Tolerance of whitefish embryos to Pseudomonas fluorescens linked to genetic and maternal effects, and reduced by previous exposure.

Juvenile or adult fish can alter their behaviour and rely on an innate and adaptive immune system to avoid/counteract pathogens, while fish embryos have to depend on egg characteristics and may be partly protected by their developing immune system that is building up from a certain age on. We developed an infection protocol that allows testing the reaction of individual whitefish embryos (Coregonus palaea) to repeated exposures to Pseudomonas fluorescens, an opportunistic bacterial fish pathogen. We used a full-factorial in vitro breeding design to separately test the effects of paternal and maternal contributions to the embryos' susceptibility to different kinds of pathogen exposure. We found that a first non-lethal exposure had immunosuppressive effects: pre-exposed embryos were more susceptible to future challenges with the same pathogen. At intermediate and high levels of pathogen intensity, maternal effects turned out to be crucial for the embryos' tolerance to infection. Paternal (i.e. genetic) effects played a significant role at the strongest level of infection, i.e. the embryos' own genetics already explained some of the variation in embryo susceptibility. Our findings suggest that whitefish embryos are largely protected by maternally transmitted substances, but build up some own innate immunocompetence several days before hatching.

Topical retinoids exposure during pregnancy.

Concerns have been raised with the topical use of retinoids since the publication of occasional cases associated with characteristic retinoid embryopathy, originally described after oral use. Epidemiological data are still scant. A collaborative study was carried out to evaluate the rate of congenital malformations following 1st trimester topical retinoid exposure. Using a standardized protocol exposed pregnancies and non exposed controls were prospectively recorded by the European Network of Teratology Information Services (ENTIS). A population of 222 pregnant women exposed to topical retinoids (median age [range]: 30 [21 - 42] years; gestational week at call: 7 [3 - 35]) were compared to 444 women not exposed (median age [range]: 32 [17 - 48] years; gestational week at call: 8 [2 - 39]). The following retinoids were identified: adapalene: 22; retinoic acid: 10; tretinoin: 135; isotretinoin:49, others: 6. The exposed and non-exposed groups did not differ in maternal alcohol and tobacco use, gestational duration, birth weight and length. There were no Abstracts: Clinical Pharmacology and Therapeutics IXth World Congress -2008 significant differences between groups in the rate of pregnancies ending in spontaneous abortion (8.7% in exposed vs. 5.9% in unexposed; P=0.18) or in infants with minor malformations (3.7% in exposed vs. 2.9% in unexposed; P=0.61) and major malformations (3.7% in exposed vs. 2.2% in unexposed; P=0.29). No child showed features of retinoid embryopathy. In conclusion, these results bring reassurance in cases of fortuitous topical retinoid exposure. However, according to the current knowledge, topical retinoids can not be recommended for use during pregnancy, as the risk/benefit ratio remains questionable.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.

OBJECTIVE: This contribution addresses the risk associated with exposure to statins during pregnancy. DESIGN: Multicentre observational prospective controlled study. SETTING: European Network of Teratology Information Services. POPULATION: Pregnant women who contacted one of 11 participating centres, seeking advice about exposure to statins during pregnancy, or to agents known to be nonteratogenic. METHODS: Pregnancies exposed during first trimester to statins were followed up prospectively, and their outcomes were compared with a matched control group. MAIN OUTCOME MEASURES: Rates of major birth defects, live births, miscarriages, elective terminations, preterm deliveries and gestational age and birthweight at delivery. RESULTS: We collected observations from 249 exposed pregnancies and 249 controls. The difference in the rate of major birth defects between the statin-exposed and the control groups was small and statistically nonsignificant (4.1% versus 2.7% odds ratio [OR] 1.5; 95% confidence interval [95% CI] 0.5-4.5, P = 0.43). In an adjusted Cox model, the difference between miscarriage rates was also small and not significant (hazard ratio 1.36, 95% CI 0.63-2.93, P = 0.43). Premature birth was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.019). Nonetheless, median gestational age at birth (39 weeks, interquartile range [IQR] 37-40 versus 39 weeks, IQR 38-40, P = 0.27) and birth weight (3280 g, IQR 2835-3590 versus 3250 g, IQR 2880-3630, P = 0.95) did not differ between exposed and non-exposed pregnancies. CONCLUSIONS: This study did not detect a teratogenic effect of statins. Its statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy.

