Detection of Toxoplasma gondii oocysts in water: proposition of a strategy and evaluation in Champagne-Ardenne Region, France

Water is a vehicle for disseminating human and veterinary toxoplasmosis due to oocyst contamination. Several outbreaks of toxoplasmosis throughout the world have been related to contaminated drinking water. We have developed a method for the detection of Toxoplasma gondii oocysts in water and we propose a strategy for the detection of multiple waterborne parasites, including Cryptosporidium spp. and Giardia. Water samples were filtered to recover Toxoplasma oocysts and, after the detection of Cryptosporidium oocysts and Giardia cysts by immunofluorescence, as recommended by French norm procedure NF T 90-455, the samples were purified on a sucrose density gradient. Detection of Toxoplasma was based on PCR amplification and mouse inoculation to determine the presence and infectivity of recovered oocysts. After experimental seeding assays, we determined that the PCR assay was more sensitive than the bioassay. This strategy was then applied to 482 environmental water samples collected since 2001. We detected Toxoplasma DNA in 37 environmental samples (7.7%), including public drinking water; however, none of them were positive by bioassay. This strategy efficiently detects Toxoplasma oocysts in water and may be suitable as a public health sentinel method. Alternative methods can be used in conjunction with this one to determine the infectivity of parasites that were detected by molecular methods.

Use of geoprocessing to define malaria risk areas and evaluation of the vectorial importance of anopheline mosquitoes (Diptera: Culicidae) in Espírito Santo, Brazil

In Brazil, introduced malaria occurs from the flat to the sloping hot areas, predominantly outside the Amazon Region, where endemic malaria has occurred in the past. This is a consequence of human migrations to other Brazilian states, including the state of Espírito Santo (ES). The objective of this study was to use geoprocessing to define the areas at risk of introduced malaria transmission and evaluate the vectorial importance of species of anophelines in ES. Anophelines were sampled from 1997-2005 in 297 rural localities identified or not identified as foci of malaria during the last 20 years. The geoclimatic variables temperature, relief and marine influence were obtained from a database of the ES Natural Units. The 14,663 anophelines captured belonged to 22 species. A significant association was found between the occurrence of malaria foci and the presence of hot, low-lying areas or gently undulating to undulating relief. The occurrence of the disease was associated with the presence of Anopheles darlingi and Anopheles aquasalis. Geoprocessing was determined to be a useful tool for defining areas at risk for malaria and vectors in ES.

Development and evaluation of a shaken baby syndrome prevention program.

OBJECTIVE: To evaluate parents' and nurses' opinions regarding the adequacy of an educational program on shaken baby syndrome: the Perinatal Shaken Baby Syndrome Prevention Program (PSBSPP). DESIGN: Qualitative and quantitative assessments in the form of interviews and questionnaires administered in French. SETTING: Two birthing institutions in Montréal, QC, Canada: a university hospital and a regional center. PARTICIPANTS: Two hundred and sixty-three parents (73.8% mothers, 26.2% fathers) received the intervention after the birth of their child, and 69 nurses administered it. METHODS: Parents' and nurses' assessments of the adequacy and relevance of the program and nurses' assessments of the training they received to administer the program were evaluated. RESULTS: Both parents and nurses supported this initiative. Most parents appreciated the usefulness of the information. Nurses believed the program was adequate, and their training to deliver the program was satisfactory. All participants reported that the program was highly relevant, especially for new parents. CONCLUSION: The Perinatal Shaken Baby Syndrome Prevention Program achieves the goals of (a) increasing parents' knowledge about infant crying, anger, and shaken baby syndrome and (b) helping parents identify coping strategies. The relevance of introducing the PSBSPP in all birthing institutions is supported. Future studies should focus on vulnerable and culturally diverse populations, and longitudinal follow-up could help determine if the PSBSPP reduces the incidence of shaken baby syndrome.

Analysis and evaluation of techniques for the extraction of classes in the ontology learning process

This paper analyzes and evaluates, in the context of Ontology learning, some techniques to identify and extract candidate terms to classes of a taxonomy. Besides, this work points out some inconsistencies that may be occurring in the preprocessing of text corpus, and proposes techniques to obtain good terms candidate to classes of a taxonomy.

Design and evaluation of a panel os single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Implementation and evaluation of an internet health site for adolescents in Switzerland.

Ciao is a website specifically designed for young people and focuses mainly on health issues. This report presents the process of setting up the site and a first evaluation undertaken by using two self-administered questionnaires administered via the website itself. It suggests that it is possible to provide young people with authoritative health information and to facilitate their access to counseling and health care facilities by having young people use such a website.

