Health effects of occupational exposure to traffic particles and noise

Exposure to fine particles and noise has been linked to cardiovascular diseases and elevated cardiovascular mortality affecting the worldwide population. Residence and/or work in proximity to emission sources as for example road traffic leads to an elevated exposure and a higher risk for adverse health effects. Highway maintenance workers spend most of their work time in traffic and are exposed regularly to particles and noise. The aims of this thesis were to provide a better understanding of the workers' mixed exposure to particles and noise and to assess cardiopulmonary short term health effects in relation to this exposure. Exposure and health data were collected in collaboration with 8 maintenance centers of the Swiss Road Maintenance Services located in the cantons Bern, Fribourg and Vaud in western Switzerland. Repeated measurements with 18 subjects were conducted during 50 non-consecutive work shifts between Mai 2010 and February 2012, equally distributed over all seasons. In the first part of this thesis we tested and validated measurements of ultrafine particles with a miniature diffusion size classifier (miniDiSC) - a novel particle counting device that was used for the exposure assessment during highway maintenance work. We found that particle numbers and average particle size measured by the miniDiSC were highly correlated with data from the P-TRAK, a condensation particle counter (CPC), as well as from a scanning mobility particle sizer (SMPS). However, the miniDiSC measured significantly more particles than the P-TRAK and significantly less than the SMPS in its full size range. Our data suggests that the instrument specific cutoffs were the main reason for the different particle counts. The first main objective of this thesis was to investigate the exposure of highway maintenance workers to air pollutants and noise, in relation to the different maintenance activities. We have seen that the workers are regularly exposed to high particle and noise levels. This was a consequence of close proximity to highway traffic and the use of motorized working equipment such as brush cutters, chain saws, generators and pneumatic hammers during which the highest exposure levels occurred. Although exposure to air pollutants were not critical if compared to occupational exposure limits, the elevated exposure to particles and noise may lead to a higher risk for cardiovascular diseases in this worker population. The second main objective was to investigate cardiopulmonary short-term health effects in relation to the particle and noise exposure during highway maintenance work. We observed a PM2.5 related increase of the acute-phase inflammation markers C-reactive protein and serum amyloid A and a decrease of TNFa. Heart rate variability increased as a consequence of particle as well as noise exposure. Increased high frequency power indicated a stronger parasympathetic influence on the heart. Elevated noise levels during recreational time, after work, were related to increased blood pressure. Our data confirmed that highway maintenance workers are exposed to elevated levels of particles and noise as compared to the average population. This exposure poses a cardiovascular health risk and it is therefore important to make efforts to better protect the workers health. The use of cleaner machines during maintenance work would be a major step to improve the workers' situation. Furthermore, regulatory policies with the aim of reducing combustion and non-combustion emissions from road traffic are important for the protection of workers in traffic environments and the entire population.

Assessment of particulate exposure and surface characteristics in association with urinary levels of 8-hydroxy-2'-deoxyguanosine, considered as marker of oxidative stress

