Toxicokinetic modeling of folpet fungicide and its ring-biomarkers of exposure in humans.

A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg(-1) and dermally 10 mg kg(-1) of folpet. In the case of oral administration, the mean elimination half-life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half-life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0-96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h(-1) while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data.

Allergic rhinitis in patients with asthma: the Swiss LARA (Link Allergic Rhinitis in Asthma) survey.

OBJECTIVE: To determine the characteristics of asthma (A) and allergic rhinitis (AR) among asthma patients in primary care practice. RESEARCH DESIGN AND METHODS: Primary care physicians, pulmonologists, and allergologists were asked to recruit consecutive asthma patients with or without allergic rhinitis from their daily practice. Cross-sectional data on symptoms, severity, treatment and impact on quality of life of A and AR were recorded and examined using descriptive statistics. Patients with and without AR were then compared. RESULTS: 1244 asthma patients were included by 211 physicians. Asthma was controlled in 19%, partially controlled in 27% and not controlled in 54%. Asthma treatment was generally based on inhaled corticosteroids (ICS) with or without long acting beta 2 agonists (78%). A leukotriene receptor antagonist (LTRA) was used by 46% of the patients. Overall, 950 (76%) asthma patients had AR (A + AR) and 294 (24%) did not (A - AR). Compared to patients with A - AR, A + AR patients were generally younger (mean age +/- standard deviation: 42 +/- 16 vs. 50 +/- 19 years, p < 0.001) and fewer used ICS (75% vs. 88%, p < 0.001). LTRA usage was similar in both groups (46% vs. 48%). Asthma was uncontrolled in 53% of A + AR and 57% of A - AR patients. Allergic rhinitis was treated with a mean of 1.9 specific AR medications: antihistamines (77%), nasal steroids (66%) and/or vasoconstrictors (38%), and/or LTRA (42%). Rhinorrhoea, nasal obstruction, or nasal itching were the most frequently reported AR symptoms and the greatest reported degree of impairment was in daily activities/sports (55%). CONCLUSIONS: Allergic rhinitis was more common among younger asthma patients, increased the burden of symptoms and the need for additional medication but was associated with improved asthma control. However, most asthma patients remained suboptimally controlled regardl-ess of concomitant AR.

Transcutaneous carbon dioxide pressure for monitoring patients with severe croup.

In a prospective investigation of 17 children with severe croup, we analyzed the effect of epinephrine inhalations and mild sedation with chloral hydrate on transcutaneous carbon dioxide pressure (tcPCO2), pulse oximetry measurements, and croup scores. There was a highly significant reduction (p less than 0.001) in the tcPCO2 values and croup scores after inhalation of epinephrine. The changes in the tcPCO2 values correlated with the clinical findings. Mild sedation also significantly improved the croup scores but failed to influence the tcPCO2 values. There was not statistically significant difference in pulse oximetry saturation, fraction of administered oxygen, heart rate, or respiratory rate before and after inhalation of epinephrine or chloral hydrate administration. Monitoring tcPCO2 appears to be a reliable and objective tool for managing patients with upper airway obstruction, whereas croup scores may be misleading.

Prevention and management of potential adverse events during transapical aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Transapical transcatheter aortic valve replacement (TAVR) is a new minimally invasive technique with a known risk of unexpected intra-procedural complications. Nevertheless, the clinical results are good and the limited amount of procedural adverse events confirms the usefulness of a synergistic surgical/anesthesiological management in case of unexpected emergencies. METHODS: A review was made of the authors' four-year database and other available literature to identify major and minor intra-procedural complications occurring during transapical TAVR procedures. All implants were performed under general anesthesia with a balloon-expandable Edwards Sapien stent-valve, and followed international guidelines on indications and techniques. RESULTS: Procedural success rates ranged between 94% and 100%. Life-threatening apical bleeding occurred very rarely (0-5%), and its incidence decreased after the first series of implants. Stent-valve embolization was also rare, with a global incidence ranging from 0-2%, with evidence of improvement after the learning curve. Rates of valve malpositioning ranged from 0% to < 3%, whereas the risk of coronary obstruction ranged from 0% to 3.5%. Aortic root rupture and dissection were dramatic events reported in 0-2% of transapical cases. Stent-valve malfunction was rarely reported (1-2%), whereas the valve-in-valve bailout procedure for malpositioning, malfunctioning or severe paravalvular leak was reported in about 1.0-3.5% of cases. Sudden hemodynamic management and bailout procedures such as valve-in-valve rescue or cannulation for cardiopulmonary bypass were more effective when planned during the preoperative phase. CONCLUSION: Despite attempts to avoid pitfalls, complications during transapical aortic valve procedures still occur. Preoperative strategic planning, including hemodynamic status management, alternative cannulation sites and bailout procedures, are highly recommended, particularly during the learning curve of this technique.