Exposition de l'enfant a des violences domestiques. Un modèle pluridisciplinaire de détection, d'evaluation et de prise en charge [Children's exposure to domestic violence. A multidisciplinary model of detection, assessment and management].

Children psychological abuse is difficult to identify. However, its consequences on child development can be as serious as physical and sexual abuses. It is therefore essential, to implement in our hospitals, structures whose missions are successively to detect victims, evaluate them on somatic and psychological levels, and elaborate a therapy. We propose a model for the achievement of these objectives through collaboration between the Medical Unit of Violence, the Pediatric CAN Team and the Unit of Les Boréales.

Cyclododecane exposure in the field of conservation and restoration of art objects

PURPOSE: Recent work practices in the conservation and restoration involve the use of cyclododecane (CDD, CAS 294-62-2) to protect fragile artifacts during their handling or transportation. Little is known about its toxicity, and no previous exposure has been reported. A short field investigation was conducted to characterize the exposure conditions to both CDD vapors and aerosols.METHODS: Measurements were conducted in the laboratory of conservation and restoration of the archeological service in Bern (Switzerland). Three indoor and four outdoor typical work situations, either during brush or spray gun applications, were investigated. Measurements were performed on charcoal adsorbent tube and analyzed by a gas chromatograph equipped with a flame ionization detector.RESULTS: Measurements have been conducted during both brush and spray gun applications. Indoor exposures were of 0.75-15.5 mg/m(3), while outdoors exposures were 19.5-53.9 mg/m(3). Exposures appear to be extremely localized due to both physicochemical properties and application methods of the CDD. Vapor exposure increases dramatically with the confinement of the workplace.CONCLUSION: Preventive measures should be undertaken to limit as much as possible these exposures. Field work in confined areas (ditches, underground) is of particular concern. CDD-coated artifacts or materials should be stored in ventilated areas to avoid delayed exposures. [Authors]

A community survey of sun exposure, sunburn and sun protection.

AIM: To describe outdoor activities, sun protection behaviours and the experience of sunburn in a sample of New Zealanders during summer weekends of 1994. METHODS: 1243 respondents to a telephone survey provided information regarding their outdoor activities for the 5 hour period around midday of the previous Saturday and Sunday. The sample was drawn from those aged 15 to 65 years in the five centres of Auckland, Hamilton, Wellington, Christchurch and Dunedin. Respondents provided information on sun exposure, sunburn, sun protection and beliefs about tanning, as well as background demographic information, skin type and previous experience of sunburn. RESULTS: 12% of the sample (or 17% of all those outdoors) reported being sunburned on the preceding weekend, and those sunburned tended to be men, and to be under age 35 years. The face, neck and limbs were the areas most frequently reported as burned. Sporting activities and beach or water activities were associated with the highest number of episodes of burning. Overall 38% of those outside reported wearing a hat and 32% reported the use of a sunscreen. Positive attitudes to tanning were quite common and probably present the main target for change in the community. CONCLUSION: On any sunny weekend in summer about three-quarters of adult New Zealanders will be out in the sun for relatively long periods of time, and many will get sunburned. The reduction of such harmful sun exposures remains an important public health goal.

Extremity exposure in nuclear medicine: preliminary results of a European study.

The Work Package 4 of the ORAMED project, a collaborative project (2008-11) supported by the European Commission within its seventh Framework Programme, is concerned with the optimisation of the extremity dosimetry of medical staff in nuclear medicine. To evaluate the extremity doses and dose distributions across the hands of medical staff working in nuclear medicine departments, an extensive measurement programme has been started in 32 nuclear medicine departments in Europe. This was done using a standard protocol recording all relevant information for radiation exposure, i.e. radiation protection devices and tools. This study shows the preliminary results obtained for this measurement campaign. For diagnostic purposes, the two most-used radionuclides were considered: (99m)Tc and (18)F. For therapeutic treatments, Zevalin(®) and DOTATOC (both labelled with (90)Y) were chosen. Large variations of doses were observed across the hands depending on different parameters. Furthermore, this study highlights the importance of the positioning of the extremity dosemeter for a correct estimate of the maximum skin doses.