Epidemiological studies have demonstrated that exposure to fine particles is associated to adverse health effects, including cancer, respiratory and cardiovascular diseases. However, mechanisms by which particles induce health effects remain unclear. According to one of the most investigated hypotheses, particles cause adverse effects through the production of reactive oxygen species (ROS), which are very hazardous compounds able to attack directly biological structures, including the DNA strand or the lipid bilayer of the cells. If the defense mechanisms, constituted of antioxidants, are not able to counter ROS, then these compounds will cause in the body a range of oxidation reactions called "oxidative stress". The aim of the present research project was to better understand mechanisms by which exposure to fine particles induces oxidative stress. The first point of this project was to check whether exposure to high levels of fine particles is directly linked to oxidative stress, and whether this oxidative stress is accompanied by the activation of the defense mechanisms (antioxidants). The second point was to study the role played by the particle surface characteristics in the oxidative stress process. For that purpose, a study was conducted in bus depots with the participation of 40 mechanics. First, occupational exposure to particles (PM4) and to other pollutants (NOx, O3) was measured over a two-day period. Then, urine samples of mechanics were collected in order to measure levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and antioxidants. 8OHdG is a molecule formed by the oxidation of DNA and allowing to assess the oxidative stress status of the mechanics. Finally, particles were collected on filters, and functional groups located on the particle surface were analyzed in the laboratory using a Knudsen flow reactor. This technique allows not only to quantify functional groups on the particle surface, but also to measure the reaction kinetics. Results obtained during the field campaign in bus depots showed that mechanics were exposed to rather low levels of PM4 (20-85 μg/m3) and of pollutants (NOx: 100-1000 ppb; O3: <15 ppb). However, despite this low exposure, urinary levels of the oxidative stress biomarker (8OHdG) increased significantly for non-smoking workers over a two-day period of shift. This oxidative stress was accompanied by an increase of antioxidants, indicating the activation of defense mechanisms. On the other hand, the analysis of functional groups on the particle surface showed important differences, depending on the workplace, the date and the activities of workers. The particle surface contained simultaneously antagonistic functional groups which did not undergo internal reactions (such as acids and bases), and was usually characterized by a high density of carbonyl functions and a low density of acidic sites. Reaction kinetics measured using the Knudsen flow reactor pointed out fast reactions of oxidizable groups and slow reactions of acidic sites. Several exposure parameters were significantly correlated with the increase of the oxidative stress status: the presence of acidic sites, carbonyl functions and oxidizable groups on the particle surface; reaction kinetics of functional groups on the particle surface; particulate iron and copper concentrations; and NOx concentration.

GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.

Clairvoyance de l'utilité et de la désirabilité sociales dans les situations d'évaluation

Résumé Le concept de clairvoyance normative (Py & Somat, 1991), qui a vu le jour dans la continuité des études sur la norme d'internalité (Beauvois, 1984), traduit la connaissance du caractère normatif ou contre-normatif d'un type de comportements ou d'un type de jugements. Un certain nombre de recherches semble alors attester que la clairvoyance normative participe à l'obtention d'une évaluation positive. Toutefois, ces différentes recherches font toutes fi de l'idée qu'il existerait deux dimensions de la valeur sociale : l'utilité sociale et la désirabilité sociale. La prise en compte de ces deux dimensions, surtout si l'on admet que les normes sociales ne renvoient pas toutes à la même dimension (Beauvois, 1995 ; Dubois & Beauvois, 2005 ; Dubois, 2005), vient alors quelque peu compliquer le modèle liant clairvoyance normative et évaluation positive car elle suggère que la clairvoyance de certaines normes aidera avant tout à être bien évalué sur le plan de l'utilité sociale alors que la clairvoyance d'autres normes participera davantage à être évalué favorablement sur le plan de la désirabilité sociale. Ces réflexions ont été à la base de ce travail de thèse et ont conduit à la réalisation de notre première étude. Les quelques résultats inattendus que nous avons obtenus nous ont cependant incité par la suite à reconsidérer la pertinence de rattacher la notion de clairvoyance à certains types de contenu (internalité, autosuffisance, etc.), ce qui nous a amené à la proposition de deux nouvelles notions : la clairvoyance de l'utilité sociale et la clairvoyance de la désirabilité sociale. C'est dans l'optique de valider cette proposition que deux nouvelles études ont alors été réalisées. Si celles-ci appuient dans leur ensemble l'idée que les clairvoyances de l'utilité et de la désirabilité sociales seraient des indicateurs plus performants d'une évaluation sociale positive que ne le seraient les clairvoyances des normes sociales de jugement, elles n'ont néanmoins pas manqué de soulever de nouvelles questions. Cela nous a ainsi mené, dans un troisième temps, à nous interroger sur ce qui détermine la valeur en jeu dans une situation d'évaluation. Nos trois dernières études ont été construites dans ce dessein et ont participé, en conclusion de ce travail, à étayer l'idée que la clairvoyance de la valeur sociale des jugements ne permettrait l'obtention d'une évaluation positive que si celle-ci va de pair avec une certaine clairvoyance de la valeur sociale des éléments constitutifs de la situation d'interaction. Abstract The concept of normative clearsightedness (Py & Somat, 1991), born in continuity with studies on the norm of internality (Beauvois, 1984), reflects the knowledge of the normative or counter-normative nature of a type of behaviour or a type of judgement. Several researches appear to show that normative clearsightedness helps to obtain a positive evaluation. However, none of these researches takes into account the idea that there might be two dimensions of social value: social utility and social desirability. Considering those two dimensions, especially if we accept that not all social norms refer to the same dimension (Beauvois, 1995; Dubois & Beauvois, 2005; Dubois, 2005), somehow complicates the model linking normative clearsightedness with a positive evaluation. It suggests indeed that while clearsightedness of some norms will help first of all to get a good evaluation on the dimension of social utility, clearsightedness of other norms will help above all to get a good evaluation on the dimension of social desirability. These considerations were the foundation of this work and led to our first study. However, we reached some unexpected results that prompted us thereafter to reconsider the pertinence to attach the notion of clearsightedness to particular types of content (internality, self-sufficiency, etc.), which led us to propose two new notions: clearsightedness of social utility and clearsightedness of social desirability. Two new studies were thus executed to challenge this proposal. While these researches support as a whole that clearsightedness of social utility and social desirability are better indicators of positive evaluation than clearsightedness of social norms of judgement, they also raised new questions, which led us, in a third time, to wonder about what will determine the dominating social value in an evaluative situation. Our last three studies were designed to this purpose and helped to support the idea, in conclusion of this work, that the clearsightedness of the social value of judgements would bring a positive evaluation only if this clearsightedness is combined with a kind of clearsightedness of the social value of elements constituting the interaction's situation.

