Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Repeated exposure to Lutzomyia intermedia sand fly saliva induces local expression of interferon-inducible genes both at the site of injection in mice and in human blood.

During a blood meal, Lutzomyia intermedia sand flies transmit Leishmania braziliensis, a parasite causing tegumentary leishmaniasis. In experimental leishmaniasis, pre-exposure to saliva of most blood-feeding sand flies results in parasite establishment in absence of any skin damages in mice challenged with dermotropic Leishmania species together with saliva. In contrast, pre-immunization with Lu. intermedia salivary gland sonicate (SGS) results in enhanced skin inflammatory exacerbation upon co-inoculation of Lu. intermedia SGS and L. braziliensis. These data highlight potential unique features of both L. braziliensis and Lu. intermedia. In this study, we investigated the genes modulated by Lu. intermedia SGS immunization to understand their potential impact on the subsequent cutaneous immune response following inoculation of both SGS and L. braziliensis. The cellular recruitment and global gene expression profile was analyzed in mice repeatedly inoculated or not with Lu. intermedia. Microarray gene analysis revealed the upregulation of a distinct set of IFN-inducible genes, an immune signature not seen to the same extent in control animals. Of note this INF-inducible gene set was not induced in SGS pre-immunized mice subsequently co-inoculated with SGS and L. braziliensis. These data suggest the parasite prevented the upregulation of this Lu. intermedia saliva-related immune signature. The presence of these IFN-inducible genes was further analyzed in peripheral blood mononuclear cells (PBMCs) sampled from uninfected human individuals living in a L. braziliensis-endemic region of Brazil thus regularly exposed to Lu. intermedia bites. PBMCs were cultured in presence or absence of Lu. intermedia SGS. Using qRT-PCR we established that the IFN-inducible genes induced in the skin of SGS pre-immunized mice, were also upregulated by SGS in PBMCs from human individuals regularly exposed to Lu. intermedia bites, but not in PBMCs of control subjects. These data demonstrate that repeated exposure to Lu. intermedia SGS induces the expression of potentially host-protective IFN-inducible genes.

Molecular epidemiology of pseudomonas aeruginosae in intensive care units (ICUs) over a 10-year period (1998-2007)