Panel index VAR models: Specification, Estimation, Testing and Leading Indicators

This paper proposes a method to conduct inference in panel VAR models with cross unit interdependencies and time variations in the coefficients. The approach can be used to obtain multi-unit forecasts and leading indicators and to conduct policy analysis in a multiunit setups. The framework of analysis is Bayesian and MCMC methods are used to estimate the posterior distribution of the features of interest. The model is reparametrized to resemble an observable index model and specification searches are discussed. As an example, we construct leading indicators for inflation and GDP growth in the Euro area using G-7 information.

Development and evaluation of antibody-MHC/peptide conjugates as a new form of cancer immunotherapy

Summary One of the major goals of cancer immunotherapy is the induction of a specific and effective antitumor cytotoxic T lymphocyte (CTL) response. However, the downregulation of Class I Major Histocompatibility Complexes (MHC) expression and the low level of tumor peptide presentation on tumor cell surface, ás well as the low immunogenicity of tumor specific antigens, limit the effectiveness of anti-tumor CTL responses. On the other hand, monoclonal antibodies, which bind with high affinity to tumor cell surface markers, are powerful tumor targeting tools. However, their capacity to .kill cancer cells is limited and mAb cancer treatments usually require the addition of different form of chemotherapy. The new cancer immunotherapy strategy described herein combines the advantage of the high tumor targeting capacity of monoclonal antibodies (mAb) with the powerful cytotoxicity of CD8 T lymphocytes directed against highly antigenic peptide-MHC complexes. Monoclonal antibody Fab fragments directed against a cell surface tumor associated antigen (TAA) are chemically coupled to soluble MHC class I complexes carrying a highly antigenic peptide. Antibody guided targeting and oligomerization of numerous antigenic class IMHC/peptide complexes on tumor cell surfaces can redirect the cytotoxicity of peptide-specific CD8 T cells towards target cancer cells. After the description of the production of murine anti-tumor xMHC/peptide conjugates in the first part of this thesis, the therapeutic potential of such conjugates were sequentially investigated in different syngeneic tumor mouse models. As a first proof of principle, transgenic OT-1 mice and later CEA transgenic C57BL/6 (B6) mice, adoptively transferred with OT-1 spleen cells and immunized with ovalbumin, were used as a model of high frequency of ova peptide specific T cells. In these mice, growth inhibition and regression of palpable colon carcinoma expressing CEA, were obtained by systemic injection of anti-CEA Fab/H-2Kb/ova peptide conjugates. Next, LCMV virus and influenza virus infection of B6 mice were used as viral models to redirect natural antiviral CTL responses to tumors via conjugates loaded with viral peptides. We showed that in mice infected with the LCMV virus, subcutaneous CEA-expressing tumor cells were inhibited by the H2Db/GP33 restricted anti-viral CTL response when preincubated before grafting with anti-CEA Fab-H-2Db/GP33 peptide conjugates. In mice infected with the influenza virus, lung metastases expressing the HER2 antigen were inhibited by the H-2Db/NP366 restricted CTLs response when preincubated before injection with anti-Her2 Fab-H-2Db/NP366 peptide conjugates. In the last chapter, the stability of the peptide in the anti-CEA Fab-H-2Db/GP33 conjugates was improved by the covalent photocross-link of the GP33 peptide in the H-2Db MHC groove. Thus, LCMV immune mice could reject CEA expressing tumors when treated with systemic injections of anti-CEA FabH-2Db/GP33 cross-linked conjugates. These results are encouraging for the potential application of this strategy in clinic. Such conjugates could be used alone in patients boosted by the relevant virus, or used in combination with existing T cell based ìmmunotherapy. Résumé Une des principales approches utilisées dans l'immunothérapie contre le cancer consiste en l'induction d'une réponse T cytotoxique (CTL) spécifiquement dirigée contre la tumeur. Cependant, le faible niveau d'expression des complexes majeurs d'histocompatibilité de classe I (CMH I) et de présentation des peptides tumoraux à la surface des cellules cancéreuses ainsi que la faible immunogenicité des antigens tumoraux, limitent l'efficacité de la réponse CTL. D'autre part,. l'injection d'anticorps monoclonaux (mAb), se liant avec une haute affinité aux marqueurs de surface des cellules tumorales, a fourni des résultats cliniques encourageant. Cependant l'efficacité de ces mAbs contre des tumeur solides reste limitée et necessite souvent l'addition de chimiotherapie. La nouvelle stratégie thérapeutique décrite dans ce travail associe le fort pouvoir de localisation des anticorps monoclonaux et le fort pouvoir cytotoxique des lymphocytes T CD8+. Des fragments Fab d'anticorps monoclonaux, dirigés contre des antigènes surexprimés à la surface de cellules tumorales, ont été chimiquement couplés à des CMH I solubles, portant un peptide fortement antigénique. Le ciblage et l'oligomérisation à la surface des cellules tumorales de nombreux CMH I présentant un peptide antigénique, va réorienter la cytotoxicité des cellules T CD8+ spécifiques du peptide présenté, vers les cellules tumorales cibles. Après une description de la production de conjugé anti-tumeur x CMH Upeptide dans la première partie de cette thèse, le potentiel thérapeutique de tels conjugés a été successivement étudiés in vivo dans différents modèles de tumeur syngénéiques. Tout d'abord, des souris OT-1 transgéniques, puis des souris C57BL/6 (B6) transférées avec des cellules de rate OT-1 puis immunisées avec l'ovalbumine, ont été employées comme modèle de haute fréquence de cellules