Effect of chronic hypoglycaemia on glucose concentration and glycogen content in rat brain: A localized 13C NMR study.

While chronic hypoglycaemia has been reported to increase unidirectional glucose transport across the blood-brain barrier (BBB) and to increase GLUT1 expression at the endothelium, the effect on steady-state brain d-glucose and brain glycogen content is currently unknown. Brain glucose and glycogen concentrations were directly measured in vivo using localized 13C magnetic resonance spectroscopy (MRS) following 12-14 days of hypoglycaemia. Brain glucose content was significantly increased by 48%, which is consistent with an increase in the maximal glucose transport rate, Tmax, by 58% compared with the sham-treated animals. The localized 13C NMR measurements of brain glucose were directly validated by comparison with biochemically determined brain glucose content after rapid focused microwave fixation (1.4 s at 4 kW). Both in vivo MRS and biochemical measurements implied that brain glycogen content was not affected by chronic hypoglycaemia, consistent with brain glucose being a major factor controlling brain glycogen content. We conclude that the increased glucose transporter expression in chronic hypoglycaemia leads to increased brain glucose content at a given level of glycaemia. Such increased brain glucose concentrations can result in a lowered glycaemic threshold of counter-regulation observed in chronic hypoglycaemia.

A hybrid zone with coincident clines for autosomal and sex-specific markers in the Sorex araneus group.

In hybrid zones, endogenous counter-selection of hybrids is usually first expressed as reduced fertility or viability in hybrids of the heterogametic sex, a mechanism known as Haldane's rule. This phenomenon often leads to a differential of gene flow between sex-linked markers. Here, we address the possibility of a differential gene flow for Y chromosome, mtDNA and autosomal markers across the hybrid zone between the genetically and chromosomally well-differentiated species Sorex antinorii and Sorex araneus race Vaud. Intermarker comparison clearly revealed coincidental centre and very abrupt clines for all three types of markers. The overall level of genetic differentiation between the two species must be strong enough to hinder asymmetric introgression. Cyto-nuclear mismatches were also observed in the centre of hybrid zone. The significantly lower number of mismatches observed in males than in females possibly results from Y chromosome-mtDNA interactions. Results are compared with those previously reported in another hybrid zone between S. antinori and S. araneus race Cordon.

Controlled dynamic generation of standard 1,6-hexamethylene diisocyanate aerosols

A procedure for the dynamic generation of 1,6-hexamethylene diisocyanate (HDI) aerosol atmospheres of 70 micrograms m-3 (0.01 ppm) to 1.75 mg m-3 (0.25 ppm), based on the precise control of the evaporation of pure liquid HDI and subsequent dilution with air, was developed. The apparatus consisted of a home-made glass nebulizer coupled with a separation stage to exclude non-respirable droplets (greater than 10 microns). The aerosol concentrations were achieved by passing air through the nebulizer at 1.5-4.5 l. min-1 to generate dynamically 0.01-0.25 ppm of diisocyanate in an experimental chamber of 8.55 m3. The distribution of the liquid aerosol was established with an optical counter and the diisocyanate concentration was determined from samples collected in impingers by a high-pressure liquid chromatographic method. The atmospheres generated were suitable for the evaluation both of sampling procedures full scale, and of analytical methods: at 140 micrograms m-3 (0.02 ppm) they remained stable for 15-min provocation tests in clinical asthma, as verified by breath-zone sampling of exposed patients.

