sample-enrichment methodologies used for exhaled breath-vapor analysis. We discuss the different parameters affecting each of the above steps, taking into account the requirements for breath analysis in exposure assessments and the need to analyze target compounds at sub-ppbv levels. Finally, we summarize the practical applications of exposure analysis in the past two decades

Predictors of smoking craving during virtual reality exposure

Cue exposure treatment (CET) consists of controlled and repeated exposure to drugrelated stimuli in order to reduce cue-reactivity. Virtual reality (VR) has proved to be a promising tool for exposition. However, identifying the variables that can modulate the efficacy of this technique is essential for selecting the most appropriate exposure modality. The aim of this study was to determine the relation between several individual variables and self-reported craving in smokers exposed to VR environments. Fortysix smokers were exposed to seven complex virtual environments that reproduce typical situations in which people smoke. Self-reported craving was selected as the criterion variable and three types of variables were selected as the predictor variables: related to nicotine dependence, related to anxiety and impulsivity, and related to the sense of presence in the virtual environments. Sense of presence was the only predictor of self-reported craving in all the experimental virtual environments. Nicotine dependence variables added predictive power to the model only in the virtual breakfast at home. No relation was found between anxiety or impulsivity and self-reported craving. Virtual reality technology can be very helpful for improving CET for substance use disorders. However, the use of virtual environments would make sense only insofar as the sense of presence was high. Otherwise, the effectiveness of exposure might be affected. © 2012 by the Massachusetts Institute of Technology.

Association between Long-Term Exposure to Traffic-Related Air Pollution and Subclinical Atherosclerosis: The REGICOR Study

Background: Epidemiological evidence of the effects of long-term exposure to air pollu tion on the chronic processes of athero genesis is limited. Objective: We investigated the association of long-term exposure to traffic-related air pollu tion with subclinical atherosclerosis, measured by carotid intima media thickness (IMT) and ankle–brachial index (ABI). Methods: We performed a cross-sectional analysis using data collected during the reexamination (2007–2010) of 2,780 participants in the REGICOR (Registre Gironí del Cor: the Gerona Heart Register) study, a population-based prospective cohort in Girona, Spain. Long-term exposure across residences was calculated as the last 10 years’ time-weighted average of residential nitrogen dioxide (NO2) estimates (based on a local-scale land-use regression model), traffic intensity in the nearest street, and traffic intensity in a 100 m buffer. Associations with IMT and ABI were estimated using linear regression and multinomial logistic regression, respectively, controlling for sex, age, smoking status, education, marital status, and several other potential confounders or intermediates. Results: Exposure contrasts between the 5th and 95th percentiles for NO2 (25 μg/m), traffic intensity in the nearest street (15,000 vehicles/day), and traffic load within 100 m (7,200,000 vehicle-m/day) were associated with differences of 0.56% (95% CI: –1.5, 2.6%), 2.32% (95% CI: 0.48, 4.17%), and 1.91% (95% CI: –0.24, 4.06) percent difference in IMT, respectively. Exposures were positively associated with an ABI of > 1.3, but not an ABI of < 0.9. Stronger associations were observed among those with a high level of education and in men ≥ 60 years of age. Conclusions: Long-term traffic-related exposures were associated with subclinical markers of atherosclerosis. Prospective studies are needed to confirm associations and further examine differences among population subgroups.key words: ankle–brachial index, average daily traffic, cardiovascular disease, exposure assessment, exposure to tailpipe emissions, intima media thickness, land use regression model, Mediterranean diet, nitrogen dioxide

Exposure to Tobacco Smoke and Markers of Subclinical Atherosclerosis in Children and Adolescents. The STRIP Study.

Background: Measurement of serum cotinine, a major metabolite of nicotine, provides a valid marker for quantifying exposure to tobacco smoke. Exposure to tobacco smoke causes vascular damage by multiple mechanisms, and it has been acknowledged as a risk factor for atherosclerosis. Multifactorial atherosclerosis begins in childhood, but the relationship between exposure to tobacco smoke and arterial changes related to early atherosclerosis have not been studied in children. Aims: The aim of the present study was to evaluate exposure to tobacco smoke with a biomarker, serum cotinine concentration, and its associations with markers of subclinical atherosclerosis and lipid profile in school-aged children and adolescents. Subjects and Methods: Serum cotinine concentration was measured using a gas chromatographic method annually between the ages 8 and 13 years in 538-625 children participating since infancy in a randomized, prospective atherosclerosis prevention trial STRIP (Special Turku coronary Risk factor Intervention Project). Conventional atherosclerosis risk factors were measured repeatedly. Vascular ultrasound studies were performed among 402 healthy 11-year-old children and among 494 adolescents aged 13 years. Results: According to serum cotinine measurements, a notable number of the school aged children and adolescents were exposed to tobacco smoke, but the exposure levels were only moderate. Exposure to tobacco smoke was associated with decreased endothelial function as measured with flow-mediated dilation of the brachial artery, decreased elasticity of the aorta, and increased carotid and aortic intima-media thickness. Longitudinal exposure to tobacco smoke was also related with increased apolipoprotein B and triglyceride levels in 13-year-old adolescents, whose body mass index and nutrient intakes did not differ. Conclusions: These findings suggest that exposure to tobacco smoke in childhood may play a significant role in the development of early atherosclerosis. Key Words: arterial elasticity, atherosclerosis, children, cotinine, endothelial function, environmental tobacco smoke, intima-media thickness, risk factors, ultrasound