Pseudomonas aeruginosa, une bactérie environnementale ubiquitaire, est un des pathogènes nosocomiaux les plus fréquents aux soins intensifs. La source de ce microorganisme peut être soit endogène, 2,6 à 24 % des patients hospitalisés étant colonisés au niveau digestif, soit exogène. La proportion des cas d'infections à P. aeruginosa d'origine exogène, donc secondaires à une transmission par manuportage ou par l'eau du réseau utilisée pour la toilette ou d'autres soins, reste débattue. Or une meilleure évaluation du taux d'infections exogènes est importante pour la mise en place de mesures de contrôle appropriées. Le but de cette étude était de déterminer sur une période de 10 ans les rôles respectifs des sources exogènes (robinets, autres patients) et endogène dans la colonisation et/ou l'infection par P.aeruginosa chez les patients des Soins Intensifs, ainsi que de documenter les variations épidémiologiques au cours du temps. L'étude a été menée dans les unités de Soins Intensifs du Centre Hospitalier Universitaire Vaudois (CHUV). Les patients colonisés et/ou infectés par P. aeruginosa entre 1998 et 2007ont été identifiés via la base de données du laboratoire de microbiologie. Ils ont été inclus dans l'étude s'ils étaient hospitalisés dans une des unités de Soins Intensifs, Durant cette période, des prélèvements pour recherche de P. aeruginosa ont été effectués sur des robinets des soins intensifs. Un typage moléculaire a été effectué sur toutes les souches cliniques et environnementales isolées en 1998, 2000, 2003, 2004 et 2007. Les patients inclus dans l'étude ont été répartis en quatre catégories (A-D) selon le résultat du typage moléculaire leur souche de P. aeruginosa. La catégorie A inclut les cas pour lesquels le génotype de P. aeruginosa est identique à un des génotypes retrouvé dans l'environnement. La catégorie B comprend les cas pour lesquels le génotype est identique à celui d'au moins un autre patient. La catégorie C comprend les cas avec un génotype unique et la catégorie D comprend les cas pour lesquels la souche était non disponible pour le typage. Les cas des catégories A et B sont considérés comme ayant une origine exogène. Au cours des années de l'étude, le nombre d'admissions aux soins intensifs est resté stable. En moyenne, 86 patients par année ont été identifiés colonisés ou infectés par P. aeruginosa aux Soins Intensifs. Durant la première année d'investigation, un grand nombre de patients colonisés par une souche de P. aeruginosa identique à une de celles retrouvées dans l'environnement a été mis en évidence. Par la suite, possiblement suite à l'augmentation de la température du réseau d'eau chaude, le nombre de cas dans la catégorie A a diminué. Dans la catégorie B, le nombre de cas varie de 1,9 à 20 cas/1000 admissions selon les années. Ce nombre est supérieur à 10 cas/1000 admissions en 1998, 2003 et 2007 et correspond à des situations épidémiques transitoires. Tout au long des 10 ans de l'étude, le nombre de cas dans la catégorie C (source endogène) est demeuré stable et indépendant des variations du nombre de cas dans les catégories A et B. En conclusion, la contribution relative des réservoirs endogène et exogène dans la colonisation et/ou l'infection des patients de soins Intensifs varie au cours du temps. Les facteurs principaux qui contribuent à de telles variations sont probablement le degré de contamination de l'environnement, la compliance des soignants aux mesures de contrôle des infections et la génétique du pathogène lui-même. Etant donné que ce germe est ubiquitaire dans l'environnement aqueux et colonise jusqu'à 15% des patients hospitalisés, la disparition de son réservoir endogène semble difficile. Cependant, cette étude démontre que son contrôle est possible dans l'environnement, notamment dans les robinets en augmentant la température de l'eau. De plus, si une souche multi-résistante est retrouvée de manière répétée dans l'environnement, des efforts doivent être mis en place pour éliminer cette souche. Des efforts doivent être également entrepris afin de limiter la transmission entre les patients, qui est une cause importante et récurrente de contamination exogène. - Pseudomonas aeruginosa is one of the leading nosocomial pathogens in intensive care units (ICUs). The source of this microorganism can be either endogenous or exogenous. The proportion of cases as a result of transmission is still debated, and its elucidation is important for implementing appropriate control measures. To understand the relative importance of exogenous vs. endogenous sources of P. aeru¬ginosa, molecular typing was performed on all available P. aeruginosa isolated from ICU clinical and environmental specimens in 1998, 2000, 2003, 2004 and 2007. Patient samples were classified according to their P. aeruginosa genotypes into three categories: (A) identical to isolate from faucet; (B) identical to at least one other patient sample and not found in faucet; and (C) unique genotype. Cases in cat¬egories A and Β were considered as possibly exogenous, and cases in category C as possibly endogenous. A mean of 34 cases per 1000 admissions per year were found to be colonized or infected by P. aeruginosa. Higher levels of faucet contamination were correlated with a higher number of cases in category A. The number of cases in category Β varied from 1.9 to 20 cases per 1000 admissions. This num¬ber exceeded 10/1000 admissions on three occasions and was correlated with an outbreak on one occasion. The number of cases con¬sidered as endogenous (category C) was stable and independent of the number of cases in categories A and B. The present study shows that repeated molecular typing can help identify variations in the epidemiology of P. aeruginosa in ICU patients and guide infection control measures.

Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans.

BACKGROUND AND PURPOSE: The use of ± 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') is associated with cardiovascular complications and hyperthermia. EXPERIMENTAL APPROACH: We assessed the effects of the α(1) - and β-adrenoceptor antagonist carvedilol on the cardiostimulant, thermogenic and subjective responses to MDMA in 16 healthy subjects. Carvedilol (50 mg) or placebo was administered 1 h before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, four-period crossover design. KEY RESULTS Carvedilol reduced MDMA-induced elevations in blood pressure, heart rate and body temperature. Carvedilol did not affect the subjective effects of MDMA including MDMA-induced good drug effects, drug high, drug liking, stimulation or adverse effects. Carvedilol did not alter the plasma exposure to MDMA. CONCLUSIONS AND IMPLICATIONS: α(1) - and β-Adrenoceptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans but not to its psychotropic effects. Carvedilol could be useful in the treatment of cardiovascular and hyperthermic complications associated with ecstasy use.