T CD8+ spécifiques du peptide ova. Chez ces souris, l'inhibition de la croissance et la régression de nodules palpables de carcinomes exprimant l'antigène caccino embryonaire (ACE), ont été obtenues par l'injection systémique de conjugés anti-ACE Fab/H-2Kb/ova. Par la suite, l'infection de souris B6 par le virus LCMV et par le virus de la grippe, ont été utilisés comme modèles viraux pour redirigées des réponses anti-virales naturelles vers les tumeurs, en utilisant des conjugés chargés avec des peptides viraux. Nous avons montré que .chez les souris infectées par le LCMV, la croissance de carcinome sous-cutané est empêchée par la réponse anti-virale, spécifique du complexe H2Db/GP33, lorsque les cellules tumorales greffées sont pré-incubées avec des conjugés anti-CEA Fab-H-2Db/GP33. Dans le cas de souris infectées par le virus de la grippe, la métastatisation de mélanomes pulmonaires exprimant l'antigène HER-2 est inhibée par la réponse anti-virale spécifique du complexe H-2Db/NP366, après pré-incubation des cellules tumorales avec des conjugés anti-Her2 FabxH-2Db/NP366. Dans le dernier chapitre, la liaison covalente du peptide GP33 dans le complexe H-2Db a amélioré la stabilité des conjugés correspondants et a permis le traitement systémique de souris greffées avec des tumeurs exprimant l'ACE et infectées par le LCMV. L'ensemble de ces résultats sont encourageant pour l'application de cette strategie en clinique. De tels conjugués pourraient être employés seuls ou en combinaison avec des protocols d'immunisation peptidique anti-tumoral. Résumé pour un large public Dans les pays industrialisés, le cancer se situe au deuxième rang des causes de mortalité après les maladies cardiovasculaires. Les principaux traitement de nombreux cancers sont la chirurgie, en association avec la radiothérapie et la chimiothérapie. L'immunothérapie est l'une des nouvelles approches mises en oeuvre pour la lutte contre le cancer. Elle peut être humorale, et s'appuyer alors sur la perfusion d'anticorps monoclonaux dirigés contre des antigènes tumoraux, par exemple les anticorps dirigés contre les protéines oncogéniques Her-2/neu dans le cancer du sein. Ces anticorps ont le grand avantage de spécifiquement se localiser à la tumeur et d'induire la lyse ou d'inhiber la proliferation des cellules tumorales exprimant l'antigène. Certains sont utilisés en clinique pour le traitement de lymphomes, de carcinomes de l'ovaire et du sein ou encore de carcinomes metastatiques du côlon. Cependant l'efficacité de ces anticorps contre des tumeurs solides reste limitée et les traitements exigent souvent d'être combiner avec de la chimiothérapie. L'immunothérapie spécifique peut également être cellulaire et reposer sur une démarche de type vaccinal, consistant à générer des lymphocytes T cytotoxiques (cytotoxic T lymphocytes :CTL) capables de détruire spécifiquement les cellules malignes. Pour obtenir une réponse lymphocytaire T cytotoxique antitumorale, la cellule T doit reconnaître un antigène associé à la tumeur, présenté sous forme de peptide dans un complexe majeur d'histocompatibilité de classe I. Or les cellules tumorales ne presentent pas efficacement les peptides antigèniques, car elles se caractérisent par une diminution ou une absence d'expression des antigènes d'histocompatibilité de classe I, des molécules d'adhésion et des cytokines costimulatrices, et par une faible expression des antigènes associés aux tumeurs. C'est en partie pourquoi, malgré l'induction de fortes réponses CTL specifiquement dirigés contre des antigens tumoraux, les régressions tumorales obtenus grace à ces vaccinations sont relativement rares. Alors que chez les personnes atteintes du cancer on observe l'instauration d'une tolérance immunitaire vis-à-vis de la tumeur, à l'inverse, notre systeme immunitaire reste parfaitement capable de combattre des infection virales classiques, tels que la grippe, qui font aussi appel à une réponse T cytotoxique. Notre groupe de recherche a donc eu l'idee de développer une nouvelle approche thérapeutique où une réponse immunitaire anti-virale très efficace serait redirigée vers les tumeurs par des anticorps monoclonaux. Concrètement, nous avons chimiquement couplés des fragments d'anticorps monoclonaux dirigés contre des antigènes surexprimés à la surface de cellules tumorales, à des CMH I portant un peptide viral antigénique. Les cellules tumorales, ciblées par le fragment anticorps et couvertes d' antigènes viraux présentés par des molécules de CMH I, peuvent ainsi tromper les lymphocytes cytotoxiques anti-viraux qui vont détruire les cellules tumorales comme si elles étaient infectées par le virus. Suite à des résultats prometteurs obtenus in vitro avec différents conjugués anticorps-CMH humain de type HLA.A2/peptide Flu, le but du projet était de tester in vivo des conjugués anticorps-CMH I murins sur des modèles expérimentaux de souris. Tout d'abord, des souris transgéniques pour un recepteur T specifique du peptide ova, puis des transferts adoptifs de ces cellules T specifiques dans des souris immunocompétentes, ont été choisi comme modèle de haute fréquence des cellules T spécifiques, et ont permi de valider le principe de la strategie in vivo. Puis, deux modèles viraux ont été elaboré avec le virus LCMV et le virus Influenza, pour réorienter des réponses antivirales naturelles vers les tumeurs grâce à des conjugés chargés avec des peptides viraux. Nous avons montré la grande capacité de nos conjugués à rediriger des réponses cytotoxiques vers les tumeurs et inhiber la croissance de tumeurs syngénéiques sous cutanés et pulmonaires. Ces résultats d'inhibition tumorales obtenus dans des souris immunocompétentes, grâce à l'injection de conjugués anticorps xCMH/peptide et réorientant deux réponses antivirales différentes vers deux modèles tumoraux syngeneiques, sont encourageant pour l'application de cette nouvelle stratégie en clinique.