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A Knudsen flow reactor has been used to quantify functional groups on the surface of seven different types of combustion particle samples: 3 amorphous carbons (FS 101, Printex 60, FW 2), 2 flame soots (hexane soot generated from a rich and a lean diffusion flame), and 2 Diesel particles (SRM 2975, Diesel soot recovered from a Diesel particulate filter). The technique is based on a heterogeneous titration reaction between a probe gas and a specific functional group on the particle surface. Six probe gases have been selected for the quantification of important functional groups: N(CH3)3 for the titration of acidic sites, NH2OH for carbonyl functions of aldehydes and ketones, CF3COOH and HCl for basic sites of different strength, O3 and NO2 for oxidizable groups. The limit of detection was generally well below 1% of a formal monolayer of adsorbed probe gas. Results obtained with N(CH3)3 were higher for the FW 2 amorphous carbon (post-oxidized sample, according to the manufacturer) and the Diesel particles (between 5.2·10 13 and 5.8·10 13 molecule/cm2), indicating a higher state of oxidation than for the other samples (between 1.3·10 12 and 3.7·10 12 molecule/cm2). The ratio of uptakes of CF3COOH and HCl inferred the presence of basic oxides on the particle surface, owing to the larger stability of the acetate compared to the chloride counter ion in the resulting pyrylium salt. The reactivity of the FS 101 amorphous carbon (3.7·10 15 molecule/cm2) and the hexane flame soot (between 1.9·10 15 and 2.7·10 15 molecule/cm2) towards O3 was very high, indicating the presence of a huge amount of oxidizable or reduced groups on the surface of these samples. Besides the quantification of surface functional groups, the kinetics of reactions between particles and probe gases has also been studied. The uptake coefficient γ0 was roughly correlated with the amount of probe gas taken up by the samples. Indeed, the presence of a high density of functional groups led to fast uptake of the probe gas. These different findings indicate that the particle surface appeared multi-functional, with the simultaneous presence of antagonistic functional groups which do not undergo internal chemical reactions, such as acid-base neutralization. Results also point to important differences in the surface reactivity of the samples, depending on the combustion conditions. The relative distribution of the surface functional groups may be a useful indicator for the state of oxidation and the reactivity of the particle surface.