Estradiol and progesterone strongly inhibit the innate immune response of mononuclear cells in newborns.

Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-κB pathway but not the mitogen-activated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period.

Interhuman transmission as a potential key parameter for geographical variation in the prevalence of Pneumocystis jirovecii dihydropteroate synthase mutations.

BACKGROUND: Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations are associated with failure of prophylaxis with sulfa drugs. This retrospective study sought to better understand the geographical variation in the prevalence of these mutations. METHODS: DHPS polymorphisms in 394 clinical specimens from immunosuppressed patients who received a diagnosis of P. jirovecii pneumonia and who were hospitalized in 3 European cities were examined using polymerase chain reaction (PCR) single-strand conformation polymorphism. Demographic and clinical characteristics were obtained from patients' medical charts. RESULTS: Of the 394 patients, 79 (20%) were infected with a P. jirovecii strain harboring one or both of the previously reported DHPS mutations. The prevalence of DHPS mutations was significantly higher in Lyon than in Switzerland (33.0% vs 7.5%; P < .001). The proportion of patients with no evidence of sulfa exposure who harbored a mutant P. jirovecii DHPS genotype was significantly higher in Lyon than in Switzerland (29.7% vs 3.0%; P < .001). During the study period in Lyon, in contrast to the Swiss hospitals, measures to prevent dissemination of P. jirovecii from patients with P. jirovecii pneumonia were generally not implemented, and most patients received suboptimal prophylaxis, the failure of which was strictly associated with mutated P. jirovecii. Thus, nosocomial interhuman transmission of mutated strains directly or indirectly from other individuals in whom selection of mutants occurred may explain the high proportion of mutations without sulfa exposure in Lyon. CONCLUSIONS: Interhuman transmission of P. jirovecii, rather than selection pressure by sulfa prophylaxis, may play a predominant role in the geographical variation in the prevalence in the P. jirovecii DHPS mutations.

Dietary supplementation with omega-3 in cystic fibrosis patients

Accumulation of neutr ophils releasing proteolytic enzymes and free radicals induceprogressive lung tissue destruction in CF. Among several hfflammatory mediatorsimplicated in this process, leukotriene B 4 (LTB4) product of arachidonic (AA;20:4n 6) omega 6 polytmsaturated fatty acid (PUFA) plays an important role.Various anti inflammatory strategies including dietary supplementation of omega 3PUFA, known to favor the synthesis of less active leukotriene B 5 (LTBs), have beeninvestigated. To further explore this nutritional approach, biological effects of anomega 3 PUFA oral supplementation (n 3 OS) were measured in 17 CF patients haa prospective, randomized, double blind, crossover study. CF patients (mean age:18 + 9 years, FEVI: 66 + 29 %) received a dietary supplementation enriched, or not,ha omega 3 PUFA during a 2 x 6 months period. A modification in neutrophilmembrane PUFA composition was observed under n 3 OS with an increase in EPA(20:5n 3) PUFA (from 0.66 ± 0.56 to 1.60 ± 0.61 ~tmol %, P< 0.01). The LTB jLTB 5ratio was decreased (from 72 + 27 to 24 + 7, P< 0.C~31), in CF patients taking n 3OS. However, n 3 OS supplementation did neither affect the internalization of bothIL 8 receptors following IL 8 exposure, nor IL 8 induced neutrophil chemotaxis.Our results show that n 3 PUFA are absorbed and incorporated in neutrophilmembrmae. The consecutive decrease ha LTBjLTB 5 ratio suggests that, ha theseconditions, neutr ophils may produce less toxic mediators from the AA pathway. Thepotential clinical benefit for CF patients still needs to be assessed with furtherstudies of longer duration and including more patients.

Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.

In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.

Modulation of the airway allergic response : characterization of the cellular and molecular mechanisms

ABSTRACT Allergic asthma is a major complication of atopy. Its severity correlates with the presence of activated T lymphocytes and eosinophils in the bronchoalveolar lavage fluid (BALF). Mechanisms that protect against asthma are poorly understood. Based on oral models of mucosal tolerance induction, models using the nasal route showed that uptake of important amounts of antigen can induce tolerance and reverse the allergic phenotype. 1L-10 producing regulatory T cells were proposed as key players in tolerance induction, but other players, e.g. dendritic cells (DC), B cells and epithelial cells may have to be taken into consideration. The objective of the present study is to characterize the effects of a therapeutic intranasal treatment (INT) in a murine model of asthma and to determine, in this model, the cellular and molecular mechanisms leading to protection against asthma. First, we established an asthma model by sensitizing the BALB/c mouse to ovalbumin (OVA) by two intraperitoneal injections of alum-adsorbed OVA and three inhalations of aerosolized OVA. Then OVA was applied to the nasal mucosa of OVA- sensitized mice. Mice were later re-exposed to OVA aerosols to assess the protection induced by OVA INT. OVA sensitization induced strong eosinophil recruitment, OVA-specific T cell proliferation and IgE production. Three intranasal treatments at 24-hour intervals with 1.5 mg OVA drastically reduced inflammatory cell recruitment into the BALF and inhibited OVA-specific IgE production upon allergen re-exposure. T cell proliferation in ex vivo bronchial lymph node (BLN) cells was inhibited, as well as TH2 cytokine production. Protection against OVA-induced bronchial inflammation was effective for an extended period of time and treated mice resisted a second re-exposure. Transfer of CD4+ cells from BLN and lungs of OVA-treated mice protected asthmatic recipient mice from subsequent aerosol challenge indicating an involvement of CD4+ T regulatory cells in this protection. RESUME L'asthme allergique est une manifestation clinique majeure de l'atopie. La sévérité de l'asthme est liée à la présence de lymphocytes T activés ainsi que d'éosinophiles dans le lavage broncho-alvéolaire (LBA). Les mécanismes permettant de se prémunir contre l'asthme sont mal connus. Basés sur des modèles muqueux d'induction de tolérance par la voie orale, des modèles utilisant la voie nasale ont montré que d'importantes quantités d'antigène peuvent induire une tolérance et ainsi reverser le phénotype allergique. Des cellules régulatrices produisant de l'IL-10 pourraient jouer un rôle clé dans l'induction de la tolérance mais d'autres acteurs tels que les cellules dendritiques, les cellules B et les cellules épithéliales doivent aussi être prises en compte. L'objectif de la présente étude est de caractériser les effets d'un traitement intranasal thérapeutique dans un modèle murin d'asthme et de déterminer dans ce modèle les mécanismes cellulaires et moléculaires conférant une protection contre l'asthme. En premier lieu, un modèle d'asthme allergique a été établi en sensibilisant des souris BALB/c à l'ovalbumine (OVA) par deux injections intraperitonéales d'OVA adsorbé sur de l'alum et trois séances d'OVA en aérosol. Dans un second temps, de l'OVA a été administrée sur la muqueuse nasale des souris sensibilisées à l'OVA. Les souris furent ensuite challengées par des aérosols d'OVA afin d'évaluer la protection conférée par le traitement intranasal à l'OVA. La sensibilisation à l'OVA a induit un fort recrutement d'éosinophiles, une réponse proliférative des cellules T à l'OVA ainsi qu'une production d'lgE spécifiques. Trois traitements intranasaux à 24 heures d'intervalle avec 1.5 mg d'OVA ont permis de réduire drastiquement le recrutement des cellules inflammatoires dans le LBA ainsi que d'inhiber la production d'lgE spécifiques à l'OVA produits lors d'une ré-exposition à l'OVA. La prolifération en réponse à l'OVA de cellules extraites ex vivo de ganglions bronchiques a, elle aussi, été inhibée de même que la production de cytokines TH2. La protection contre l'inflammation provoquée par l'aérosol est efficace pour une longue période et les souris traitées résistent à une seconde ré- exposition. Le transfert de cellules CD4+ issues de ganglions bronchiques et de poumons de souris traitées à l'OVA protège les souris asthmatiques receveuses contre les effets inflammatoires d'un aérosol, indiquant que des cellules T CD4+ régulatrices pourraient être impliquées dans cette protection. RESUME DESTINE A UN LARGE PUBLIC L'asthme est une affection des voies respiratoires qui se caractérise par une contraction de la musculature des voies aériennes, une production de mucus et d'anticorps de l'allergie (IgE). On parle d'asthme allergique lorsque les facteurs déclenchant l'asthme sont des allergènes inhalés tels que acariens, pollens ou poils d'animaux. Le système immunitaire des patients asthmatiques a un défaut de programmation qui le rend réactif à des substances qui sont normalement inoffensives. Le traitement actuel de l'asthme repose sur le soulagement des symptômes grâce à des produits à base de stéroïdes. Les techniques permettant de reprogrammer le système immunitaire (immunothérapie) ne sont pas efficaces pour tous les antigènes et prennent beaucoup de temps. En conséquence, il est nécessaire de mieux comprendre les mécanismes sous-tendant une telle reprogrammation afin d'en améliorer le rendement et l'efficacité. Dans ce but, des modèles d'immunothérapie ont été mis au point chez la souris. Ils permettent une plus grande liberté d'investigation. Dans cette étude, un modèle d'asthme allergique dans la souris a été établi par une sensibilisation à un antigène particulier : l'ovalbumine (OVA). Ce modèle présente les caractéristiques principales de l'asthme humain : recrutement de cellules inflammatoires dans les poumons, augmentation de la production d'anticorps et de la résistance des bronches aux flux respiratoires. Cette souris asthmatique a ensuite été traitée par application nasale d'OVA. Comparées aux souris non traitées, les souris traitées à l'OVA ont moins de cellules inflammatoires dans leurs poumons et produisent moins d'anticorps IgE. D'autres marqueurs inflammatoires sont aussi fortement diminués. Des cellules de poumons ou de ganglions bronchiques prélevées sur des souris traitées injectées dans des souris asthmatiques améliorent les symptômes de l'asthme. Ces cellules pourraient donc avoir un rôle régulateur dans l'asthme. Les caractériser et les étudier afin d'être capable de les générer est crucial pour les futures thérapies de l'asthme.