Comparison and evaluation of states of health

Starting from a finite or countable set of states of health, and assumingthe existence of an objective transitive preference relation on that set,we propose a way of performing interpersonal comparisons of states ofhealth. In so doing, we first consider the population divided into types,and consider that two individuals of a different type have a comparablestate of health whenever they sit at the same centile of their respectivetype. A way of comparing and evaluating states of health for differentgroups is then proposed and rationalized. This can be viewed as both analternative and an extension of the traditional QALY approach.

Whole-body 3D T1-weighted MR imaging in patients with prostate cancer: feasibility and evaluation in screening for metastatic disease.

PURPOSE: To develop and assess the diagnostic performance of a three-dimensional (3D) whole-body T1-weighted magnetic resonance (MR) imaging pulse sequence at 3.0 T for bone and node staging in patients with prostate cancer. MATERIALS AND METHODS This prospective study was approved by the institutional ethics committee; informed consent was obtained from all patients. Thirty patients with prostate cancer at high risk for metastases underwent whole-body 3D T1-weighted imaging in addition to the routine MR imaging protocol for node and/or bone metastasis screening, which included coronal two-dimensional (2D) whole-body T1-weighted MR imaging, sagittal proton-density fat-saturated (PDFS) imaging of the spine, and whole-body diffusion-weighted MR imaging. Two observers read the 2D and 3D images separately in a blinded manner for bone and node screening. Images were read in random order. The consensus review of MR images and the findings at prospective clinical and MR imaging follow-up at 6 months were used as the standard of reference. The interobserver agreement and diagnostic performance of each sequence were assessed on per-patient and per-lesion bases. RESULTS: The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher with whole-body 3D T1-weighted imaging than with whole-body 2D T1-weighted imaging regardless of the reference region (bone or fat) and lesion location (bone or node) (P < .003 for all). For node metastasis, diagnostic performance (area under the receiver operating characteristic curve) was higher for whole-body 3D T1-weighted imaging (per-patient analysis; observer 1: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P = .006 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging), as was sensitivity (per-lesion analysis; observer 1: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging). CONCLUSION: Whole-body MR imaging is feasible with a 3D T1-weighted sequence and provides better SNR and CNR compared with 2D sequences, with a diagnostic performance that is as good or better for the detection of bone metastases and better for the detection of lymph node metastases.

Candida species distribution and antifungal susceptibility testing according to European Committee on Antimicrobial Susceptibility Testing and new vs. old Clinical and Laboratory Standards Institute clinical breakpoints: a 6-year prospective candidaemia survey from the fungal infection network of Switzerland.