Exposure of highway maintenance workers to fine particulate matter and noise

In this study, we assessed the mixed exposure of highway maintenance workers to airborne particles, noise, and gaseous co-pollutants. The aim was to provide a better understanding of the workers' exposure to facilitate the evaluation of short-term effects on cardiovascular health endpoints. To quantify the workers' exposure, we monitored 18 subjects during 50 non-consecutive work shifts. Exposure assessment was based on personal and work site measurements and included fine particulate matter (PM2.5), particle number concentration (PNC), noise (Leq), and the gaseous co-pollutants: carbon monoxide, nitrogen dioxide, and ozone. Mean work shift PM2.5 concentrations (gravimetric measurements) ranged from 20.3 to 321 μg m(-3) (mean 62 μg m(-3)) and PNC were between 1.6×10(4) and 4.1×10(5) particles cm(-3) (8.9×10(4) particles cm(-3)). Noise levels were generally high with Leq over work shifts from 73.3 to 96.0 dB(A); the averaged Leq over all work shifts was 87.2 dB(A). The highest exposure to fine and ultrafine particles was measured during grass mowing and lumbering when motorized brush cutters and chain saws were used. Highest noise levels, caused by pneumatic hammers, were measured during paving and guardrail repair. We found moderate Spearman correlations between PNC and PM2.5 (r = 0.56); PNC, PM2.5, and CO (r = 0.60 and r = 0.50) as well as PNC and noise (r = 0.50). Variability and correlation of parameters were influenced by work activities that included equipment causing combined air pollutant and noise emissions (e.g. brush cutters and chain saws). We conclude that highway maintenance workers are frequently exposed to elevated airborne particle and noise levels compared with the average population. This elevated exposure is a consequence of the permanent proximity to highway traffic with additional peak exposures caused by emissions of the work-related equipment.

Pharmacogenetic Study on Risperidone Long-Acting Injection: Influence of Cytochrome P450 2D6 and Pregnane X Receptor on Risperidone Exposure and Drug-Induced Side-Effects.

Risperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.

Evaluation of occupational exposure: comparison of biological and environmental variabilities using physiologically based toxicokinetic modeling

PURPOSE: Few studies compare the variabilities that characterize environmental (EM) and biological monitoring (BM) data. Indeed, comparing their respective variabilities can help to identify the best strategy for evaluating occupational exposure. The objective of this study is to quantify the biological variability associated with 18 bio-indicators currently used in work environments. METHOD: Intra-individual (BV(intra)), inter-individual (BV(inter)), and total biological variability (BV(total)) were quantified using validated physiologically based toxicokinetic (PBTK) models coupled with Monte Carlo simulations. Two environmental exposure profiles with different levels of variability were considered (GSD of 1.5 and 2.0). RESULTS: PBTK models coupled with Monte Carlo simulations were successfully used to predict the biological variability of biological exposure indicators. The predicted values follow a lognormal distribution, characterized by GSD ranging from 1.1 to 2.3. Our results show that there is a link between biological variability and the half-life of bio-indicators, since BV(intra) and BV(total) both decrease as the biological indicator half-lives increase. BV(intra) is always lower than the variability in the air concentrations. On an individual basis, this means that the variability associated with the measurement of biological indicators is always lower than the variability characterizing airborne levels of contaminants. For a group of workers, BM is less variable than EM for bio-indicators with half-lives longer than 10-15 h. CONCLUSION: The variability data obtained in the present study can be useful in the development of BM strategies for exposure assessment and can be used to calculate the number of samples required for guiding industrial hygienists or medical doctors in decision-making.