Assessment of diesel exhaust particulate exposure and surface characteristics in association with levels of oxidative stress biomarkers

Exposure to PM10 and PM2.5 (particulate matter with aerodynamic diameter smaller than 10 μm and 2.5 μm, respectively) is associated with a range of adverse health effects, including cancer, pulmonary and cardiovascular diseases. Surface characteristics (chemical reactivity, surface area) are considered of prime importance to understand the mechanisms which lead to harmful effects. A hypothetical mechanism to explain these adverse effects is the ability of components (organics, metal ions) adsorbed on these particles to generate Reactive Oxygen Species (ROS), and thereby to cause oxidative stress in biological systems (Donaldson et al., 2003). ROS can attack almost any cellular structure, like DNA or cellular membrane, leading to the formation of a wide variety of degradation products which can be used as a biomarker of oxidative stress. The aim of the present research project is to test whether there is a correlation between the exposure to Diesel Exhaust Particulate (DEP) and the oxidative stress status. For that purpose, a survey has been conducted in real occupational situations where workers were exposed to DEP (bus depots). Different exposure variables have been considered: - particulate number, size distribution and surface area (SMPS); - particulate mass - PM2.5 and PM4 (gravimetry); - elemental and organic carbon (coulometry); - total adsorbed heavy metals - iron, copper, manganese (atomic adsorption); - surface functional groups present on aerosols (Knudsen flow reactor). (Demirdjian et al., 2005). Several biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and several aldehydes) have been determined either in urine or serum of volunteers. Results obtained during the sampling campaign in several bus depots indicated that the occupational exposure to particulates in these places was rather low (40-50 μg/m3 for PM4). Size distributions indicated that particles are within the nanometric range. Surface characteristics of sampled particles varied strongly, depending on the bus depot. They were usually characterized by high carbonyl and low acidic sites content. Among the different biomarkers which have been analyzed within the framework of this study, mean levels of 8- hydroxy-2'-deoxyguanosine and several aldehydes (hexanal, heptanal, octanal, nonanal) increased during two consecutive days of exposure for non-smokers. In order to bring some insight into the relation between the particulate characteristics and the formation of ROS by-products, biomarkers levels will be discussed in relation with exposure variables.