We analyzed the species distribution of Candida blood isolates (CBIs), prospectively collected between 2004 and 2009 within FUNGINOS, and compared their antifungal susceptibility according to clinical breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2013, and the Clinical and Laboratory Standards Institute (CLSI) in 2008 (old CLSI breakpoints) and 2012 (new CLSI breakpoints). CBIs were tested for susceptiblity to fluconazole, voriconazole and caspofungin by microtitre broth dilution (Sensititre(®) YeastOne? test panel). Of 1090 CBIs, 675 (61.9%) were C. albicans, 191 (17.5%) C. glabrata, 64 (5.9%) C. tropicalis, 59 (5.4%) C. parapsilosis, 33 (3%) C. dubliniensis, 22 (2%) C. krusei and 46 (4.2%) rare Candida species. Independently of the breakpoints applied, C. albicans was almost uniformly (>98%) susceptible to all three antifungal agents. In contrast, the proportions of fluconazole- and voriconazole-susceptible C. tropicalis and F-susceptible C. parapsilosis were lower according to EUCAST/new CLSI breakpoints than to the old CLSI breakpoints. For caspofungin, non-susceptibility occurred mainly in C. krusei (63.3%) and C. glabrata (9.4%). Nine isolates (five C. tropicalis, three C. albicans and one C. parapsilosis) were cross-resistant to azoles according to EUCAST breakpoints, compared with three isolates (two C. albicans and one C. tropicalis) according to new and two (2 C. albicans) according to old CLSI breakpoints. Four species (C. albicans, C. glabrata, C. tropicalis and C. parapsilosis) represented >90% of all CBIs. In vitro resistance to fluconazole, voriconazole and caspofungin was rare among C. albicans, but an increase of non-susceptibile isolates was observed among C. tropicalis/C. parapsilosis for the azoles and C. glabrata/C. krusei for caspofungin according to EUCAST and new CLSI breakpoints compared with old CLSI breakpoints.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

Assessment of the occurrence of nanoparticles in Swiss industry and evaluation of the appropriatenesss of the measurement devices to determine the workforce exposure