The economics of anti-parasite defences in animal societies

RESUME : De nombreuses espèces animales vivent en groupe. Du simple grégarisme aux colonies hautement intégrées de fourmis, la vie sociale a atteint des degrés divers de complexité. Les nombreuses interactions entre membres d'une société favorisent la transmission de parasites. Cela représente un coût potentiel de la vie sociale. Cette thèse s'intéresse aux défenses permettant de réduire le coût du parasitisme dans les colonies de fourmis ainsi qu'à la manière dont le parasitisme a pu façonner certains aspects de ces sociétés. Les colonies de fourmis des bois (Forimica paralugubris) contiennent de grandes quantités de résine de conifères. Cette résine réduit la densité microbienne dans le nid et augmente la survie des ouvrières lors d'infections parasitaires. Dans cette thèse, nous montrons, d'une part, que les ouvrières collectent activement la résine et que ce comportement est plutôt préventif que curatif et, d'autre part, que la résine permet aux ouvrières une utilisation moindre de leurs défenses immunitaires. Ces résultats permettent de conclure que ce comportement réduit l'exposition au parasitisme et qu'il a une fonction adaptative. L'émergence d'un tel comportement de médication chez une espèce d'insectes sociaux illustre le fait que la socialité, bien yue provoquant une exposition accrue au parasitisme, permet également l'émergence de mécanismes sociaux de défense. II a été suggéré que la présence de plusieurs reines au sein d'un même nid (polygynie) améliore la résistance aux parasites en augmentant la diversité génétique au sein de la colonie. En accord avec cette hypothèse, nous montrons qu'une augmentation de la diversité génétique au sein de groupes expérimentaux de Formica selysi améliore leur survie lors d'une infection parasitaire. Cependant, nous suggérons également que sur le terrain, d'autres facteurs corrélés à la polygynie ont des effets antagoniques sur la résistance. Nous montrons par exemple que les ouvrières polygynes semblent avoir une capacité moindre à monter une réponse immunitaire. Certains aspects de la reproduction des fourmis ont pu également être façonnés par le parasitisme. L'accouplement n'a lieu que lors d'une courte période au début de la vie adulte, généralement à l'extérieur de la colonie. Les reines stockent ensuite le sperme et l'utilisent parcimonieusement au cours de leur vie alors que les males meurent rapidement. Nous montrons que les défenses immunitaires des reines de fourmis des bois (F. paralugubris) sont fortement affectées par l'accouplement. Ces modulations immunitaires sont probablement liées à une augmentation de l'exposition au parasitisme lors de l'accouplement ainsi qu'à des blessures copulatoires. I1 semble donc que l'accouplement soit accompagné de coûts immunitaires pour les reines. Dans son ensemble, cette thèse illustre la diversité des mécanismes de défenses contre les parasites dans les sociétés de fourmis. La vie sociale, en offrant un nouveau niveau d'interaction, permet en effet l'émergence d'adaptations originales. Cela explique probablement le grand succès écologique des espèces sociales. SUMMARY : Sociality is widespread among animals and has reached variable degrees of complexity, from loose social Groups to highly integrated ant colonies. The many interactions between members of a social group promote the spread of parasites, but social life also permits the evolution of original defence mechanisms. This thesis sheds light on how ant colonies defend themselves against parasites, and on how parasitism shapes certain aspects of these societies. Wood ants nests (Formica paralugubris) contain large amounts of conifer resin which reduces the microbial density in ant nests and enhances the survival of ants challenged by some pathogens. We show that resin is actively collected by workers and that resin collection is rather a prophylactic than a curative behaviour. Moreover, we suggest that resin reduces the use of the immune defences of workers. Altogether, these results indicate that the use of resin is a collective adaptation to prevent the spread of parasites. The emergence of medication in a social insect species illustrates that sociality does not only increase the exposure to parasites but also allows the emergence of social mechanisms to counter this threat. The number of reproducing queens per colony is a variable trait in ants. It has been suggested that polygyny (the occurrence of multiple queens within a colony), by increasing the colonial genetic diversity, improves disease resistance. In line with this hypothesis, we show that in a socially polymorphic ant (Formica selysi), an experimental increase of colony genetic diversity enhances disease resistance. However, we also suggest that factors covarying with queen number variation in the field have antagonistic effects on parasite resistance. We show for instance that polygyne workers seem to have lower immune defences. Parasites may also shape some aspects of ant queen reproductive biology. Ant queens mate at the beginning of their adult life, usually outside of the colony, and store sperm for several years to fertilize eggs. Males die shortly after mating and queens never remate later in life, which drastically reduces sexual conflicts. Moreover, mating and nest founding occur away from the collective defence mechanisms of the natal colony and might be associated with an increased risk of parasitism. We show that mating affects the immune defences of wood ant queens (F. paralugubris) in multiple ways that are consistent with mating wounds and increased risk of parasitism. We suggest that mating is associated with immunity costs in ants, despite the reduced level of sexual conflicts. Altogether, my thesis illustrates the diversity of anti-parasite mechanisms in ant societies. This sheds light on how sociality, by offering a new level of interactions, allows the evolution of original adaptations, which may explain the wide ecological success of social species.

Actions of β2-adrenoceptor agonist drug on human soleus muscle contraction.