Holter implantable: reveal [The implantable loop recorder]

The implantable loop recorder developed by Medtronic (Reveal plus) is a small device inserted subcutaneously under local anesthesia in patients with syncope of unexplained origin. This device enables a single lead-ECG recording and has autonomy of two years. Memories are activated during episodes of bradycardia or tachycardia, either automatically or manually. Several studies have shown a high diagnostic rate reaching 50% and demonstrated its cost-effectiveness. There is also a significant reduction in syncopal episodes and a higher quality of life score in patients with syncope of unexplained origin.

Eugenol as an anesthetic for juvenile common snook

The objective of this work was to evaluate the efficacy of eugenol as an anesthetic for juvenile common snook, and to determine the minimum effective concentration for use in handling procedures. In the first trial, juvenile common snook were subjected to immersion baths at 25, 50, 75, 100, 125, and 150 mg L-1 eugenol concentrations, after which induction and recovery times were evaluated. In the second experiment, the lethal exposure time (LT50) at 75 mg L-1 was estimated. Minimum effective eugenol concentration was 50 mg L-1, andthe stage of deep anesthesia and recovery were, respectively, reached at 126.3 and 208.8 s. At 75 mg L-1, LT50 was 1,314 s, and induction time and recovery were also satisfactory; however, fish cannot tolerate over 229 s exposure.

Termination of pregnancy among teenagers - why more surgical terminations?

Introduction: In 2012, a study by K. Chatziioannidou and S-C. Renteria showed that teenagers chose to undergo a surgical termination of pregnancy (TOP) more often than a medical TOP (mifepristone followed by misoprostol) when they decided to terminate a pregnancy. It also showed that the teenagers' choice for a medical versus surgical method is inversely proportional to the adults' choice although the efficiency of the medical method showed even better results for teenagers than for adults. According to the hypothesis made, the reasons for this choice might be influenced by the following facts: (i) the belated call to make an appointment, the medical procedure not being available after 9 weeks of gestation; (ii) the imperative request for confidentiality; (iii) the beliefs and subjective appreciation of the medical staff. Objectives: The aim of this retrospective and qualitative study is to analyse the reasons why, in case of a TOP, teenagers chose the surgical method more often than their adult counterparts. Material: (i) All teenagers who were admitted for an abortive procedure during 2011 in the in- or outpatient ward. (ii) The professional team (midwives and sexual and reproductive counsellors) in charge in the case of a TOP request. Methods: The information about the patient's history and the biopsycho- social data was retrieved from the patient files filled out by midwives and sexual and reproductive health counsellors during the first appointment for a TOP request or during its process. The professionals' appreciation was evaluated by means of a semi-structured questionnaire. Results: Concerning the choice of the method for a pregnancy termination, the results of our research show that: (i) Out of 47 teenagers, 27 chose the surgical method and 17 the medical method. (ii) Three had a second trimester abortion (which includes use of the medical method). (iii) Fifteen teenagers out of the 27 who chose a surgical method consulted between the 9th and 14th weeks of amenorrhoea and therefore did not have any other choice. The reasons for their 'late arrival' will be explained in detail. The 12 teenagers who arrived before the 8th week of amenorrhoea and chose to undertake abortion by suction & curettage under general anaesthesia did it for the following reasons: (i) Four were afraid of bleeding and pain. (ii) Five thought that the organisation of the surgical procedure was easier. (iii) Two did not trust the abortion pill. (iv) One was taken to her mother's gynaecologist where she had a D&C. Confidentiality was requested nine times out of 27 when choosing the surgical method, and six times out of 17 when choosing the medical method. Therefore, although confidentiality concerns a third of the teenagers' pregnancy termination requests, it does not seem to be a significant element for the choice of the method. As for the subjective appreciation of the professionals, the first results of the discussions seem to show that teenagers were reluctant or resistant towards the medical method. Conclusion: This study shows that the reasons why teenagers still prefer the use of the surgical over the medical method compared to adults, seem to include the late request for an appointment, fear of pain and bleeding and organisational issues. Confidentiality does not seem to greatly influence the teenagers' choice. Nonetheless, medical professionals seem to favour the suction curettage procedure performed under anesthesia because they associate young age with vulnerability and psychological frailty and consequently diminished ability to cope with pain and emotional distress during the medical procedures.