Abstract : The occupational health risk involved with handling nanoparticles is the probability that a worker will experience an adverse health effect: this is calculated as a function of the worker's exposure relative to the potential biological hazard of the material. Addressing the risks of nanoparticles requires therefore knowledge on occupational exposure and the release of nanoparticles into the environment as well as toxicological data. However, information on exposure is currently not systematically collected; therefore this risk assessment lacks quantitative data. This thesis aimed at, first creating the fundamental data necessary for a quantitative assessment and, second, evaluating methods to measure the occupational nanoparticle exposure. The first goal was to determine what is being used where in Swiss industries. This was followed by an evaluation of the adequacy of existing measurement methods to assess workplace nanopaiticle exposure to complex size distributions and concentration gradients. The study was conceived as a series of methodological evaluations aimed at better understanding nanoparticle measurement devices and methods. lt focused on inhalation exposure to airborne particles, as respiration is considered to be the most important entrance pathway for nanoparticles in the body in terms of risk. The targeted survey (pilot study) was conducted as a feasibility study for a later nationwide survey on the handling of nanoparticles and the applications of specific protection means in industry. The study consisted of targeted phone interviews with health and safety officers of Swiss companies that were believed to use or produce nanoparticles. This was followed by a representative survey on the level of nanoparticle usage in Switzerland. lt was designed based on the results of the pilot study. The study was conducted among a representative selection of clients of the Swiss National Accident Insurance Fund (SUVA), covering about 85% of Swiss production companies. The third part of this thesis focused on the methods to measure nanoparticles. Several pre- studies were conducted studying the limits of commonly used measurement devices in the presence of nanoparticle agglomerates, This focus was chosen, because several discussions with users and producers of the measurement devices raised questions about their accuracy measuring nanoparticle agglomerates and because, at the same time, the two survey studies revealed that such powders are frequently used in industry. The first preparatory experiment focused on the accuracy of the scanning mobility particle sizer (SMPS), which showed an improbable size distribution when measuring powders of nanoparticle agglomerates. Furthermore, the thesis includes a series of smaller experiments that took a closer look at problems encountered with other measurement devices in the presence of nanoparticle agglomerates: condensation particle counters (CPC), portable aerosol spectrometer (PAS) a device to estimate the aerodynamic diameter, as well as diffusion size classifiers. Some initial feasibility tests for the efficiency of filter based sampling and subsequent counting of carbon nanotubes (CNT) were conducted last. The pilot study provided a detailed picture of the types and amounts of nanoparticles used and the knowledge of the health and safety experts in the companies. Considerable maximal quantities (> l'000 kg/year per company) of Ag, Al-Ox, Fe-Ox, SiO2, TiO2, and ZnO (mainly first generation particles) were declared by the contacted Swiss companies, The median quantity of handled nanoparticles, however, was 100 kg/year. The representative survey was conducted by contacting by post mail a representative selection of l '626 SUVA-clients (Swiss Accident Insurance Fund). It allowed estimation of the number of companies and workers dealing with nanoparticles in Switzerland. The extrapolation from the surveyed companies to all companies of the Swiss production sector suggested that l'309 workers (95%-confidence interval l'073 to l'545) of the Swiss production sector are potentially exposed to nanoparticles in 586 companies (145 to l'027). These numbers correspond to 0.08% (0.06% to 0.09%) of all workers and to 0.6% (0.2% to 1.1%) of companies in the Swiss production sector. To measure airborne concentrations of sub micrometre-sized particles, a few well known methods exist. However, it was unclear how well the different instruments perform in the presence of the often quite large agglomerates of nanostructured materials. The evaluation of devices and methods focused on nanoparticle agglomerate powders. lt allowed the identification of the following potential sources of inaccurate measurements at workplaces with considerable high concentrations of airborne agglomerates: - A standard SMPS showed bi-modal particle size distributions when measuring large nanoparticle agglomerates. - Differences in the range of a factor of a thousand were shown between diffusion size classifiers and CPC/SMPS. - The comparison between CPC/SMPS and portable aerosol Spectrometer (PAS) was much better, but depending on the concentration, size or type of the powders measured, the differences were still of a high order of magnitude - Specific difficulties and uncertainties in the assessment of workplaces were identified: the background particles can interact with particles created by a process, which make the handling of background concentration difficult. - Electric motors produce high numbers of nanoparticles and confound the measurement of the process-related exposure. Conclusion: The surveys showed that nanoparticles applications exist in many industrial sectors in Switzerland and that some companies already use high quantities of them. The representative survey demonstrated a low prevalence of nanoparticle usage in most branches of the Swiss industry and led to the conclusion that the introduction of applications using nanoparticles (especially outside industrial chemistry) is only beginning. Even though the number of potentially exposed workers was reportedly rather small, it nevertheless underscores the need for exposure assessments. Understanding exposure and how to measure it correctly is very important because the potential health effects of nanornaterials are not yet fully understood. The evaluation showed that many devices and methods of measuring nanoparticles need to be validated for nanoparticles agglomerates before large exposure assessment studies can begin. Zusammenfassung : Das Gesundheitsrisiko von Nanopartikel am Arbeitsplatz ist die Wahrscheinlichkeit dass ein Arbeitnehmer einen möglichen Gesundheitsschaden erleidet wenn er diesem Stoff ausgesetzt ist: sie wird gewöhnlich als Produkt von Schaden mal Exposition gerechnet. Für eine gründliche Abklärung möglicher Risiken von Nanomaterialien müssen also auf der einen Seite Informationen über die Freisetzung von solchen Materialien in die Umwelt vorhanden sein und auf der anderen Seite solche über die Exposition von Arbeitnehmenden. Viele dieser Informationen werden heute noch nicht systematisch gesarnmelt und felilen daher für Risikoanalysen, Die Doktorarbeit hatte als Ziel, die