Percutaneous access versus standard femoral exposure for endovascular abdominal aortic aneurysm repair: a randomized, controlled trial

The treatment of abdominal aortic aneurysm (AAA) has shifted from the exposure of the aorta artery in an open repair technique to a small groin cut in an endovascular repair. Recently, a percutaneous access for endovascular repair has appeared. This new technique aims to minimize the complications of the common femoral artery exposure, the patient discomfort and the length of hospitalizationObjectives: To compare the proportion of discharged patients within the first 48 postoperative hours of two common femoral artery accesses for endovascular repair of AAA: the open exposure technique and the percutaneous technique. Secondary objectives include to evaluate the total procedure time, the femoral access complications, the need for extra analgesia and the patient satisfaction and groin discomfort of the two techniquesDesign: Randomized controlled trial conducted between 2014 and 2017Participants: Patients diagnosed with abdominal aortic aneurysm with elective endovascular repair indication

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Bread is one of the most widely consumed foods. Its impact on human health is currently of special interest for researchers. We aimed to identify biomarkers of bread consumption by applying a nutrimetabolomic approach to a free-living population. An untargeted HPLC q-TOF-MS and multivariate analysis was applied to human urine from 155 subjects stratified by habitual bread consumption in three groups: non-consumers of bread (n = 56), white-bread consumers (n = 48) and whole-grain bread consumers (n = 51). The most differential metabolites (variable importance for projection ≥1.5) included compounds originating from cereal plant phytochemicals such as benzoxazinoids and alkylresorcinol metabolites, and compounds produced by gut microbiota (such as enterolactones, hydroxybenzoic and dihydroferulic acid metabolites). Pyrraline, riboflavin, 3-indolecarboxylic acid glucuronide, 2,8-dihydroxyquinoline glucuronide and N-α-acetylcitrulline were also tentatively identified. In order to combine multiple metabolites in a model to predict bread consumption, a stepwise logistic regression analysis was used. Receiver operating curves were constructed to evaluate the global performance of individual metabolites and their combination. The area under the curve values [AUC (95 % CI)] of combined models ranged from 77.8 % (69.1 86.4 %) to 93.7 % (89.4 98.1 %), whereas the AUC for the metabolites included in the models had weak values when they were evaluated individually: from 58.1 % (46.6 69.7 %) to 78.4 % (69.8 87.1 %). Our study showed that a daily bread intake significantly impacted on the urinary metabolome, despite being examined under uncontrolled free-living conditions. We further concluded that a combination of several biomarkers of exposure is better than a single biomarker for the predictive ability of discriminative analysis.

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Bread is one of the most widely consumed foods. Its impact on human health is currently of special interest for researchers. We aimed to identify biomarkers of bread consumption by applying a nutrimetabolomic approach to a free-living population. An untargeted HPLC q-TOF-MS and multivariate analysis was applied to human urine from 155 subjects stratified by habitual bread consumption in three groups: non-consumers of bread (n = 56), white-bread consumers (n = 48) and whole-grain bread consumers (n = 51). The most differential metabolites (variable importance for projection ≥1.5) included compounds originating from cereal plant phytochemicals such as benzoxazinoids and alkylresorcinol metabolites, and compounds produced by gut microbiota (such as enterolactones, hydroxybenzoic and dihydroferulic acid metabolites). Pyrraline, riboflavin, 3-indolecarboxylic acid glucuronide, 2,8-dihydroxyquinoline glucuronide and N-α-acetylcitrulline were also tentatively identified. In order to combine multiple metabolites in a model to predict bread consumption, a stepwise logistic regression analysis was used. Receiver operating curves were constructed to evaluate the global performance of individual metabolites and their combination. The area under the curve values [AUC (95 % CI)] of combined models ranged from 77.8 % (69.1 86.4 %) to 93.7 % (89.4 98.1 %), whereas the AUC for the metabolites included in the models had weak values when they were evaluated individually: from 58.1 % (46.6 69.7 %) to 78.4 % (69.8 87.1 %). Our study showed that a daily bread intake significantly impacted on the urinary metabolome, despite being examined under uncontrolled free-living conditions. We further concluded that a combination of several biomarkers of exposure is better than a single biomarker for the predictive ability of discriminative analysis.