Evaluation des risques liés aux nanomatériaux pour la population générale et pour l'environnement : rapport d'expertise collective

Une expertise collective sur l'évaluation des risques liés aux nanomatériaux pour la population générale et pour l'environnement a identifié plusieurs centaines de produits de grande consommation contenant des nanomatériaux, présents dans notre quotidien : textiles, cosmétiques, alimentaires, équipements sportifs, matériaux de construction... Des études nouvelles suggèrent la possibilité de risques pour la santé et pour l'environnement de certains produits. Face à cette situation d'incertitude, l'Afsset recommande d'agir sans attendre au nom du principe de précaution et de 1) Rendre obligatoire la traçabilité des nanomatériaux. Cela passe par une obligation de déclaration par les industriels, 2) la mise en place un étiquetage clair qui mentionne la présence de nanomatériaux dans les produits et informe sur la possibilité de relargage à l'usage, 3) d'aller jusqu'à l'interdiction de certains usages des nanomatériaux pour lesquels l'utilité est faible par rapport aux dangers potentiels, 4) l'harmonisation des cadres réglementaires français et européens pour généraliser les meilleures pratiques : déclaration, autorisation, substitution. En particulier, une révision de REACh s'impose pour prendre en compte les nanomatériaux manufacturés de manière spécifique et quel que soit leur tonnage. L'expertise fait également des recommandations pour construire une méthode renouvelée d'évaluation des risques sanitaires qui soit adaptée aux spécificités des nanomatériaux. Pour cela l'Afsset a testé les méthodologies classiques d'évaluation des risques sur 4 produits particuliers et courants : la chaussette antibactérienne (nanoparticules d'argent), le ciment autonettoyant et le lait solaire (nanoparticules de dioxyde de titane), la silice alimentaire à l'état nanométrique. Ces 4 produits représentent bien les voies d'exposition de l'homme (cutanée, inhalation, ingestion) et la possibilité de dispersion environnementale. Ces travaux font apparaître une urgence à faire progresser les connaissances sur les expositions et les dangers potentiels des nanomatériaux. Aujourd'hui, seuls 2% des études publiées sur les nanomatériaux concernent leurs risques pour la santé et l'environnement. Le premier effort devra porter sur la normalisation des caractéristiques des nanomatériaux. Les priorités de la recherche devront cibler la toxicologie, l'écotoxicologie et la mesure des expositions. Enfin, l'Afsset prévoit de s'autosaisir pour définir en 2 ans, avec son groupe de travail, un outil simplifié d'évaluation des risques. Il s'agit d'une grille de cotation des risques qui permet de catégoriser les produits en plusieurs gammes de risques. Face à ce chantier considérable, une mise en réseau entre les organismes européens et internationaux pour se partager le travail est nécessaire. Elle a commencé autour de l'OCDE qui coordonne des travaux d'évaluation des risques et de l'ISO qui travaille à la mise en place de nouvelles normes. [Auteurs]

Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β.

Nanoparticles are increasingly used in various fields, including biomedicine and electronics. One application utilizes the opacifying effect of nano-TiO(2), which is frequently used as pigment in cosmetics. Although TiO(2) is believed to be biologically inert, an emerging literature reports increased incidence of respiratory diseases in people exposed to TiO(2). Here, we show that nano-TiO(2) and nano-SiO(2), but not nano-ZnO, activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome, leading to IL-1β release and in addition, induce the regulated release of IL-1α. Unlike other particulate Nlrp3 agonists, nano-TiO(2)-dependent-Nlrp3 activity does not require cytoskeleton-dependent phagocytosis and induces IL-1α/β secretion in nonphagocytic keratinocytes. Inhalation of nano-TiO(2) provokes lung inflammation which is strongly suppressed in IL-1R- and IL-1α-deficient mice. Thus, the inflammation caused by nano-TiO(2) in vivo is largely caused by the biological effect of IL-1α. The current use of nano-TiO(2) may present a health hazard due to its capacity to induce IL-1R signaling, a situation reminiscent of inflammation provoked by asbestos exposure.

Effects of particulate matters on inflammatory markers in the general adult population