Grundlagen zu schaffen für eine quantitative Schatzung der Exposition gegenüber Nanopartikel am Arbeitsplatz und die Methoden zu evaluieren die zur Messung einer solchen Exposition nötig sind. Die Studie sollte untersuchen, in welchem Ausmass Nanopartikel bereits in der Schweizer Industrie eingesetzt werden, wie viele Arbeitnehrner damit potentiel] in Kontakt komrrien ob die Messtechnologie für die nötigen Arbeitsplatzbelastungsmessungen bereits genügt, Die Studie folcussierte dabei auf Exposition gegenüber luftgetragenen Partikel, weil die Atmung als Haupteintrittspforte iïlr Partikel in den Körper angesehen wird. Die Doktorarbeit besteht baut auf drei Phasen auf eine qualitative Umfrage (Pilotstudie), eine repräsentative, schweizerische Umfrage und mehrere technische Stndien welche dem spezitischen Verständnis der Mëglichkeiten und Grenzen einzelner Messgeräte und - teclmikeri dienen. Die qualitative Telephonumfrage wurde durchgeführt als Vorstudie zu einer nationalen und repräsentativen Umfrage in der Schweizer Industrie. Sie zielte auf Informationen ab zum Vorkommen von Nanopartikeln, und den angewendeten Schutzmassnahmen. Die Studie bestand aus gezielten Telefoninterviews mit Arbeit- und Gesundheitsfachpersonen von Schweizer Unternehmen. Die Untemehmen wurden aufgrund von offentlich zugànglichen lnformationen ausgewählt die darauf hinwiesen, dass sie mit Nanopartikeln umgehen. Der zweite Teil der Dolctorarbeit war die repräsentative Studie zur Evalniernng der Verbreitnng von Nanopaitikelanwendungen in der Schweizer lndustrie. Die Studie baute auf lnformationen der Pilotstudie auf und wurde mit einer repräsentativen Selektion von Firmen der Schweizerischen Unfall Versicherungsanstalt (SUVA) durchgeüihxt. Die Mehrheit der Schweizerischen Unternehmen im lndustrieselctor wurde damit abgedeckt. Der dritte Teil der Doktorarbeit fokussierte auf die Methodik zur Messung von Nanopartikeln. Mehrere Vorstudien wurden dnrchgefîihrt, um die Grenzen von oft eingesetzten Nanopartikelmessgeräten auszuloten, wenn sie grösseren Mengen von Nanopartikel Agglomeraten ausgesetzt messen sollen. Dieser F okns wurde ans zwei Gründen gewählt: weil mehrere Dislcussionen rnit Anwendem und auch dem Produzent der Messgeràte dort eine Schwachstelle vermuten liessen, welche Zweifel an der Genauigkeit der Messgeräte aufkommen liessen und weil in den zwei Umfragestudien ein häufiges Vorkommen von solchen Nanopartikel-Agglomeraten aufgezeigt wurde. i Als erstes widmete sich eine Vorstndie der Genauigkeit des Scanning Mobility Particle Sizer (SMPS). Dieses Messgerät zeigte in Präsenz von Nanopartikel Agglorneraten unsinnige bimodale Partikelgrössenverteilung an. Eine Serie von kurzen Experimenten folgte, welche sich auf andere Messgeräte und deren Probleme beim Messen von Nanopartikel-Agglomeraten konzentrierten. Der Condensation Particle Counter (CPC), der portable aerosol spectrometer (PAS), ein Gerät zur Schàtzung des aerodynamischen Durchniessers von Teilchen, sowie der Diffusion Size Classifier wurden getestet. Einige erste Machbarkeitstests zur Ermittlnng der Effizienz von tilterbasierter Messung von luftgetragenen Carbon Nanotubes (CNT) wnrden als letztes durchgeiührt. Die Pilotstudie hat ein detailliiertes Bild der Typen und Mengen von genutzten Nanopartikel in Schweizer Unternehmen geliefert, und hat den Stand des Wissens der interviewten Gesundheitsschntz und Sicherheitsfachleute aufgezeigt. Folgende Typen von Nanopaitikeln wurden von den kontaktierten Firmen als Maximalmengen angegeben (> 1'000 kg pro Jahr / Unternehrnen): Ag, Al-Ox, Fe-Ox, SiO2, TiO2, und ZnO (hauptsächlich Nanopartikel der ersten Generation). Die Quantitäten von eingesetzten Nanopartikeln waren stark verschieden mit einem ein Median von 100 kg pro Jahr. ln der quantitativen Fragebogenstudie wurden l'626 Unternehmen brieflich kontaktiert; allesamt Klienten der Schweizerischen Unfallversicherringsanstalt (SUVA). Die Resultate der Umfrage erlaubten eine Abschätzung der Anzahl von Unternehmen und Arbeiter, welche Nanopartikel in der Schweiz anwenden. Die Hochrechnung auf den Schweizer lndnstriesektor hat folgendes Bild ergeben: ln 586 Unternehmen (95% Vertrauensintervallz 145 bis 1'027 Unternehmen) sind 1'309 Arbeiter potentiell gegenüber Nanopartikel exponiert (95%-Vl: l'073 bis l'545). Diese Zahlen stehen für 0.6% der Schweizer Unternehmen (95%-Vl: 0.2% bis 1.1%) und 0.08% der Arbeiternehmerschaft (95%-V1: 0.06% bis 0.09%). Es gibt einige gut etablierte Technologien um die Luftkonzentration von Submikrometerpartikel zu messen. Es besteht jedoch Zweifel daran, inwiefern sich diese Technologien auch für die Messurrg von künstlich hergestellten Nanopartikeln verwenden lassen. Aus diesem Grund folcussierten die vorbereitenden Studien für die Arbeitsplatzbeurteilnngen auf die Messung von Pulverri, welche Nan0partike1-Agg10merate enthalten. Sie erlaubten die ldentifikation folgender rnöglicher Quellen von fehlerhaften Messungen an Arbeitsplätzen mit erhöhter Luft-K0nzentrati0n von Nanopartikel Agglomeratenz - Ein Standard SMPS zeigte eine unglaubwürdige bimodale Partikelgrössenverteilung wenn er grössere Nan0par'til<e1Agg10merate gemessen hat. - Grosse Unterschiede im Bereich von Faktor tausend wurden festgestellt zwischen einem Diffusion Size Classiîier und einigen CPC (beziehungsweise dem SMPS). - Die Unterschiede zwischen CPC/SMPS und dem PAS waren geringer, aber abhängig von Grosse oder Typ des gemessenen Pulvers waren sie dennoch in der Grössenordnung von einer guten Grössenordnung. - Spezifische Schwierigkeiten und Unsicherheiten im Bereich von Arbeitsplatzmessungen wurden identitiziert: Hintergrundpartikel können mit Partikeln interagieren die während einem Arbeitsprozess freigesetzt werden. Solche Interaktionen erschweren eine korrekte Einbettung der Hintergrunds-Partikel-Konzentration in die Messdaten. - Elektromotoren produzieren grosse Mengen von Nanopartikeln und können so die Messung der prozessbezogenen Exposition stören. Fazit: Die Umfragen zeigten, dass Nanopartikel bereits Realitàt sind in der Schweizer Industrie und dass einige Unternehmen bereits grosse Mengen davon einsetzen. Die repräsentative Umfrage hat diese explosive Nachricht jedoch etwas moderiert, indem sie aufgezeigt hat, dass die Zahl der Unternehmen in der gesamtschweizerischen Industrie relativ gering ist. In den meisten Branchen (vor allem ausserhalb der Chemischen Industrie) wurden wenig oder keine Anwendungen gefunden, was schliessen last, dass die Einführung dieser neuen Technologie erst am Anfang einer Entwicklung steht. Auch wenn die Zahl der potentiell exponierten Arbeiter immer noch relativ gering ist, so unterstreicht die Studie dennoch die Notwendigkeit von Expositionsmessungen an diesen Arbeitsplätzen. Kenntnisse um die Exposition und das Wissen, wie solche Exposition korrekt zu messen, sind sehr wichtig, vor allem weil die möglichen Auswirkungen auf die Gesundheit noch nicht völlig verstanden sind. Die Evaluation einiger Geräte und Methoden zeigte jedoch, dass hier noch Nachholbedarf herrscht. Bevor grössere Mess-Studien durgefîihrt werden können, müssen die Geräte und Methodem für den Einsatz mit Nanopartikel-Agglomeraten validiert werden.