Evaluation of roof slope and exposure with different roofing materials in reduced models of animal production facilities in spring and summer

The present study was conducted at the Department of Rural Engineering and the Department of Animal Morphology and Physiology of FCAV/Unesp, Jaboticabal, SP, Brazil. The objective was to verify the influence of roof slope, exposure and roofing material on the internal temperature of reduced models of animal production facilities. For the development of the research, 48 reduced and dissemble models with dimensions 1.00 × 1.00 × 0.50 m were used. The roof was shed-type, and the models faced to the North or South directions, with 24 models for each side of exposure. Ceramic, galvanized-steel and fibro tiles were used to build the roofs. Slopes varied between 20, 30, 40 and 50% for the ceramic tile and 10, 30, 40 and 50% for the other two. Inside the models, temperature readings were performed at every hour, for 12 months. The results were evaluated in a general linear model in a nested 3 × 4 × 2 factorial arrangement, in which the effects of roofing material and exposure were nested on the factor Slope. Means were compared by the Tukey test at 5% of probability. After analyzing the data, we observed that with the increase in the slope and exposure to the South, there was a drop in the internal temperature within the model at the geographic coordinates of Jaboticabal city (SP/Brazil).

Work-related crisis exposure : psychological trauma and PTSD in news journalists

I avhandlingen undersöktes hur journalister själva reagerar efter att ha arbetat med en plötslig krissituation, samt vilka faktorer som kan bidra till en förhöjd risk för allvarliga långsiktiga stressymptom. Temat undersöktes (1) genom att se på hur journalisters tidigare erfarenheter av krisuppdrag och traumatiska upplevelser i privatlivet var relaterade till stressymptom (posttraumatiskt stressyndrom, sekundär traumatisk stress, depression och utmattningssyndrom), och (2) genom att studera riskfaktorer i en identifierad typ av kris, de finländska skolskjutningarna 2007-08. Avhandlingens resultat baserades på enkätsvar från finländska nyhetsjournalister (N = 503) och intervjuer med personer som jobbat på plats vid skolskjutningar (N = 28). En klar majoritet av journalisterna hade inte allvarliga långsiktiga stressymptom vid tiden för undersökningen. De som varit på ett tidigare krisuppdrag där man bevittnat många obehagliga detaljer hade fler allvarliga stressymptom. En annan riskfaktor var att ha ett förflutet med fler traumatiska händelser i privatlivet. Bland de som arbetat med skolskjutningar var starka kortsiktiga reaktioner, t.ex. hjälplöshet och chock, relativt vanliga. Reaktionerna hörde ändå oftast till den normala återhämtningsprocessen, och ledde inte till en långsiktig försämring av måendet. Journalister som i hög grad identifierade sig med krisen, t.ex. personer med egna barn, hade större risk för att drabbas av allvarliga symptom på lång sikt. Detsamma gällde de som på plats upplevt journalistiska etiska dilemman, t.ex. att beordras av överordnade till uppdrag som gick emot egna principer. För att förebygga psykisk stress bland journalister är det viktigt att inom branschen sprida kunskap om stressreaktioner och utveckla rekommendationer för etisk krisjournalistik. Därmed kan journalister få bättre verktyg för att minimera risken att via sitt yrkesutövande orsaka ytterligare skada åt krisdrabbade.

Identification and application of bile metabolites to assess the exposure of fish to pharmaceuticals in the environment

Thousands of tons of pharmaceuticals are consumed yearly worldwide. Due to the continuous and increasing consumption and their incomplete elimination in wastewater treatment plants (WWTP), pharmaceuticals and their metabolites can be detected in receiving waters, although at low concentrations (ng to low μg/L). As bioactive molecules the presence of pharmaceuticals in the aquatic environment must be considered potentially hazardous for the aquatic organisms. In this thesis, the biotransformation and excretion of pharmaceuticals in fish was studied. The main biotransformation pathways of three anti‐inflammatory drugs, diclofenac, naproxen and ibuprofen, in rainbow trout were glucuronidation and taurine conjugation of the parent compounds and their phase I metabolites. The same metabolites were present in fish bile in aquatic exposures as in fish dosed with intraperitoneal injection. Higher bioconcentration factor in bile (BCFbile) was found for ibuprofen when compared to diclofenac and naproxen. Laboratory exposure studies were followed by a study of uptake of pharmaceuticals in a wild fish population living in lake contaminated with WWTP effluents. Of the analyzed 17 pharmaceuticals and six phase I metabolites, only diclofenac, naproxen and ibuprofen was present in bream and roach bile. It was shown, that diclofenac, naproxen and ibuprofen excreted by the liver can be found in rainbow trout and in two native fish species living in the receiving waters. In the bream and roach bile, the concentrations of diclofenac, naproxen and ibuprofen were roughly 1000 times higher than those found in the lake water, while in the laboratory exposures, the bioconcentration of the compounds and their metabolites in rainbow trout bile were at the same level as in wild fish or an order of magnitude higher. Thus, the parent compounds and their metabolites in fish bile can be used as a reliable biomarker to monitor the exposure of fish to environmental pharmaceuticals present in water receiving discharges from WWTPs.