Summary: Particulate air pollution is associated with increased cardiovascular risk. The induction of systemic inflammation following particle inhalation represents a plausible mechanistic pathway. The purpose of this study was to assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers in 6183 adults in Lausanne, Switzerland. The results show that short-term exposure to PM10 was associated with higher levels of circulating IL-6 and TNF-α. The positive association of PM10 with markers of systemic inflammation materializes the link between air pollution and cardiovascular risk. Background: Variations in short-term exposure to particulate matters (PM) have been repeatedly associated with daily all-cause mortality. Particle-induced inflammation has been postulated to be one of the important mechanisms for increased cardiovascular risk. Experimental in-vitro, in-vivo and controlled human studies suggest that interleukin 6 (IL-6) and tumor-necrosis-factor alpha (TNF-α) could represent key mediators of the inflammatory response to PM. The associations of short-term exposure to ambient PM with circulating inflammatory markers have been inconsistent in studies including specific subgroups so far. The epidemiological evidence linking short-term exposure to ambient PM and systemic inflammation in the general population is scarce. So far, large-scale population-based studies have not explored important inflammatory markers such as IL-6, IL-1β or TNF-α. We therefore analyzed the associations between short-term exposure to ambient PM10 and circulating levels of high-sensitive CRP (hs-CRP), IL-6, IL-1β and TNF-α in the population-based CoLaus study. Objectives: To assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers, including hs-CRP, IL-6, IL-1β and TNF-α, in adults aged 35 to 75 years from the general population. Methodology: All study subjects were participants to the CoLaus study (www.colaus.ch) and the baseline examination was carried out from 2003 to 2006. Overall, 6184 participants were included. For the present analysis, 6183 participants had data on at least one of the four measured circulating inflammatory markers. The monitoring data was obtained from the website of Swiss National Air Pollution Monitoring Network (NABEL). We analyzed data on PM10 as well as outside air temperature, pressure and humidity. Hourly concentrations of PM10 were collected from 1 January 2003 to 31 December 2006. Robust linear regression (PROC ROBUSTREG) was used to evaluate the relationship between cytokine inflammatory and PM10. We adjusted all analyses for age, sex, body mass index, smoking status, alcohol consumption, diabetes status, hypertension status, education levels, zip code, and statin intake. All data were adjusted for the effects of weather by including temperature, barometric pressure, and season as covariates in the adjusted models. We performed simple and multiple logistic regression analyses. Descriptive statistical analysis used the Wilcoxon rank sum test (for medians). All data analyses were performed using SAS software (version 9.2; SAS Institute Inc., Cary, NC, USA), and a two-sided significance level of 5% was used. Results: PM10 levels averaged over 24 hours were significantly and positively associated with continuous IL-6 and TNF-α levels, in the whole study population both in unadjusted and adjusted analyses. For each cytokine, there was a similar seasonal pattern, with wider confidence intervals in summer than during the other seasons, which might partly be due to the smaller number of participants examined in summer. The associations of PM10 with IL-6 and TNF-α were also found after having dichotomized these cytokines into high versus low levels, which suggests that the associations of PM10 with the continuous cytokine levels are very robust to any distributional assumption and to potential outlier values. In contrast with what we observed for continuous IL-1β levels, high PM10 levels were significantly associated with high IL-1β. PM10 was significantly associated with IL-6 and TNF-α in men, but with TNF-α only in women. However, there was no significant statistical interaction between PM10 and sex. For IL-6 and TNF-α, the associations tended to be stronger in younger people, with a significant interaction between PM10 and age groups for IL-6. PM10 was significantly associated with IL-6 and TNF-α in the healthy group and also in the "non-healthy" group, although the statistical interaction between healthy status and PM10 was not significant. Conclusion: In summary, we found significant independent positive associations of short-term exposure to PM10 with circulating levels of IL-6 and TNF-α in the adult population of Lausanne. Our findings strongly support the idea that short-term exposure to PM10 is sufficient to induce systemic inflammation on a broad scale in the general population. From a public health perspective, the reported association of elevated inflammatory cytokines with short-term exposure to PM10 in a city with relatively clean air such as Lausanne supports the importance of limiting urban air pollution levels.

Early, low-level auditory-somatosensory multisensory interactions impact reaction time speed.

Several lines of research have documented early-latency non-linear response interactions between audition and touch in humans and non-human primates. That these effects have been obtained under anesthesia, passive stimulation, as well as speeded reaction time tasks would suggest that some multisensory effects are not directly influencing behavioral outcome. We investigated whether the initial non-linear neural response interactions have a direct bearing on the speed of reaction times. Electrical neuroimaging analyses were applied to event-related potentials in response to auditory, somatosensory, or simultaneous auditory-somatosensory multisensory stimulation that were in turn averaged according to trials leading to fast and slow reaction times (using a median split of individual subject data for each experimental condition). Responses to multisensory stimulus pairs were contrasted with each unisensory response as well as summed responses from the constituent unisensory conditions. Behavioral analyses indicated that neural response interactions were only implicated in the case of trials producing fast reaction times, as evidenced by facilitation in excess of probability summation. In agreement, supra-additive non-linear neural response interactions between multisensory and the sum of the constituent unisensory stimuli were evident over the 40-84 ms post-stimulus period only when reaction times were fast, whereas subsequent effects (86-128 ms) were observed independently of reaction time speed. Distributed source estimations further revealed that these earlier effects followed from supra-additive modulation of activity within posterior superior temporal cortices. These results indicate the behavioral relevance of early multisensory phenomena.