HR-243 Production and Evaluation of Calcium Magnesium Acetate, Febrauray 19, 2001

Calcium magnesium acetate (CMA) has been identified by Bjorksten Research Laboratories as an environmentally harmless alternative to sodium or calcium chloride for deicing highways. Their study found CMA to be noncorrosive to steel, aluminum and zinc with little or no anticipated environmental impact. When used, it degrades into elements found in abundance in nature. The deicing capabilities were found to be similar to sodium chloride. The neutralized CMA they produced did cause scaling of PC concrete, but they did not expect mildly alkaline CMA to have this effect. In the initial investigation of CMA at the Iowa DOT laboratory, it was found that CMA produced from hydrated lime and acetic acid was a light, fluffy material. It was recognized that a deicer in this form would be difficult to effectively distribute on highways without considerable wind loss. A process was developed to produce CMA in the presence of sand to increase particle weight. In this report the product of this process, which consists of sand particles coated with CMA, is referred to as "CMA deicer". The mixture of salts, calcium magnesium acetate, is referred to as "CMA". The major problems with CMA for deicing are: (1) it is not commercially available, (2) it is expensive with present production methods and (3) there is very little known about how it performs on highways under actual deicing conditions. In view of the potential benefits this material offers, it is highly desirable to find solutions or answers to these problems. This study provides information to advance that effort.

Hwyneeds: Methodology, Analysis and Evaluation, March 2001

The quadrennial need study was developed to assist in identifying county highway financial needs (construction, rehabilitation, maintenance, and administration) and in the distribution of the road use tax fund (RUTF) among the counties in the state. During the period since the need study was first conducted using HWYNEEDS software, between 1982 and 1998, there have been large fluctuations in the level of funds distributed to individual counties. A recent study performed by Jim Cable (HR-363, 1993), found that one of the major factors affecting the volatility in the level of fluctuations is the quality of the pavement condition data collected and the accuracy of these data. In 1998, the Center for Transportation Research and Education researchers (Maze and Smadi) completed a project to study the feasibility of using automated pavement condition data collected for the Iowa Pavement Management Program (IPMP) for the paved county roads to be used in the HWYNEEDS software (TR-418). The automated condition data are objective and also more current since they are collected in a two year cycle compared to the 10-year cycle used by HWYNEEDS right now. The study proved the use of the automated condition data in HWYNEEDS would be feasible and beneficial in educing fluctuations when applied to a pilot study area. In another recommendation from TR-418, the researchers recommended a full analysis and investigation of HWYNEEDS methodology and parameters (for more information on the project, please review the TR-418 project report). The study reported in this document builds on the previous study on using the automated condition data in HWYNEEDS and covers the analysis and investigation of the HWYNEEDS computer program methodology and parameters. The underlying hypothesis for this study is thatalong with the IPMP automated condition data, some changes need to be made to HWYNEEDS parameters to accommodate the use of the new data, which will stabilize the process of allocating resources and reduce fluctuations from one quadrennial need study to another. Another objective of this research is to investigate the gravel roads needs and study the feasibility of developing a more objective approach to determining needs on the counties gravel road network. This study identifies new procedures by which the HWYNEEDS computer program is used to conduct the quadrennial needs study on paved roads. Also, a new procedure will be developed to determine gravel roads needs outside of the HWYNEED program. Recommendations are identified for the new procedures and also in terms of making changes to the current quadrennial need study. Future research areas are also identified.