PURPOSE: The effects of β(2)-agonists on human skeletal muscle contractile properties, particularly on slow fibers, are unclear. Moreover, it remains to be ascertained whether central motor drive (CMD) during voluntary contractions could counter for eventual contractile alterations induced by β(2)-agonists. This study investigated central and peripheral neuromuscular adjustments induced by β(2)-agonist terbutaline on a predominantly slow human muscle, the soleus. METHODS: Ten recreationally active men ingested either a single dose of 8 mg of terbutaline or placebo in a randomized double-blind order (two experimental sessions). Isometric plantarflexion torque was measured during single and tetanic (10 and 100 Hz) stimulations as well as during submaximal and maximal voluntary contractions (MVC). Twitch peak torque and half-relaxation time were calculated. CMD was estimated via soleus electromyographic recordings obtained during voluntary contractions performed at approximately 50% MVC. RESULTS: MVC and twitch peak torque were not modified by terbutaline. Twitch half-relaxation time was 28% shorter after terbutaline administration compared with placebo (P < 0.001). Tetanic torques at 10 and 100 Hz were significantly lower after terbutaline intake compared with placebo (-40% and -24% respectively, P < 0.001). Despite comparable torque of submaximal voluntary contractions in the two conditions, CMD was 7% higher after terbutaline ingestion compared with placebo (P < 0.01). CONCLUSION: These results provide evidence that terbutaline modulates the contractility of the slow soleus muscle and suggest that the increased CMD during submaximal contractions may be viewed as a compensatory adjustment of the central nervous system to counter the weakening action induced by terbutaline on the contractile function of slow muscle fibers.

Dicarboxylic amino acids and glycine-betaine regulate chaperone-mediated protein-disaggregation under stress.

Active protein-disaggregation by a chaperone network composed of ClpB and DnaK + DnaJ + GrpE is essential for the recovery of stress-induced protein aggregates in vitro and in Escherichia coli cells. K-glutamate and glycine-betaine (betaine) naturally accumulate in salt-stressed cells. In addition to providing thermo-protection to native proteins, we found that these osmolytes can strongly and specifically activate ClpB, resulting in an increased efficiency of chaperone-mediated protein disaggregation. Moreover, factors that inhibited the chaperone network by impairing the stability of the ClpB oligomer, such as natural polyamines, dilution, or high salt, were efficiently counteracted by K-glutamate or betaine. The combined protective, counter-negative and net activatory effects of K-glutamate and betaine, allowed protein disaggregation and refolding under heat-shock temperatures that otherwise cause protein aggregation in vitro and in the cell. Mesophilic organisms may thus benefit from a thermotolerant osmolyte-activated chaperone mechanism that can actively rescue protein aggregates, correctly refold and maintain them in a native state under heat-shock conditions.

Comparative testing of a miniature diffusion size classifier to assess airborne ultrafine particles under field conditions

Miniature diffusion size classifiers (miniDiSC) are novel handheld devices to measure ultrafine particles (UFP). UFP have been linked to the development of cardiovascular and pulmonary diseases; thus, detection and quantification of these particles are important for evaluating their potential health hazards. As part of the UFP exposure assessments of highwaymaintenance workers in western Switzerland, we compared a miniDiSC with a portable condensation particle counter (P-TRAK). In addition, we performed stationary measurements with a miniDiSC and a scanning mobility particle sizer (SMPS) at a site immediately adjacent to a highway. Measurements with miniDiSC and P-TRAK correlated well (correlation of r = 0.84) but average particle numbers of the miniDiSC were 30%âeuro"60% higher. This difference was significantly increased for mean particle diameters below 40 nm. The correlation between theminiDiSC and the SMPSduring stationary measurements was very high (r = 0.98) although particle numbers from the miniDiSC were 30% lower. Differences between the three devices were attributed to the different cutoff diameters for detection. Correction for this size dependent effect led to very similar results across all counters.We did not observe any significant influence of other particle characteristics. Our results suggest that the miniDiSC provides accurate particle number concentrations and geometric mean diameters at traffic-influenced sites, making it a useful tool for personal exposure assessment in such settings.

Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells.

A comprehensive understanding of the complex, autologous cellular interactions and regulatory mechanisms that occur during normal dendritic cell (DC)-stimulated immune responses is critical to optimizing DC-based immunotherapy. We have found that mature, immunogenic human monocyte-derived DCs (moDCs) up-regulate the immune-inhibitory enzyme, indoleamine 2,3-dioxygenase (IDO). Under stringent autologous culture conditions without exogenous cytokines, mature moDCs expand regulatory T cells (Tregs) by an IDO-dependent mechanism. The priming of resting T cells with autologous, IDO-expressing, mature moDCs results in up to 10-fold expansion of CD4(+)CD25(bright)Foxp3(+)CD127(neg) Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4(+) CD25(bright)Foxp3(+) Tregs inhibit as much as 80% to 90% of DC-stimulated autologous and allogeneic T-cell proliferation, in a dose-dependent manner at Treg:T-cell ratios of 1:1, 1:5, and as low as 1:25. CD4(+)CD25(bright)Foxp3(+) Tregs also suppress the generation of cytotoxic T lymphocytes specific for the Wilms tumor antigen 1, resulting in more than an 80% decrease in specific target cell lysis. Suppression by Tregs is both contact-dependent and transforming growth factor-beta-mediated. Although mature moDCs can generate Tregs by this IDO-dependent mechanism to limit otherwise unrestrained immune responses, inhibition of this counter-regulatory pathway should also prove useful in sustaining responses stimulated by DC-based immunotherapy.