Modelling the effect of minor orthopaedic day surgery on patient mood at the early post-operative period: a prospective population-based cohort study.

OBJECTIVE: The effect of minor orthopaedic day surgery (MiODS) on patient's mood. METHODS: A prospective population-based cohort study of 148 consecutive patients with age above 18 and less than 65, an American Society of Anaesthesiology (ASA) score of 1, and the requirement of general anaesthesia (GA) were included. The Medical Outcomes Study - Short Form 36 (SF-36), Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were used pre- and post-operatively. RESULTS: The mean physical component score of SF-36 before surgery was 45.3 (SD=+/-10.1) and 8 weeks following surgery was 44.9 (SD=+/-11.04) [n=148, p=0.51, 95% CI=(-1.03 to 1.52)]. For the measurement of the changes in mood using BDI, BAI and SF-36, latent construct modelling was employed to increase validity. The covariance between mood pre- and post-operatively (cov=69.44) corresponded to a correlation coefficient, r=0.88 indicating that patients suffering a greater number of mood symptoms before surgery continue to have a greater number of symptoms following surgery. When the latent mood constructs were permitted to have different means the model fitted well with chi(2) (df=1)=0.86 for which p=0.77, thus the null hypothesis that MiODS has no effect on patient mood was rejected. CONCLUSIONS: MiODS affects patient mood which deteriorates at 8 weeks post-operatively regardless of the pre-operative patient mood state. More importantly patients suffering a greater number of mood symptoms before MiODS continue to have a greater number of symptoms following surgery.

Respiratory effects of an exposure to grain dust among grain workers in the Vaud region (Switzerland)

Introduction: Bioaerosols such as grain dust (GD) elicit direct immunological reactions within the human respiratory system. Workplace-dependent exposure to GD may induce asthma, chronic bronchitis, and hypersensitivity pneumonitis. Aims: To assess the clinical impact of occupational exposure to GD and to determine quantitative biological markers of bioaerosol exposure in grain workers. Methods: This longitudinal study has been conducted from summer 2012 to summer 2013, comprising 6 groups of 30 active workers with different GD exposure patterns (4 groups of grain workers, 2 control groups). Two evaluations at high- and low-exposing seasons take place, during which an occupational and a medical history are questionnaire-assessed, lung function is evaluated by spirometry, airway inflammation is measured by exhaled nitric oxide (eNO) and specific blood IgG and IgE are titrated. Results: The preliminary results are those of 2 of the 4 exposed groups, (harvesters and mill workers), compared to the control groups, at first assessment (n=100). Mean age is 38.4 [years]; 98% are male. Exposed groups differ from controls (p<0.05) in daily contact with animals (57% vs. 40%) and active smoking (39% vs. 11%). Grain workers have more respiratory (50%), nasal (57%), ocular (45%) and dermatologic (36%) occupational symptoms than controls (6.4%, 19%, 16%, 6.4% respectively, p<0.05). Lower mean peak-expiratory-flow (PEF) values (96.1 ± 18.9 vs. 108.2 ± 17.4 [% of predicted], p<0.05) and eNO values (13.9 ± 9.6 vs. 20.5 ± 14.7 [ppm], p<0.05) are observed in the exposed groups. Conclusion: Preliminary results show a higher prevalence of clinical symptoms and a lower mean PEF value in the groups exposed to GD.