Multiple Paternity in Polyandrous Barn Owls (Tyto alba).

In polyandrous species females produce successive clutches with several males. Female barn owls (Tyto alba) often desert their offspring and mate to produce a 2(nd) annual brood with a second male. We tested whether copulating during chick rearing at the 1(st) annual brood increases the male's likelihood to obtain paternity at the 2(nd) annual breeding attempt of his female mate in case she deserts their brood to produce a second brood with a different male. Using molecular paternity analyses we found that 2 out of 26 (8%) second annual broods of deserting females contained in total 6 extra-pair young out of 15 nestlings. These young were all sired by the male with whom the female had produced the 1(st) annual brood. In contrast, none of the 49 1(st) annual breeding attempts (219 offspring) and of the 20 2(nd) annual breeding attempts (93 offspring) of non-deserting females contained extra-pair young. We suggest that female desertion can select male counter-strategies to increase paternity and hence individual fitness. Alternatively, females may copulate with the 1(st) male to derive genetic benefits, since he is usually of higher quality than the 2(nd) male which is commonly a yearling individual.

Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus--a prospective single-blinded randomised crossover trial.

Aims/hypothesis We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type I diabetes at euglycaemia and hyperglycaemia with identical insulin levels.Methods This was a single-blinded randomised crossover study at a university diabetes unit in Switzerland. We studied seven physically active men with type I diabetes (mean +/- SEM age 33.5 +/- 2.4 years, diabetes duration 20.1 +/- 3.6 years, HbA(1c) 6.7 +/- 0.2% and peak oxygen uptake [VO2peak] 50.3 +/- 4.5 ml min(-1) kg(-1)). Men were studied twice while cycling for 120 min at 55 to 60% of VO2peak, with a blood glucose level randomly set either at 5 or 11 mmol/l and identical insulinaemia. The participants were blinded to the glycaemic level; allocation concealment was by opaque, sealed envelopes. Magnetic resonance spectroscopy was used to quantify intramyocellular glycogen and lipids before and after exercise. Indirect calorimetry and measurement of stable isotopes and counter-regulatory hormones complemented the assessment of local and systemic fuel metabolism.Results The contribution of lipid oxidation to overall energy metabolism was higher in euglycaemia than in hyperglycaemia (49.4 +/- 4.8 vs 30.6 +/- 4.2%; p<0.05). Carbohydrate oxidation accounted for 48.2 +/- 4.7 and 66.6 +/- 4.2% of total energy expenditure in euglycaemia and hyperglycaemia, respectively (p<0.05). The level of intramyocellular glycogen before exercise was higher in hyperglycaemia than in euglycaemia (3.4 +/- 0.3 vs 2.7 +/- 0.2 arbitrary units [AU]; p<0.05). Absolute glycogen consumption tended to be higher in hyperglycaemia than in euglycaemia (1.3 +/- 0.3 vs 0.9 +/- 0.1 AU). Cortisol and growth hormone increased more strongly in euglycaemia than in hyperglycaemia (levels at the end of exercise 634 52 vs 501 +/- 32 nmol/l and 15.5 +/- 4.5 vs 7.4 +/- 2.0 ng/ml, respectively; p<0.05).Conclusions/interpretation Substrate oxidation in type I diabetic patients performing aerobic exercise in euglycaemia is similar to that in healthy individuals revealing a shift towards lipid oxidation during exercise. In hyperglycaemia fuel metabolism in these patients is dominated by carbohydrate oxidation. Intramyocellular glycogen was not spared in hyperglycaemia.